Neurotherapeutics

https://doi.org/10.1007/s13311-022-01229-4

CURRENT PERSPECTIVES

Deep Brain Stimulation for Addictive Disorders—Where Are We Now?

Jason Yuen1,2   · Abbas Z. Kouzani3 · Michael Berk2 · Susannah J. Tye4,5,6,7 · Aaron E. Rusheen1 · Charles D. Blaha1 ·
Kevin E. Bennet1,8 · Kendall H. Lee1,9 · Hojin Shin1 · Jee Hyun Kim2 · Yoonbae Oh1,9

Accepted: 18 March 2022

© The Author(s) 2022

Abstract
In the face of a global epidemic of drug addiction, neglecting to develop new effective therapies will perpetuate the stagger-
ing human and economic costs of substance use. This review aims to summarize and evaluate the preclinical and clinical
studies of deep brain stimulation (DBS) as a novel therapy for refractory addiction, in hopes to engage and inform future
research in this promising novel treatment avenue. An electronic database search (MEDLINE, EMBASE, Cochrane library)
was performed using keywords and predefined inclusion criteria between 1974 and 6/18/2021 (registered on Open Science
Registry). Selected articles were reviewed in full text and key details were summarized and analyzed to understand DBS’
therapeutic potential and possible mechanisms of action. The search yielded 25 animal and 22 human studies. Animal stud-
ies showed that DBS of targets such as nucleus accumbens (NAc), insula, and subthalamic nucleus reduces drug use and
seeking. All human studies were case series/reports (level 4/5 evidence), mostly targeting the NAc with generally positive
outcomes. From the limited evidence in the literature, DBS, particularly of the NAc, appears to be a reasonable last resort
option for refractory addictive disorders. We propose that future research in objective electrophysiological (e.g., local field
potentials) and neurochemical (e.g., extracellular dopamine levels) biomarkers would assist monitoring the progress of treat-
ment and developing a closed-loop DBS system. Preclinical literature also highlighted the prefrontal cortex as a promising
DBS target, which should be explored in human research.

Keywords  Deep brain stimulation · Addiction · Biomarkers · Animal models · Neuromodulation · Neuropsychiatry

Introduction
Addictive substances pose significant socioeconomic
impact on society and the healthcare system, costing
hundreds of billion dollars annually in the USA alone [1,
2]. Psychological and adjunctive pharmacological treat-
ments are the current mainstay for addiction therapeutics.
However, the risk of relapse remains high, with some cit-
ing relapse rates as high as 75 to 98% within 1 year of
treatment [3]. Investigations into new treatment modali-
ties are urgently warranted. To develop novel therapies
for addiction, researchers are focusing on the behavioral
and neuroscience aspects in the biopsychosocial model
(Fig.  1). Deep brain stimulation (DBS) in particular is

4
* Jee Hyun Kim Queensland Brain Institute, The University of Queensland,
drjeehyunkim@gmail.com St Lucia, QLD 4072, Australia
5
* Yoonbae Oh Department of Psychiatry & Psychology, Mayo Clinic,
oh.yoonbae@mayo.edu Rochester, MN 55905, USA
6
1 Department of Psychiatry, University of Minnesota,
Department of Neurologic Surgery, Mayo Clinic, Rochester,
Minneapolis, MN 55455, USA
MN 55905, USA
7
2 Department of Psychiatry, Emory University, Atlanta,
Deakin University, IMPACT, The Institute for Mental
GA 30322, USA
and Physical Health and Clinical Translation, School
8
of Medicine, Geelong VIC 3216, Australia Division of Engineering, Mayo Clinic, Rochester, MN 55905,
3 USA
School of Engineering, Deakin University,
9
Geelong VIC 3216, Australia Department of Biomedical Engineering, Mayo Clinic,
Rochester, MN 55905, USA

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Fig. 1  Biopsychosocial model depicting the different dimensions
in consideration of addiction treatment. The stages of the addiction
cycle of behavior are shown (inset) [140]. Interactions between com-
ponents in different domains lead to addictive behaviors. Created with
Biorender.com
a neuroscience-based potential treatment for medically
refractory addictive disorders, given its diminishing sur-
gical risks. “Medically refractory” cases have no formal
definition, although these are generally regarded when con-
ventional treatments repeatedly fail [4].
Recent advances in neuromodulation techniques and
devices led the indication of DBS to include movement
disorders, such as Parkinson’s disease, to neuropsychiat-
ric conditions, such as depression, Tourette’s syndrome,
and obsessive–compulsive disorder (OCD) [5–8]. The use
of DBS to reduce substance use has also been explored
in both preclinical and clinical settings [9–12], offering a
beacon of hope to patients suffering from medically refrac-
tory addictive disorders. This review aims to summarize
and evaluate the potential therapeutic efficacy, mechanisms
of action, and biomarkers involved in the use of DBS in
the treatment of addictive disorders. We cautiously report
that DBS is promising to treat certain refractory addictive
disorders. Recommendations for the future directions are
also provided.
Addiction Neurobiology: a Brief Overview
Addiction is a highly complex process involving multiple
neurochemicals and brain structures. A highly simplified
model highlights the central role of dopamine in mediat-
ing drug reward learning and drug seeking (compulsive)
behaviors (Fig. 2). In essence, addictive drugs, such as the
psychostimulants and opioids, enhance synaptic concentra-
tions of dopamine in forebrain subcortical structures, such
as the nucleus accumbens (NAc) [13]. These drugs of abuse
significantly enhance dopamine concentrations over and
above the ability of natural rewards, hijacking the system
13
J. Yuen et al.
Fig. 2  A simplified illustration of the neurotransmitters and neuro-
anatomical structures involved in the pathophysiology of addiction
[13, 19, 20]. Other relevant areas are omitted for clarity. The effect of
dopamine receptors ­D1-R and ­D2-R is shown in inset. ­D1-R mediates
the direct pathway (positive reinforcement) and D ­ 2-R mediates the
indirect pathway (negative reinforcement). Italic descriptions denote
changes secondary to chronic drug use. 5-HT, serotonin; AMPAR,
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor;
D1/2R, dopamine 1/2 receptors; DA, dopamine;  GABA, gamma
aminobutyric acid; NAc, nucleus accumbens; NMDAR, N-methyl-
d-aspartate receptor; VTA, ventral tegmental area. Created with
Biorender.com
and encoding a more biologically salient reward association
with surrounding environmental cues [13]. Such Pavlovian
drug-environmental conditioning can trigger the desire to
seek more of the drug. For example, the drug associated cues
can elicit a surge of dopamine, which may manifest in drug
craving, seeking and ultimately use [14].
Serotonin (5-HT) is another important neurotransmitter
mediating neuroplasticity, hedonic tone, motivational, and
reinforcement processes, as well as cognitive functions [15,
16]. 5-HT2A and 5-HT2C receptors in the prefrontal cortex
(PFC), NAc, and ventral tegmental area in particular appear
to be critical. 5-HT2A receptor increases, and 5-HT2C recep-
tor decreases, striatal dopamine release [15]. The seroton-
ergic neuroadaptations may be accountable for emotional
components such as anhedonia and depression during drug
withdrawal [16]. Recent evidence in mice also suggest that
serotonin signaling via 5-HT1B receptor may attenuate tran-
sition from casual to compulsive cocaine use [17].
Chronic drug use ultimately alters the homeostatic neuro-
plasticity in the brain which not only results in a sensitized
dopaminergic system [18], but also leads to changes in the
glutamatergic system [13, 19, 20]. For example, calcium-
permeable ionotropic glutamatergic AMPA receptors become
upregulated relative to glutamatergic NMDA receptors [13,
19, 20]. The changes in AMPA and NMDA receptors have
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?
become a hallmark process of neuroplasticity that underpins
behavioral changes following chronic drug use [21]. Another
neurobiological adaptation that occurs with chronic drug use is
the process of “dorsalization” [22]. Here, repeated exposure to
drugs of abuse leads to recruitment of the circuit that projects
from the orbitofrontal cortex (OFC) to the dorsal striatum (cau-
date and putamen), where synaptic potentiation occurs at both
dopamine receptors 1 and 2 ­(D1-R and D ­ 2-R) on GABAergic
medium spiny neurons (MSNs).
Activation of D­ 1-Rs receptors causes excitation in the post-
synaptic cell via cyclic adenosine monophosphate production
(cAMP) production [23] that ultimately leads to promotion
of long-term potentiation [24]. ­D1-R- and NMDA recep-
tor–dependent activation of extracellular signal-regulated
kinase (ERK) in brain areas such as striatum is an important
pathway for drug-induced locomotor response and sensitiza-
tion [25–28]. For example, systemic injection of ­D1-R- or
NMDA antagonist prevents ERK phosphorylation triggered
by d-amphetamine in the mouse striatum [29]. In addition,
cocaine-induced ERK phosphorylation and locomotor sensi-
tization is prevented with mitogen-activated protein kinases/
ERK kinase inhibitor or in mutant mice with alanine-replaced
Thr-34 residue of dopamine- and cAMP-regulated phospho-
protein (DARPP-32) [29]. ­D1-R MSN structural plasticity
depends on NMDA and DARPP-32 signaling [24]. Psycho-
stimulants appear to affect ERK signaling via DARPP-32-
based ­D1-R- and NMDA intracellular pathways [29].
Importantly, ­D1-R activation inhibits long-term depres-
sion, as revealed by ­D1-R antagonist unmasking long-term
depression [30]. In contrast, D ­ 2-Rs can promote long-term
depression and prevent the induction of long-term poten-
tiation [30]. However, ­D2-Rs are particularly sensitive to
dips in the tonic dopamine level, during which they activate
protein kinase A (PKA) to induce long-term potentiation
[30–32]. Taken together, D ­ 1-R and D
­ 2-R are critical for bidi-
rectional plasticity of striatal MSNs when dopamine levels
are high vs low to guide adaptive and maladaptive behav-
iors involved in reward learning [31, 32]. Therefore, ­D1-R
and ­D2-R signaling dynamically modulates cortico-striatal
plasticity depending on the level of synaptic dopamine to
facilitate transition into persistent drug seeking and use.
While DBS appears to target these processes involved in
addiction to reduce drug seeking and taking [10, 33–37],
the potential therapeutic efficacy and mechanisms of action
of DBS in the treatment of addictive disorders are poorly
understood. We address this gap in the present review.
Methods
A search was performed using keywords, such as “deep brain
stimulation” and “addiction” in MEDLINE, EMBASE, and
Cochrane Library database between 1974 and 6/18/2021.
Details of search criteria and inclusion and exclusion criteria
are given in Supplementary Information Appendix A. Search
results are presented in a Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analyses (PRISMA) flow chart
(Fig. 3). This review was registered at the Open Science
Framework [38]. The process yielded 47 papers (25 pre-
clinical studies and 22 human studies), which were further
reviewed in full text. The results of this literature search are
summarized in the sections below.
Results and Discussion
Preclinical Models and Clinical Correlation
Animal DBS studies in the selected literature (Table 1)
predominantly used conditioned place preference (CPP) or
self-administration paradigms (Fig. 4) to model addiction.
Self-administration models have high construct, content, and
face validity relative to human addictive behaviors. Exper-
imenter-administration models such as CPP can measure
drug-induced behavioral sensitization, such as increased
locomotion, and are easier to perform. Both models also
allow modeling of withdrawal symptoms during abstinence
and/or extinction phase, followed by relapse behaviors, such
as cue or drug-induced reinstatement. Most common DBS
brain targets in the selected animal studies (Table 1) were the
NAc [33, 39–45], PFC [44, 46, 47], and subthalamic nucleus
(STN) [10, 37]. The following sections will focus on these
three most studied targets.
NAc Electrical Stimulation
The NAc is divided into core and shell subregions with dif-
ferent histopathological compositions, projections, and func-
tions [48]. Studies suggest that the shell is responsible for
reinforcing properties of novelty, rewards (both drug- and
non-drug-related), and drug relapse, whereas the core medi-
ates spatial learning, conditioned responses, responses to
motivational stimuli, and impulsive choices [14, 49]. These
features of motivated behaviors suggest NAc shell under-
lying extinction and reinstatement behavior [50], and NAc
core underlying the initial acquisition of drug taking and
cue-elicited drug seeking [48]. However, there is synergy
between the two subnuclei, and both play a role in drug
addiction.
Stimulation of either the core or shell subregions of the
NAc using a range of low and high frequencies leads to
reduced drug taking, seeking, or CPP in rats conditioned
with alcohol [34, 51, 52], nicotine [53], opioids [9, 37, 39,
41, 46, 54–57], cocaine [10, 33, 35, 40, 42, 43, 47, 58, 59],
or methamphetamine [45] (Table 1). Behavioral improve-
ment was related to the timing of when electrical stimulation
13

