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Event-Related Potentials as Biomarkers of

Behavior Change Mechanisms in Substance
Use Disorder Treatment
Rebecca J. Houston and Nicolas J. Schlienz

ABSTRACT
Substance use disorders (SUDs) are one of the most prevalent psychiatric conditions and represent a significant
public health concern. Substantial research has identified key processes related to reinforcement and cognition for
the development and maintenance of SUDs, and these processes represent viable treatment targets for psychosocial
and pharmacological interventions. Research on SUD treatments has suggested that most approaches are com-
parable in effectiveness. As a result, recent work has focused on delineating the underlying mechanisms of behavior
change that drive SUD treatment outcome. Given the rapid fluctuations associated with the key neurocognitive
processes associated with SUDs, high-temporal-resolution measures of human brain processing, namely event-
related potentials (ERPs), are uniquely suited to expand our understanding of the underlying neural mechanisms of
change during and after SUD treatment. The value of ERPs in the context of SUD treatment are discussed along with
work demonstrating the predictive validity of ERPs as biomarkers of SUD treatment response. Example associations
between multiple ERP components and psychosocial and/or pharmacological treatment outcome include the P3a
and P3b (in response to neutral and substance-related cues), the attention-related negativities (e.g., N170, N200), the
late positive potential, and the error-related negativity. Also addressed are limitations of the biomarker approach to
underscore the need for research programs evaluating mechanisms of change. Finally, we emphasize the advantages
of ERPs as indices of behavior change in SUD treatment and outline issues relevant for future directions in this
context.
Keywords: Addiction, Behavior change, Biomarkers, Event-related potentials, Substance use disorder, Treatment
https://doi.org/10.1016/j.bpsc.2017.09.006

In 2015, substance use disorders (SUDs) affected 20.8 million
individuals in the United States (1). Despite significant
advances in our understanding of risk factors and validation of
psychosocial and pharmacological interventions, SUDs are
widespread and represent a substantial public health concern
and economic burden. The research literature on SUDs is
substantial, and historically, basic and applied lines of inquiry
are often conducted in parallel rather than in an integrated
fashion. More recently there has been a call for an increase in
interdisciplinary research in an effort to rapidly advance our
understanding of and successful treatments for SUDs (2,3).
Thus, the current article briefly summarizes 1) existing
research on neural mechanisms and cognitive processes
related to chronic substance use and 2) current research di-
rections related to mechanisms of behavior change in SUD
treatment. We emphasize these publications as a means to
highlight the unique potential of high-temporal-resolution
measures of human brain processing, particularly event-
related potentials (ERPs), for enhancing our knowledge on the
effects of SUDs and ultimately, to improve prevention and
treatment. Specifically, we aim to capitalize on the momentum
of research demonstrating the importance of examining
mechanisms of behavior change in SUD treatment to under-
score the distinctive applicability of ERPs for examining the
neural underpinnings of behavior change in this context. As part
of this effort, we summarize published work that demonstrates
the promise that ERPs hold as clinically meaningful biomarkers
of treatment response and acknowledge the limitations of this
approach. Finally, we outline the advantages and disadvan-
tages of ERPs as a method for gauging SUD-related behavior
change and delineate issues relevant for future directions in the
application of ERPs in the context of SUD treatment.
NEURAL MECHANISMS UNDERLYING SUD
Research has identified a series of alterations to neurophysi-
ological processes that are proposed determinants of SUDs
and represent the acute and long-term consequences of SUDs
(4,5). Prominent theoretical models of addiction highlight
dysfunction in corticostriatal circuitry due to a vulnerability
and/or the adverse effects of repeated substance use (6–8). In
particular, drug-related plasticity and reorganization of neural
circuitry appear to be strongly linked to dopamine function as
well as other neurotransmitters such as glutamate and

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ERPs and Behavior Change in SUD Treatment
gamma-aminobutyric acid (9,10). These alterations in cortico-
striatal reward circuitry seemingly result in hypersensitivity to
drug rewards and hyposensitivity to natural nondrug rewards.
Indeed, both preclinical and functional magnetic resonance
imaging (fMRI) studies of individuals with SUDs have shown
significant increases in brain activity in the ventral tegmental
area in response to drug cues as well as diminished neural
responses to natural rewards (11–13).
SUDs are also associated with cognitive control deficits
characterized by hypoactivity in the prefrontal cortex and
cingulate gyrus (14–16), key structures in the execution of
goal-directed and self-regulatory behaviors (17–19). For
example, fMRI studies have revealed diminished activity in the
anterior cingulate cortex and prefrontal cortex among
individuals with problematic substance use on tasks that
assess inhibitory control, working memory, and attention (13).
Thus, a growing literature maintains that alterations in reward
processing and cognitive control processes attributed to SUDs
represent logical targets for treatment interventions (20–28).
Hence, the convergence of much of this literature has sug-
gested that neurocognitive measures may be highly valuable
predictors of substance use treatment outcomes (28,29).
MECHANISMS OF BEHAVIOR CHANGE IN SUD
TREATMENT
Apart from an increased understanding of the neurobiological
processes associated with addiction, recent years have also
witnessed significant progress in the development and
evaluation of effective SUD treatments. Presently, there are a
number of U.S. Food and Drug Administration-approved
pharmacological treatments for specific SUDs (30–32) as well
as empirical support for off-label use of several prescription
medications (32,33). Evidence-based behavioral and psycho-
social interventions for SUDs (34,35) include, but are not limited
to, cognitive behavioral therapy (36,37), motivational inter-
viewing (MI) and motivational enhancement therapy (38–40),
contingency management (41–43), and 12-step facilitation (44).
While the efficacy of these interventions is well documented,
many individuals do not respond to these treatments, as evi-
denced by high relapse rates at follow-up (45–48). Moreover,
studies comparing the effectiveness of evidenced-based
pharmacological, psychosocial, and combined treatments
have failed to single out any one particular treatment approach
as being clearly superior (49–51). Consequently, there has been
an exponential increase in research on mechanisms, media-