Fig. 3  Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart of literature search. Other sources include
those found by reviewing the references from included papers
was given—that is, stimulation given before a self-adminis-
tration session or CPP acquisition would reduce drug intake
or prevent CPP, respectively [39, 45]. When given during
abstinence or reinstatement, stimulation would diminish
drug or cue-induced drug seeking after extinction and/or
forced abstinence phase [40–43, 45]. Such efficacy of stimu-
lation during abstinence to prevent relapse is particularly
promising in the clinical context.
While most animal and human studies (Table 2) show
success in modulating addictive behavior using NAc stimu-
lation, there are two main issues. First, there is conflicting
13
J. Yuen et al.
evidence in animal studies regarding the efficacy of NAc
core vs shell stimulation. Both high- and low-frequency
stimulation (HFS, LFS) of NAc (electrodes placed across
core and shell) can reduce cocaine-primed drug seeking fol-
lowing 24 days of abstinence [43]. Other studies using core
as the DBS target showed reduced morphine-induced CPP
[39], ethanol self-administration [51], and heroin reinstate-
ment [41]. The shell was also shown to be an effective tar-
get for morphine-induced CPP [55], cocaine reinstatement
[40], ethanol self-administration [44, 51, 52], and metham-
phetamine reinstatement [45]. In contrast, Vassoler et al.
 Table 1  Summary of animal studies in deep brain stimulation and addiction, listed in chronological order. ACC​, anterior cingulate cortex; BLA, basolateral amygdala; CPP, conditioned place
preference; EA, experimenter-administration; EtOH, alcohol (ethanol); FR, fixed ratio; GABA, γ–aminobutyric acid; HFS, high-frequency stimulation; i.p., intraperitoneal injection; LFS, low-
frequency stimulation; LH, lateral hypothalamus; (m)PFC, (medial) prefrontal cortex; NAc, nucleus accumbens; OD, once daily; OFT, open field test; PAG, peri-aqueductal gray; pCREB, phos-
phorylated cyclic AMP-response element binding protein; SA, self-administration; s.c., subcutaneous injection; STN, subthalamic nucleus; vHipp, ventral hippocampus; VTA, ventral tegmental
area; NA, data not available

Author and year Species and strain Target; laterality Behavioral paradigm Stimulation parameters Main outcomes
(sample size)
Hz Pulse width Current DBS session

Pinel et al. Black-hooded male Amygdaloid Alcohol (1000– 60 NA 400 μA 45 stimulations Stimulation was performed to induce kindling
(1975) [85] rats (N = 27) complex; 2018 mg/kg ethanol) (1 s duration), (until displaying at least 1 seizure), and alcohol
unilateral (side via experimenter 3 × /day, 5 days/ was administered after stimulation. The
unspecified) intubation week withdrawal syndrome observed 9 h following
alcohol administration in kindled (stimulated)
animals was much more severe than that of the
controls
Beaulieu and Long-Evans male PAG; midline Subcutaneous morphine 50 NA 20–200 30 min after Large range of current applied to different rats
Thorn (1986) rats (N = 29) target 72 mg pellet (for 72 h) μA naloxone- (depending on analgesia threshold)
[54] vs placebo precipitated Stim. attenuated morphine withdrawal behaviors,
withdrawal esp. the recessive behaviors associated with
autonomic changes (e.g., eye-twitching) lasting
2 h or more
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?

Levy et al. Sprague–Dawley Lateral Cocaine (1 mg/kg 20, 100 100 μs 200–400 30 min/day for DBS (100 Hz) in lateral hypothalamus or PFC
(2007) [35] male rats hypothalamus reducing to 0.5 mg/kg) μA 10 days reduced cocaine-, but not sucrose seeking. DBS
(N = 7–14/group) (100 Hz) or PFC self-administration. (100 Hz) in the PFC also reduced cocaine taking
(20 Hz, 100 Hz); Progressive ratio in a progressive ratio self-administration test
bilateral was also assessed at Cocaine-induced locomotor hyperactivity was
0.5 mg/kg exaggerated by lateral hypothalamus DBS but
Locomotion following was reduced by PFC DSB
cocaine challenge The behavioral findings were accompanied by
15 mg/kg (i.p.) GluR1 alterations in the NAc (increased) and the
VTA (variable depending on subregion)
Liu et al. (2008) Sprague–Dawley NAc core; right CPP induced by i.p. 130 210 μs 200–500 3 h (15-min trains Pre-conditioning DBS sessions prevented
[39] rats of unspecified morphine μA with 45-min morphine-induced CPP compared to sham
sex (N = 32) 10–60 mg/kg (increasing intervals)
dose)
Vassoler et al. Sprague–Dawley NAc shell or Cocaine self- 160 60 μs 150 μA Continuous DBS in NAc immediately following 10 or 20 mg/
(2008) [40] male rats dorsal striatum; administration during 2-h kg cocaine prime attenuated cocaine-induced
(N = 7–12/group) bilateral FR1 (250 μg/kg per reinstatement reinstatement compared to sham DBS. DBS in
infusion) progressing sessions dorsal striatum had no effects on reinstatement
to FR5
Knapp et al. Long-Evans male NAc shell or NAc Alcohol (0–10% ethanol) 160 200 μs 0–150 μA 5 min At 150 μA, but not at 100 μA or less, DBS in
(2009) [51] rats (N = 4–5/ core (2 groups); self-administration shell or core given prior to established alcohol
group) bilateral self-administration sessions reduced alcohol
consumption

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Table 1  (continued)
Author and year Species and strain Target; laterality Behavioral paradigm Stimulation parameters Main outcomes
(sample size)

13
Hz Pulse width Current DBS session

Friedman et al. Sprague–Dawley Lateral habenula; Cocaine self- 10–100 500 μs 200 μA For 15 min at LFS alone appeared to have superior effect on
(2010) [58] male rats (N = NA) right administration start of task seeking behavior compared to HFS
0.25, 0.5, and 1 mg/kg With DBS consisting of a combination between 10
i.v. for 21 days and 100 Hz, drug seeking behavior was reduced
Reinstatement: 0, 5, 10, in self-administration, extinction and relapse
20 mg/kg i.p phases
Lesioning actually increases drug seeking behavior
(increased number of presses during extinction)
Tests controlled by forced swim test (depression-
like behavior), open-field test (locomotion), etc
Western blot showed elevated glutamatergic
receptor subunits NR1 and GluR1 and
scaffolding
Protein PSD95, but not GABA Ab, protein levels
in VTA with cocaine SA but normalized after
DBS
DBS reduced cocaine seeking behavior during
both self-administration and extinction training,
as well as lever-pressing behavior during
reinstatement
Henderson et al. Alcohol-preferring NAc shell; Home cage alcohol 140–150 60 μs 200 μA 1 h on 1 h off DBS given prior to established alcohol self-
(2010) [52] male rats (N = 20) bilateral (10% ethanol) self- DBS stage 2: administration sessions reduced alcohol
administration 24 h when free consumption and preference over water. DBS
access was given prior to alcohol-induced relapse following
allowed again 4–6 weeks of abstinence also reduced alcohol
consumption and preference over water
Rouaud et al. Long-Evans male STN; bilateral Cocaine self- 130 60 μs 50–130 DBS was applied DBS decreased cocaine but not food taking
(2010) [59] rats (N = 88) administration μA throughout Progressive ratio tests showed that DBS decreases
FR 1 (0.25 mg per each behavioral motivation to attain cocaine but increased
infusion) session motivation to attain food. Similar dissociation
Progressive ratio was was observed with CPP, with DBS reducing
also assessed at cocaine CPP but increasing food CPP
0.25 mg per infusion
CPP induced by cocaine
(10 mg/kg i.p.)
Guo et al. (2013) Sprague–Dawley NAc core; mixed Heroin self- 130 100 μs 0, 75, or 1-h continuous Daily DBS (75 and 150 μA) sessions during
[41] male rats (N = 54) unilateral or administration 150 μA stimulation abstinence reduced subsequent cue- and heroin-
bilateral FR1 (50 μg/kg per induced drug seeking, except for DBS only in the
infusion) paired with a left NAc. DBS increased pCREB but decreased
light cue ΔFosB in NAc core and shell
DBS did not affect locomotion, nor spatial learning
and memory
J. Yuen et al.
 Table 1  (continued)
Author and year Species and strain Target; laterality Behavioral paradigm Stimulation parameters Main outcomes
(sample size)
Hz Pulse width Current DBS session

Ma et al. (2013) Sprague–Dawley NAc shell; Morphine EA 130 60 μs 2 V (stim. 60 min, 5 × /day CPP training was first given with increasing doses
[55] male rats (N = 25) bilateral 5 mg/kg i.p. voltages) for 30 days of morphine; naloxone then given to precipitate
progressing to “withdrawal.”
90 mg/kg i.p. over DBS prevented drug seeking behavior (in terms of CPP
12 days measurements) during re-instatement of morphine
Reinstatement— Place navigation studies were performed (Morris
2.5 mg/kg i.p water maze) to assess learning and memory—no
change by DBS
Pushparaj et al. Sprague–Dawley Insular cortex; Nicotine SA 130 90 μs 50 μA HFS started from DBS significantly attenuated nicotine taking, under
(2013) [53] male rats bilateral 0.03 mg/kg i.v. 5 min before both FR5 and progressive ratio schedules, as well
(N = 6–12/group) per infusion under a behavioral as nicotine seeking behavior induced by cues and
FR-5 then sessions and priming; no effect on food taking behavior
progressive ratio lasted throughout HFS of brain slices containing the insular region
schedule the sessions was found to inactivate insular neurons
Reinstatement dose
was 0.15 mg/kg s.c
Vassoler et al. Sprague–Dawley NAc shell or core; Cocaine self- 160 60 μs 150 μA Continuous DBS of NAc shell, but not core, immediately
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?

(2013) [42] male rats bilateral administration during 2-h following 10 mg/kg cocaine prime attenuated
(N = 5–12/group) FR1 (250 μg/kg per reinstatement cocaine-induced reinstatement compared to sham
infusion) progressing sessions DBS (0 μA)
to FR5 DBS of NAc shell induced c-Fos expression
locally and in the infralimbic cortex
Wilden et al. Alcohol-preferring NAc shell; Alcohol (15% ethanol) 150 100 μs 100 or 200 65 min DBS (200 μA but not 100 μA) starting 5 min prior
(2014) [34] female rats (N = 7) unilateral self-administration μA to and throughout established daily alcohol self-
administration sessions reduced alcohol taking.
Alcohol taking resumed at baseline levels post
DBS sessions
Creed et al. C57BL/6 NAc shell; Locomotor sensitization 12 or 90 μs 50 μA 60 min DBS at 130 Hz, but not at 12 Hz, given
(2015) [33] transgenic male bilateral induced by cocaine 130 immediately before test transiently suppresses
mice (N = 6–12/ 20 mg/kg i.p locomotor sensitization. DBS had no behavioral
group) effects when applied 4 or 24 h before test
DBS at 130 Hz 24 h before did not affect cocaine-
evoked plasticity
DBS at 12 Hz in combination with a D ­ 1-R
antagonist reversed cocaine-induced
hyperlocomotion and plasticity. DBS at 12 Hz
had no effects by itself
Hamilton et al. Long-Evans male NAc; right Cocaine self- 20 or 100 μs 50–200 30 min A single DBS session did not affect cocaine taking.
(2015) [43] rats (N = 6–8/ hemisphere administration 160 μA Daily DBS 20 or 160 Hz sessions during 14 days
group) FR1 (500 μg/kg per of abstinence led to attenuated cocaine seeking
infusion) progressing following a 5 mg/kg cocaine prime when tested
to FR3 1 day, but not 14 days, after the last DBS session

13


Table 1  (continued)
Author and year Species and strain Target; laterality Behavioral paradigm Stimulation parameters Main outcomes
(sample size)

13
Hz Pulse width Current DBS session

Mehdipour et al. Wistar male rats Prelimbic cortex; Light–dark shock 60 NA 25, 20 min (duration Methodology was unclear (e.g., interval between
(2015) [46] (N = 6 in each right hemisphere passive avoidance 50, of 1 s every 5 s) doses and shock). Short-term stimulation was
group) reversed by morphine 100, or given
(10, 20, or 40 mg/ 150 μA DBS at 50 and 100 μA stimulation reversed
kg) i.p passive avoidance memory attenuation by
morphine. DBS at 25 and 150 μA had no effects
Hadar et al. Wistar male rats NAc shell, Home cage alcohol (5, 130 90 μs 5.25 V 24 h or 4 days Compared to sham DBS, 4 days of NAc shell
(2016) [44] (N = 6–15/group) infralimbic 10, or 20% ethanol) (stim. DBS led to augmented alcohol-induced relapse
cortex, or and water two voltages) following chronic abstinence. Acute (24 h)
striatum bottle choice self- DBS reduced alcohol-induced relapse. DBS in
(caudate, administration infralimbic cortex or striatum had no effects on
putamen); behavior. Acute NAc DBS (24 h) increased local
bilateral dopamine levels in alcohol-exposed rats
Martínez-Rivera Sprague–Dawley Ventral capsule/ Morphine EA 20 or 100 μs 100–200 60 min/day HFS of dorsal VS impaired extinction training
et al. (2016) male rats (N = 87) ventral striatum 5 mg/kg s.c./day for 130 μA over 9 days of and extinction memory but no effect for HFS of
[56] (VS); bilateral 4 days with CPP extinction ventral VS
training LFS of dorsal VS strengthened extinction memory
when tested 2 or 9 days after the cessation of
stimulation
Both HFS and LFS increased c-Fos expression in
infralimbic PFC, but only LFS increased c-Fos in
the basal amygdala and the medial portion of the
central amygdala
Batra et al. Wistar male rats NAc shell; Methamphetamine self- 130 60 μs 200 μA 3 h The first two daily sessions of DBS prior
(2017) [45] (N = 18) bilateral administration to self-administration sessions reduced
FR1 (0.05 mg/kg per methamphetamine taking compared to sham
infusion) DBS, while the remaining 3 DBS sessions had
no effects. These DBS sessions reduced cue-
induced reinstatement when tested 20–28 days
later
Wade et al. Wistar male rats STN; bilateral Heroin SA 130 60 μs 50–130 Throughout the STN HFS attenuated re-escalation of heroin intake
(2017) [37] (N = 32) 60 μg/kg i.v μA SA sessions post-abstinence in rats with extended access to
FR1 heroin
3- or 12-h sessions STN HFS inhibited substantia nigra,
5 days per week entopeduncular nucleus, and NAc shell
(measured with brain mapping analyses of
immediate-early gene expression) but not PFC,
and silenced STN neurons (measured using
recording ex vivo)
J. Yuen et al.
 Table 1  (continued)
Author and year Species and strain Target; laterality Behavioral paradigm Stimulation parameters Main outcomes
(sample size)
Hz Pulse width Current DBS session

Chang et al. Sprague–Dawley Anterior insular CPP induced by 130 90 μs 150 μA 11 or 14 days 14 days of DBS during abstinence attenuated the
(2020) [57] male rats cortex; bilateral subcutaneous injection during expression of morphine-CPP but CPP relapsed
(N = 9–15/group) of morphine (10 mg/ extinction or 10 days after the cessation of DBS. Eleven
kg) abstinence days of DBS during CPP extinction facilitated
extinction acquisition as well as alleviating
morphine-induced reinstatement
OFT and novel object recognition test showed
no impairment to locomotion and recognition
memory
Proteomic analysis revealed the expression levels
of 8 morphine-regulated proteins in the anterior
insula were reversely changed by HF-DBS
Fakhrieh-Asl Wistar male rats Orbitofrontal CPP induced by 13 or 100 μs 150 μA 20 or 40 min, HFS but not LFS given daily for 3 days of
et al. (2020) (N = 108) cortex; bilateral subcutaneous 130 once daily conditioning significantly prevented CPP
[9] injections of morphine acquisition
3–7 mg/kg (increasing HFS but not LFS given daily for 6–10 days of
dose) extinction facilitated extinction acquisition and
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?

blocked morphine-induced reinstatement

DBS did not cause any changes in locomotor
activity, novel objection recognition memory, nor
anxiety-like behavior
Guercio et al. Sprague–Dawley Infralimbic cortex, Cocaine self- 160 60 μs 150 μA Continuous DBS at BLA, vHipp, and infralimbic cortex
(2020) [47] male rats (N = 6–8/ prelimbic administration during 2 h immediately following 10 mg/kg cocaine prime
group) cortex, anterior FR1 (250 μg/kg per reinstatement attenuated cocaine-induced reinstatement
cingulate cortex, infusion) progressing sessions compared to sham DBS (0 μA), but BLA and
BLA or vHipp; to FR5 vHipp also attenuated sucrose reinstatement
bilateral Anterior cingulate cortex and prelimbic cortex
DBS did not attenuate either
Degoulet et al. Male Lister STN; bilateral Cocaine SA 8, 30, or 80 μs 50–150 DBS turned on 30 Hz but not 130 Hz DBS reduced pathological
(2021) [10] Hooded rats FR1 progressing to 130 μA and intensity cocaine seeking during treatment, whereas
(N = 84) random interval until was increased 130 Hz actually increased seeking behavior
120 s to reach acutely
Punishment sessions predetermined Compulsive, i.e., shock-resistant rats
(foot shock) also parameters exhibit pathological STN low-frequency
applied (rats divided prior to start oscillations (LFP) during cocaine escalation
into shock-resistant of behavioral (especially < 20 Hz)
and shock-sensitive session, and
subgroups) continued
during session

13

demonstrated that stimulation of the NAc shell but not the
core attenuated cocaine-induced reinstatement [42].
The contradicting evidence above may be explained by
the large activation volume of stimulation pulses, such that
pulses centered on the core may also affect the shell, and
vice versa. From human studies, the volume of activation
was estimated to be between 30 and 120 ­mm3 [60] and the
human NAc volume is around 700 m ­ m3 [61]. However,
for adult Sprague–Dawley rats, the total volume of NAc is
approximately 5 m ­ m3 with the NAc core making up half
of that [62]. Therefore, neighboring structures could be
co-stimulated in rats. Notably, the core and shell divide is
functionally present in humans while they are less distinct
in rodents [63, 64].
The second issue concerns laterality. While most studies
used bilateral stimulation, some studies only used unilateral
NAc stimulation [34, 39, 41, 43]. One study used left, right,
and bilateral NAc core stimulation, demonstrating only the
latter two were effective in reducing heroin seeking behavior
[41]. It is unclear why such asymmetry exists. Dopamine
concentration in the NAc is reported to be higher on the side
ipsilateral to the paw-dominance of a mouse [65]; however,
morphometric NAc human studies based on laterality have
been controversial [49].
Almost all of these published studies in humans show
some improvement from DBS in the NAc in addiction-
related behaviors (Table 2) as well as cognitive improvement,
which raises the possibility of potential publication bias.
With this precaution in mind, NAc DBS is likely the low-
est hanging fruit for refractory addictive disorders. A recent
systematic review supports NAc DBS to treat substance
use disorders, demonstrating that NAc DBS in patients led
to a relapse rate of ~ 39% with a reasonable safety profile,
which is an improvement compared to the ~ 60% relapse rate
reported in that population (selection bias factors notwith-
standing) [66]. In addition, individual case reports revealed
that those with comorbid psychiatric disorders, such as
depression and OCD, showed improvement in these other
symptoms with NAc DBS with or without anterior limb of
internal capsule (ALIC) intervention (DBS or capsulotomy)
[12, 67, 68]. DBS may provide additional benefit for patients
with multiple psychiatric comorbidities.
Cortical Stimulation
The PFC is believed to provide top-down control of NAc
in addiction (Fig. 2). DBS of the PFC (subregion not speci-
fied) significantly reduced cocaine seeking and motivation
to take cocaine measured by progressive ratio test [35].
Stimulation of the infralimbic cortex of the PFC following
a cocaine prime also reduced cocaine reinstatement [47].
Notably, mPFC stimulation in rats showed increased phasic
13
J. Yuen et al.
dopamine release in the NAc, which might explain the stim-
ulation effect [69]. However, stimulation of the infralimbic
cortex starting 1 h or 4 days before alcohol prime did not
affect alcohol-induced relapse following abstinence in rats
[44]. The contrasting findings may be due to the different
mechanisms of actions of the drugs being given (alcohol is
a depressant whereas cocaine is a stimulant). Alternatively,
infralimbic cortex stimulation may be more effective in
reducing relapse-like behaviors following extinction rather
than forced abstinence, consistent with the well-known role
of the infralimbic cortex in extinction [70]. Infralimbic cor-
tical DBS success is concordant with reduced craving by
transcranial direct current stimulation (tDCS) of dorsolat-
eral PFC in humans [71]. However, DBS of the prelimbic
cortex following cocaine priming had no effect on cocaine
reinstatement in rats [47].
In the OFC, DBS prevented rats from learning morphine-
induced CPP, while DBS during extinction facilitated extinc-
tion acquisition and prevented morphine-induced reinstate-
ment [9]. Chronic DBS of the anterior insular cortex either
during 11 days of extinction or 14 days of abstinence reduced
CPP, but CPP relapsed 10 days after chronic DBS [57]. This
finding is consistent with how repetitive transcranial mag-
netic stimulation (rTMS) reduced heavy drinking only dur-
ing the intervention but not after in alcohol-dependents [72].
The insula’s superficial location and delicate anatomy may
be better suited for non-invasive interventions such as rTMS
rather than DBS.
Anterior cingulate cortex (ACC) dysfunction can disrupt
ongoing processing and detection of erroneous outcomes
relevant for reward learning [73, 74]. ACC DBS following
cocaine prime did not alter reinstatement following self-
administration in rats [47]. However, when people with
alcohol dependence received bilateral DBS (6- or 10-Hz
stimulation), craving was significantly reduced [75]. The
reduced craving was associated with a reduction in beta-1
band (13–18 Hz) current density on electroencephalogram
(EEG) post-stimulation in the rostrodorsal ACC [75]. Alco-
hol craving also correlated with beta activity in the dorsal
ACC in a case report, although relapse was associated with
increased gamma band activity [76]. Another case report
showed that a patient with concomitant OCD and alcohol
dependence was successfully treated with ACC rTMS [77].
Interestingly, NAc DBS reduced craving correlated with
improvement in error-related negativity in LFP in the ACC
in humans [78], suggesting the effect of NAc DBS may alle-
viate ACC dysfunction. In addition to DBS, rTMS of the
dorsal ACC demonstrated improvement in alcohol craving
and concomitantly reduced NAc activation on fMRI [76].
Taken together, DBS in ACC may be particularly relevant
for alcohol use.
Most of these cortical regions project to the NAc, rais-
ing the possibility that their DBS effects are mediated
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?
via these connections [49, 79]. Animal studies show not
only strong projections from the cortex to NAc, but also a
high degree of interplay between the two regions [80]. For
example, c-Fos reactivity is observed in infralimbic cortex
and NAc during DBS [42, 56] Pharmacological silencing
of cortical interneurons can reinstate drug seeking [42, 81],
which is consistent with silencing effects observed in the
NAc [81]. Nevertheless, NAc is unlikely to be the sole
driver of effects of DBS in the PFC considering that DBS
in the prelimbic cortex does not affect drug seeking in rats,
even though prelimbic cortex has strong connections to
NAc [47].
STN Stimulation
Parkinson’s patients who take dopaminergic medications for
their movement disorder may chronically feel compulsion to
over-consume such agents, even at the expense of dyskine-
sia and other side effects. Studies suggest that STN DBS in
humans may improve movement symptoms as well as reduce
compulsive use of medications [82, 83].
STN DBS or lesions in rats have been shown to reduce
motivation for cocaine taking, while increasing motivation
to consume more common rewards such as food [10, 37, 59,
84]. The lesion study in particular suggests that STN DBS
may work via local inactivation [59, 84]. Further evidence
shows STN HFS in rats inhibiting substantia nigra, entope-
duncular nucleus, and NAc shell measured with brain map-
ping analyses of immediate-early gene expression but not
PFC, and silencing STN neurons measured using recording
ex vivo [37].
Although HFS of STN in rats reduced both cocaine tak-
ing and heroin seeking [37, 59], a conflicting study demon-
strated only LFS (30 Hz) but not HFS modulates cocaine
taking behavior in the presence of foot-shock punishment
[10]. Abnormal alpha/theta and low-beta oscillatory activ-
ity during escalation of the cocaine intake phase also pre-
dicted the subsequent emergence of compulsive-like seeking
behavior, where the animals were shock-resistant [10]. The
discrepancy here may be explained by the absence/presence
of punishment during drug taking, but further studies are
warranted to understand STN LFS vs HFS outcomes.
Other Brain Regions
Electrical stimulation targeting other brain regions in ani-
mals—amygdala [47, 85], hippocampus [47], periaqueductal
gray matter [54], lateral hypothalamus [35], dorsal striatum
[40, 44], and lateral habenula [58]—has also been described
in the literature (Table 1). However, due to the limited num-
ber of studies per brain region, meaningful conclusions are
difficult to draw. Hence, these regions are beyond the scope
of this review.
Fig. 4  Illustration of two most widely used experimental para-
digms for the study of drug addiction in animals. On the left, con-
ditioned place preference (CPP) is shown, where “non-contingent”
drug-administration is associated with one side of the chamber dur-
ing drug-side associated conditioning. If the drug is experienced as
rewarding, the animal will spend more time in the drug-administered
side relative to the other side, even in the absence of further drug
administration. On the right, “contingent” drug self-administration
paradigm allows the animal to regulate its own drug intake (e.g., via
nose-poke or lever-pressing). A discrete light and/or tone cue may be
provided in association with the drug intake to serve as a drug-associ-
ated cue. In extinction, the animal is placed back into the environment
where CPP or self-administration is acquired but without drug avail-
ability. Extinction sessions lead to reduced place preference or drug
seeking. During reinstatement, the drug, the drug-associated cue,
and/or stress can be given, which can lead to “relapse” measured by
preference or drug seeking. Created with Biorender.com
High‑ Versus Low‑Frequency Stimulations
Whereas most animal studies reported HFS (> 130  Hz)
effects on behavior, some used a lower frequency (< 20 Hz)
and observed beneficial effects targeting the NAc [43], lat-
eral habernula [58], ventral striatum [56], and periaque-
ductal gray [54] even at frequencies as low as 8 Hz (STN)
[10] (Table 1). In contrast, LFS targeting the NAc shell [33],
PFC [35], or OFC [9] were ineffective. Interestingly, DBS
at 12 Hz alone did not affect cocaine-induced locomotor
sensitization, but combined with dopamine D ­ 1-R antagonist,
reversed cocaine-induced hyperlocomotion and plasticity in
the NAc shell [33]. Such findings suggest that LFS may be
effective only when basal dopamine signaling is low.
The effect of HFS in NAc shell may be short-lived, lasting
less than 4 h in a cocaine experimenter-administered mouse
model [33] or 1 day in an alcohol self-administration rat model
[34]. However, reduction in cue-induced seeking behavior was
maintained more than 4 weeks post-HFS (NAc shell) com-
pared to the sham group in rats that self-administered meth-
amphetamine [45]. Yet, LFS and HFS (mixture of NAc core
and shell) effects lasted at least 2 weeks but less than 30 days
in a cocaine self-administration rat model [43]. The different
DBS parameters, targets, drugs, rodents, and tests across these
studies (Table 1) pose a challenge to evaluate the best DBS
protocol to reduce drug use.
13


Table 2  Summary of human studies, listed in chronological order. ACC​, anterior cingulate cortex; ALIC, anterior limb of internal capsule; AMP, amphetamine; BNST, bed nucleus of stria ter-
minalis; BZ, benzodiazepine; CT, computed tomography; EEG, electroencephalogram; EtOH, alcohol; F, female; LFP, local field potential; M, male; MRI, magnetic resonance imaging; NAc,
nucleus accumbens; OCD, obsessive–compulsive disorder; PD, Parkinson’s disease; PET, positron-emission tomography; QoL, quality of life; STN, subthalamic nucleus; VC/VS, ventral cap-
sule/ventral striatum; NA, data not available

13
Author and Indication for Target Drug Stimulation parameters Laterality Adverse events Outcome
year DBS (N; age
sex) Hz μs V

Witjas et al. PD (2; 53 M, STN Dopaminergic High NA NA Bilateral None reported Drugs stopped or much reduced immediately post-
(2005) [82] 38 M) agent (despite operation
severe At 2 years’ follow-up, continue to be show benefit
dyskinesia) Dyskinesia and mood also much improved with no
change in cognition
Kuhn et al. Addiction (1; NAc EtOH 130 90 4.5 V Bilateral None reported Comorbid anxiety and depressive disorders
(2007) [141] 54 M) Reported feeling of “inner appeasement” acutely
After 12 months of treatment, the alcohol consumption
and craving reduced dramatically
Kuhn et al. Tourette’s NAc Nicotine 130–145 90, 180 3–6 V 5 bilateral, 5 None reported Fagerström Test for Nicotine Dependence was used to
(2009) [93] syndrome unilateral assess smoking behavior
(4), OCD (5) At 30-month follow-up, 3 out of 10 stopped smoking
or anxiety but the others mostly had no changes
disorders Those who quit smoking had higher stimulating voltages
(1) (10; but difficult to compare due to small numbers
7 M and 3F,
range from
28–58 years)
Mantione et al. OCD (1; 47F) NAc Nicotine 185 90 3.5 V Bilateral None reported Comorbid mild anxiety and depression
(2010) [94] Dramatic improvement in OCD, anxiety, and depression
Smoking cessation and weight loss was observed after
10 months post-operation (up to at least 2-year follow-up)
Kuhn et al. Addiction (1; NAc EtOH 130 120 5.5 V Bilateral None reported Abstinence after 1 year of treatment
(2011) [78] 69 M) Improvement seen in psychometric score
EEG showed enlargement in error-related negativity
(amplitude when error occurs during test) and
reduction in error rate
Zhou et al. Addiction (1; NAc Heroin 145 90 2.5 V Bilateral Transient Abstinent for 6 years from implantation (removed after
(2011) [90] 24 M) confusion first 3 years)
and urinary Improvement in cognition and memory
incontinence
initially
Heldmann Addiction (1; NAc EtOH 130 90 3.5 V Bilateral None reported Risk taking behavior was assessed by gambling task—
et al. (2012) 38 M) less risk taking behavior when DBS was switched on,
[92] compared to off-state
PET showed activations in the paracingulate cortex, temporal
poles, precuneus and hippocampus with active DBS
Except for the temporal pole, these activations were not
seen when DBS was off
J. Yuen et al.
 Table 2  (continued)
Author and Indication for Target Drug Stimulation parameters Laterality Adverse events Outcome
year DBS (N; age
sex) Hz μs V

Valencia- Addiction (1; NAc Heroin 180 90 3.5 V Bilateral None reported Mostly clean for 6 months apart from self-limiting
Alfonso 47 M) relapse (although activation of some contacts initially
et al. (2012) increased craving)
[142] Intracranial EEG showed higher power for drug-related
compared with non-drug-related cues in the gamma-
band (40–60 Hz), which also has a lower correlation to
frontal theta signal compared with the drug-unrelated
responses on the right side
Voges et al. Addiction (5; NAc EtOH 130 90 3.5 V Bilateral Transient Average follow-up was 38 months
(2013) all male, hypomania LFP using externalized electrodes showed error-related
[143] Cases range from modulations at NAc during neuropsychological
overlap with 36–65 years) task and error-related negativity obtained from NAc
Muller et al. preceded the surface error-related activity
(2009) [144] All subjects experienced significant improvement of
and Heinze craving. Two remained completely abstinent for more
et al. (2009) than 4 years
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?

[145]
Kuhn et al. Addiction (2; NAc EtOH and AMP, 140 120 5 V Bilateral 1 seizure (known Improved depressive and anxious symptoms, as well as
(2014) [67] 33 M, 31F) AMP and BZ 130 90 4.5 V epilepsy) consumption and craving in methadone and heroin
Patients started to consume other psychotropic
substance and continued to consume amphetamine out
of “boredom” and for weight-related reason without
subjective craving
Gonçalves- Addiction (1; NAc, BNST, Cocaine 130 150 2.5–4 V Bilateral Only transient, Previous comorbid heroin addiction
Ferreira 36 M) ALIC e.g., metallic DBS at ALIC showed no efficacy but posterior NAc and
et al. (2016) taste, warm BNST appeared to be effective targets
[146] sensation at high After 2.5 years, including a blinded on/off period, DBS
voltages resulted in improvement in cocaine dependence both
objectively and subjectively
Müller et al. Addiction (5; NAc EtOH 130 90 3.5–4.5 V Bilateral None reported All patients reported complete absence of craving for
(2016) [11] all males, Initial alcohol
Cases (3) range transient Follow-up was up to 8 years (2 died after 4 and 8 years)
overlap with from 35 to hypomania Two remained abstinent for years and 3 showed a
Muller et al. 55 years) reduction of consumption
(2009) [144]

13


Table 2  (continued)
Author and Indication for Target Drug Stimulation parameters Laterality Adverse events Outcome
year DBS (N; age

13
sex) Hz μs V

Ge et al. Addiction (7; NAc +  Heroin 145 150–240 2.0– Bilateral None reported Abstinence ranges from 3 months (lost to follow-up)
(2018) 6 × M and ALIC (NAc) 3.3 V to at least 40 months (4 out of 7 have been abstinent
[107]—5 1 × F, range 185 for > 20 months); mood also improved for most
patients from 26 to (ALIC) patients
overlap with 50 years) Pre-DBS LFP: Both NAc and ALIC showed prominent
Chen et al. theta and alpha band activity
(2019) [12] A distinct beta band peak was also detected at ALIC
There was a significant negative correlation between
the power of theta band of ALIC and craving score,
and a positive correlation between the power of alpha
band of NAc and scores on the Hamilton depression
inventory
LFPs of the NAc and ALIC exhibited higher coherence
in the theta and alpha bands
Zhang et al. Addiction (1; VC/VS Heroin 130 90 3.5 V Bilateral Hypomania Comorbid antisocial personality disorder (baseline)
(2018) [132] 39 M) Death secondary Initial improvement but multiple relapses despite
to overdose altering DBS parameters
(after relapse)
Chen et al. Addiction (8; NAc +  Heroin 130–185 150–240 1.5–7 V Bilateral One intracranial Some had comorbid depression and OCD
(2019) 7 × M and ALIC hemorrhage Five patients were abstinent for more than 3 years, and
[12]—5 1 × F, range (< 3 mL) with the other 2 relapsed after abstaining for 6 months
patients from 22 to no neurological 1 was lost of follow-up at 3 months
overlap with 50 years) deficit Craving reduced if the patients remained abstinent.
Ge et al. Transient fever, Simultaneous DBS of NAc and ALIC also improved
(2018) [107] headache, the quality of life, alleviated psychiatric symptoms,
insomnia, and and increased glucose metabolism in certain
subjective slight addiction-related brain region (e.g., inferior frontal
memory decline gyrus) on PET scan
Ge et al. Addiction (2; NAc Methamphetamine 150, 165 210, 240 2.5, 3.3 V Bilateral Insomnia, Only one out of two patients remained abstinent (at 1.5
(2019) [147] 38 M, 49 M) hypomania, to 2.5 years), and reviewing post-operative CT and
teeth grinding at pre-operative MRI showed incorrect placement of lead
higher voltages in the subject who relapsed
Leong et al. Addiction ACC EtOH (refractory 6 or 10 NA NA Bilateral Infection (2), The self-reported alcohol craving reduced by 61% (end
(2020) [75] (8; 4 × M (rostrodorsal) to multiple Mode: Burst seizure (1), point ranged from 12 to 48 weeks, depending on
Cortical and 4 × F, treatments) (7) or tonic venous infarct presence of adverse events)
implant 20–65 years) (1) (1), psychosis Post-stimulation led to reduction in in current density at
(1), impulsive the rdACC for beta-1 band (13–18 Hz) on EEG
behavior (1)
J. Yuen et al.
 Table 2  (continued)
Author and Indication for Target Drug Stimulation parameters Laterality Adverse events Outcome
year DBS (N; age
sex) Hz μs V

Sildatke et al. Addiction (4; NAc Opioid NA NA NA Bilateral It appeared DBS EEG and LFP studies showed significant accuracy-
(2020) [148] all males, was not turned related modulations in the LFPs at the time of the
range on but the error-/correct-related negativity in 2 patients and at the
from 24 to electrodes were time of error-positivity in 3 patients (Eriksen flanker
57 years) used for LFP task)
recording
Zhang et al. Addiction (1; NAc Heroin NA NA NA Bilateral None mentioned Reduction in drug cravings and remained drug-free
(2020) [91] 42 M) (except for 1 episode at 6 months) at 1 year
Implants were removed at the end of treatment (at
patient’s request)
Zhu et al. Addiction (1; NAc DBS Bucinnazine, 160 90 2.70, Bilateral None reported Comorbid depression and anxiety disorder
(2020) [68] 28 M) combined morphine, 2.75 V Reduced craving since 3 months and abstinent for at
with anterior hypnotics least 1 year
capsulotomy (13 years) Improvement in sleep, cognition, depression/anxiety,
QoL seen
Mahoney et al. Addiction (1; NAc/ALIC Opioid and BZ 145 90 6 V Bilateral None Abstinent at 12 months
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?

(2021) [149] 30sM) Improved subjective craving, mood, frontal, and

executive function
PET scan showed an increase in glucose metabolism
in the dorsolateral prefrontal and medial premotor
cortices

13

Potential Mechanism(s) of Action
Neuronal Inhibition
Despite the promising results of DBS in addiction, the
mechanism of action is poorly understood and likely highly
complicated. Several hypotheses on the mechanism of DBS
in addiction have been suggested, such as direct inhibition/
excitation of neural activity, information lesioning, and
synaptic filtering where DBS blocks transmission of patho-
logical low-frequency oscillations [86]. In particular, the
inhibition hypothesis is supported by animal studies where
both injection of GABA agonists (i.e., temporary inhibition)
and HFS in the NAc was found to reduce alcohol use in
rats [34]. Similar effects were also seen between STN lesion
paradigms and DBS with cocaine conditioning [59, 84]. It
is likely the neurons and their respective synaptic activities
respond in a combination of different ways depending on the
stimulation frequency and the drug being tested.
Depotentiation of Excitatory Inputs onto ­D1‑R Via
Modulation of Glutamate Receptors
Evidence also suggests the interaction between dopamine
and glutamate receptors is involved in the mechanism of
DBS action. For example, NAc shell LFS (12 Hz), only
when used in combination with a D ­ 1-R antagonist, could
reverse the motor sensitization and cocaine-evoked plastic-
ity changes in ­D1-Rs on GABAergic MSNs, in the form of
increases AMPA/NMDA glutamate receptor ratio [33]. By
using a metabotropic glutamate receptor (mGluR1) antago-
nist to block the therapeutic effect, the authors proposed that
the mechanism of action of DBS is mGluR-dependent, the
activation of which depotentiates excitatory synaptic inputs
onto ­D1-Rs on GABAergic MSNs [33]. Such depotentiation
was associated with a normalization in drug-adaptive behav-
ior. The findings are also consistent with the upregulation of
GluR1 seen in the NAc in other stimulation studies [35, 36].
In contrast, both LFS (20 Hz) and HFS (160 Hz) stimula-
tion of the NAc core attenuated cocaine seeking behavior in
rats without the need of additional medications [43], similar
to the outcome of PFC stimulation [35]. The contrasting
findings between NAc core and PFC stimulations may be
explained by the different levels of basal dopamine in these
brain regions. Examining how DBS affects mGluR1 expres-
sion in different regions to affect D­ 1-R signaling would be
informative in future work.
Antidromic Activation of Cortex
Post-mortem brain c-Fos immunohistochemistry following
in vivo NAc shell HFS showed both local activation and
activation of the infralimbic cortex, suggesting that DBS of
13
J. Yuen et al.
the NAc shell led to antidromic stimulation of the cortex via
cortico-accumbal afferents [42]. Consistent with infralimbic
cortex-NAc circuitry in DBS, electrophysiological studies
showed NAc HFS but not LFS enhances both NAc-evoked
LFP responses and spontaneous LFP slow oscillatory activ-
ity in OFC in an antidromic fashion [87]. These results fur-
ther demonstrate the complex interplay between NAc and
the cortex.
Dopamine Replacement
One study showed that HFS of the NAc shell led to a para-
doxical augmentation in relapse behavior in a rat model of
alcohol addiction [44], a contrary finding to other studies
(Table 1). The authors also demonstrated an increase in
extracellular levels of dopamine as measured by microdialy-
sis. DBS-evoked increase in dopamine is reminiscent of the
intracranial self-stimulation model, where the subjects self-
administer electrical stimulation via implanted electrodes in
the brain [88]. Reinforcing effects of electrical stimulation
is presumably mediated by dopamine release in the reward
circuitry [89]. In addition, medial PFC DBS evoked dopa-
mine release in the NAc in a frequency-dependent manner
in anesthetized rats measured by fast-scan cyclic voltamme-
try (FSCV) [69]. Taken together, DBS of PFC may operate
partially via the replacement of dopamine, but whether this
can reduce drug taking or seeking has yet been tested. Most
of the DBS studies did not employ in vivo microdialysis
techniques for direct quantification; hence, replacement of
dopamine as a DBS mechanism is unconfirmed.
Limitations of Animal Models
Human subjects tend to require weeks and months of DBS
to observe an improvement, whereas animal studies show an
almost immediate effect. In animal studies, the condition-
ing occurs over days (rather than years). The short time-
frame indicates that the neuroplasticity reversal may not be
the dominating effect of DBS in animals and the dopamine
replacement caused by stimulation may mediate the acute
improvement in behavior. In humans, DBS likely operates
via reversal of neuroadaptations that have been built up on a
much longer time scale than animals subjected to condition-
ing. This interpretation is supported by case reports where
subsequent explantation of the DBS device did not reverse
the initial effect of abstinence [90, 91]. In addition, a fur-
ther case report showed that NAc DBS reduced risk taking
behavior and increased activation of brain regions implicated
in behavioral control arising from lasting neuroadaptations,
measured by positron-emission tomography [92].
Some human studies also include subjects with comorbid
OCD, depression, and anxiety [12, 93, 94]. In fact, addiction
may be part of a maladaptive coping mechanism for other
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?
underlying disease/s. DBS may alleviate addiction by reduc-
ing the severity of an underlying comorbid disease, which
is challenging to model in animals. For example, the higher
cognitive and emotional component as well as the impact of
social cues are difficult to assess in animals.
Alternatives to DBS
Given the invasive nature of DBS, other neuromodulatory
modalities are worth considering. Of note, noninvasive
techniques such as rTMS and tDCS have been of particu-
lar interest [95, 96]. A detailed review of these techniques
and outcomes is out of the scope of this article but in brief,
rTMS operates by applying a stimulating coil at the scalp,
which generates magnetic fields. The magnetic fields then
pass through the skull and induce strong focal currents in the
underlying brain tissues [97]. It is believed that long-term
repetitive stimulation can lead to neuroplasticity, which can
provide therapeutic effect to the addicted brain [97]. tDCS
involves application of a direct or alternative electrical cur-
rent to the scalp, such that current travels from a positive
(cathode) to a negative (anode) electrode. Cortical neurons
are suggested to be facilitated under the anode, whereas
those under the cathode are suppressed [98]. Although rTMS
and tDCS have been shown to be effective in preclinical
studies and small clinical case series on reducing symptoms
such as craving, more data are required to ascertain their
long-term safety profiles, efficacy, and the ideal patient pro-
file [98–100]. Although research shows that non-invasive
neuromodulation can be successful in certain cases with-
out the need for neurosurgery, the main limitations are the
focality of these non-invasive treatments and the relatively
low spatial resolution. These non-invasive interventions also
require numerous frequent visits to facilities in a specialized,
tertiary center. In contrast, DBS can be implanted as a per-
manent or chronic stimulation system, which can potentially
be programmed remotely [101].
There was a recent success of semi-invasive MRI-guided
focused ultrasound (MRgFUS) thalamotomy in the treat-
ment of movement disorders and other psychiatric disorders
(depression and OCD) [102, 103]. Such a technique would
avoid the complications associated with the implantation of
devices, which may necessitate explantation for reasons such
as lack of efficacy or infection. Alongside DBS, MRgFUS
offers a novel therapeutic avenue that should be explored to
treat refractory addictive disorders.
Invasive techniques can offer a more focal region of ther-
apy. Ablation techniques in drug addiction targeting the NAc
with promising results have long received attention [104].
Indeed, a recent systematic review showed that NAc DBS
has similar efficacy and safety profile as radiofrequency
ablation of the NAc [66]. Compared to ablation techniques,
however, DBS allows adjustment of stimulation parameters
tailored to maximize therapeutic efficacy while minimizing
side effects. Nonetheless, a recent systematic review showed
that NAc DBS has similar efficacy and safety profile as radi-
ofrequency ablation of the NAc [66].
Future Directions
Potential Biomarkers
The hunt for a reliable biomarker serves three critical pur-
poses: to facilitate patient selection, to monitor the progress
of the disease (and therapeutic effect of treatments), and
to progress towards a holy grail of DBS—a closed-loop
therapeutic system. Not only can this potentially increase
the battery longevity (hence reducing the need for battery
replacement), it also can increase the efficacy of stimula-
tion by tailoring to the patients’ neural responses. Further, a
“tolerance” effect can be observed with chronic open-loop
DBS stimulation in movement disorder patients, with the
stimulation effect wearing off after a period of time [105].
Such a tolerance is also likely in patients receiving DBS to
treat psychiatric illnesses. Closed-loop system with inter-
mittent, dynamic stimulation can potentially minimize tol-
erance. Such biomarkers need to be easy to measure and
possess a relatively high spatiotemporal resolution of meas-
urement that, in turn, correlates well with clinical/behavio-
ral changes. In our opinion, the most promising candidates
would be electrophysiological and neurochemical measure-
ments, although they will need to be tailored towards indi-
vidual addictive substances and patients.
In terms of electrophysiological measurements, LFP is
the most widely studied potential biomarker among DBS
studies. LFP’s wide use is mostly because of its measure-
ment using the stimulating electrodes themselves. In ure-
thane-anesthetized rats, NAc HFS suppressed pyramidal cell
firing and enhanced slow LFP oscillations in the OFC via
antidromic activation of cortico-striatal recurrent inhibition
[87]. In addition, prolonged NAc HFS and LFS (delivered
over 90 min) have been shown to affect both spontaneous
and evoked LFPs in the medial PFC, lateral OFC, mediodor-
sal thalamus (MD), and NAc sites [106]. HFS also produced
widespread increases in spontaneous beta and gamma power
and enhanced coherent beta activity between MD and all
other regions. In contrast, LFS elevated theta power in the
MD and NAc. Acutely, HFS increased and LFS decreased
induced relative gamma coherence. Stimulation-induced
changes in gamma coherence shows that NAc DBS may
achieve therapeutic effects by restoring the synchronicity
of a neural circuitry that is disrupted in neuropsychiatric
diseases. The differences in the effect on LFPs between
HFS and LFS may also explain the differences in behavioral
effects described above.
13

In a study assessing 7 people with heroin use disorder,
pre-DBS electrophysiology revealed prominent theta and
alpha band activity in both the NAc and ALIC [107]. Addi-
tionally, a beta band peak was detected in the power spec-
tra of ALIC LFPs, which, the authors hypothesized, may
represent the activity of striatal bridge cells. Furthermore,
there was a negative correlation between the power of the
theta band of ALIC LFPs and subjective craving, and a
positive correlation between the power of the alpha band of
NAc LFPs and depressive symptoms. LFPs of the NAc and
ALIC both exhibited higher coherence values in the theta
and alpha frequency bands. No comparison with post-DBS
recordings was given in this study. Together with the animal
and human DBS studies on NAc [108, 109], the most con-
sistent biomarker frequency is yet unknown. Further studies
are required for clarification. New technologies such as the
Medtronic Percept Stimulator [110] may be able to provide
more information by simultaneously recording from and
stimulating brain targets in humans. In addition, trials inves-
tigating electrophysiological changes secondary to DBS in
addiction (such as [111]) will provide more insights.
Unlike electrophysiological signals (i.e., action poten-
tials) that naturally lead to neurotransmitter release into
synapses, quantification of synaptic-related neurotransmit-
ter extracellular concentrations directly measures the activa-
tion of relevant neural circuits (such as the ones depicted in
Fig. 2). Most studies in addiction focus on the monoamines,
particularly dopamine, glutamate, and 5-HT. One animal
study reviewed here [44] employed in vivo microdialysis
and found that local dopamine concentrations increased after
NAc shell HFS. While in vivo microdialysis has long been
the gold standard for sampling neurochemicals, the process
necessitates an external analyzer and has low temporal reso-
lution. In contrast, in vivo electrochemical techniques, such
as FSCV, provide potential benefits such as higher temporal
resolution, less tissue damage, and the ability to be chroni-
cally implanted [112–116]. However, compared to micro-
dialysis, electrochemical techniques have other limitations.
Often, they are restricted to measurement of a single electro-
active amine at a time, such as dopamine or serotonin. Thus,
future studies which aim to develop biomarkers for DBS
efficacy will need to demonstrate suitability of neurochemi-
cal biomarkers for translation and may be limited by present
detection technology. While microdialysis provides impor-
tant measurements of the tonic (basal) extracellular levels
of neurochemicals, voltammetry can provide measurement
of phasic and tonic measures of neurochemicals [117–122].
Future Preclinical and Clinical Research Considerations
Other important considerations for future research include
inclusion of both genders in both animal and human stud-
ies (currently most studies focus on males—see Tables 1
13
J. Yuen et al.
and 2), and the use of larger animals—preclinical studies
are predominantly rodent-based, but also well suited to large
animal models. In addition, we have focused on technologies
that are currently clinically viable in this review, namely
electrical DBS devices. However, the use of optogenetics,
where a viral vector is able to transfect a specific neural
population, is increasingly popular in the preclinical study
of underlying pathophysiology of different neuropsychiatric
disorders and relevant therapies. Optogenetics has provided
new insights into DBS protocol optimization for Parkinson’s
disease with translational potential [123, 124], which may
be extended to psychiatric illnesses. In addition, recent opti-
cal imaging techniques allow combination of fiber photom-
etry and electrophysiology to study specific cell population
activity via genetically encoded calcium indicators, includ-
ing during deep brain stimulation [125, 126]. Cell-specific
viral transfection in calcium imaging or optogenetics helps
to study specific ion channels or neurotransmitters. How-
ever, the use of viruses in humans is very limited. Further
technological advancements are necessary to harness optical
methods in the clinical setting.
Currently, the use of DBS in addiction remains off-label,
primarily due to the lack of high-quality clinical evidence.
As seen in Table 2, most human studies consist of observa-
tional studies with a small sample size. However, more clini-
cal trials are currently being conducted. The ClinicalTrials.
gov database show that there are currently around 10 DBS
trials underway trying to tackle this paucity of scientific evi-
dence, targeting the NAc, ALIC, and STN [127]. As dem-
onstrated in the present review, they are all very promising
targets. In addition, we would add PFC to this list given the
success from animal studies [47] as well as human imaging
studies showing its dysfunction in subjects with substance
use disorder [128].
Supporting the potential of DBS in alleviating addic-
tion-related behaviors, DBS to treat obesity has also shown
early successes [129–131]. Given the similarities between
substance use disorders and obesity, the findings in DBS
for substance use disorder presented so far may be translat-
able to DBS for obesity. With the increasing prevalence and
comorbidities associated with excessive calorie consumption
in the modern society, this can be hugely beneficial.
While it is exciting to perform cutting-edge patient sur-
geries, it is also important to recognize that DBS is not
an immediate cure and requires careful patient selection,
consent, and patient-based optimization (including treating
other comorbidities); otherwise, DBS can lead to a risk of
major adverse outcomes [132]. DBS also has cost, transla-
tional, and capacity limitations for a highly prevalent disor-
der, but has the advantage of elucidating fundamental neural
biology capable of detecting new therapeutic targets.
In our literature search, all human studies that involve
stimulation of deep structures were conducted exclusively
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?
with high-frequency stimulation, as commonly used in DBS
for movement disorders (see Table 2). Therefore, future
work to compare how stimulation at different frequencies
may affect the biomarkers such as LFP in humans would
be beneficial.
The duration of trials may also be important. One of the
possible reasons attributed to the failure of early trials in
DBS for depression is the short treatment duration, as trials
with longer duration appeared to show significant efficacy
[6, 133–135]. DBS duration effects will need to be assessed
in larger clinical trials. Further, for neuropsychiatric condi-
tions such as addiction, careful consideration of the ethical
aspect is required.
Ethical Considerations
Although DBS is much safer than early forms of psychosur-
gery such as lobotomy, it is not a risk-free treatment [136].
Therefore, clinicians are obliged to always have the patients’
best interest in their mind. The risks and benefits of the treat-
ment need to be balanced appropriately. One of the main
issues with human trials is the principle of autonomy, as
patients with addictive disorders may not have the capacity
to consent to such process. Furthermore, there are concerns
that DBS (and indeed any forms of psychosurgery) may alter
a patient’s personality, which can lead to actions and con-
sequences that may otherwise not be performed [137–139].
Academic societies and government institutions should also
provide a medico-legal framework to ensure both medical
professionals and patients are protected. A full ethical dis-
cussion is out of the scope of this review. Nevertheless, we
recommend that the clinical team be multidisciplinary, with
access to the resources and expertise to assess and manage
the patients before and after the DBS surgery.
Conclusions
Preclinical and clinical studies suggest DBS is a potential
treatment for refractory addictive disorders after other non-
invasive options fail. Here, we reviewed these studies and
their implications. However, given the uncertainty in its
mechanism of action and a lack of large scale randomized
controlled trials, clinicians and scientists should be cau-
tiously optimistic. We also provided recommendations on
the directions of future research, such as the need to iden-
tify reliable biomarkers, for which LFPs in the NAc and
in vivo electrochemical measurement of monoamines so far
appear the most promising options. With further research,
we believe it can prove to be a highly effective treatment for
a selected group of patients.
Supplementary Information  The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 13311-0​ 22-0​ 1229-4.
Acknowledgements  We would like to acknowledge Ms. Leslie Hassett,
Outreach Librarian, Mayo Clinic, for her contribution to the thorough
literature search. M. B. is supported by a NHMRC Senior Principal
Research Fellowship (1156072).
Required Author Forms   23 provided by the authors are available with
the online version of this article.
Author contribution  K. H. L., Y. O., J. H. K., and J. Y. conceptualized
the study. J. Y. collected the data. J. Y. drafted the first manuscript.
A. Z. K., M. B., J. H. K., S. T., C. D. B., K. E. B., K. H. L., and Y. O.
critically reviewed and revised the manuscript. K. H. L., M. B., J. H.
K., H. S., and Y. O. supervised all aspects of this work. J. Y. drafted
the figures. All authors accepted the final version of the manuscript.
Funding  Open Access funding enabled and organized by CAUL and
its Member Institutions. This research was supported by the NIH
(R01NS112176) and the Minnesota Partnership for Biotechnology
and Medical Genomics (MNP #19.13).
Declarations 
Conflict of Interest  The authors declare no competing interests.
Open Access  This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
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permitted by statutory regulation or exceeds the permitted use, you will
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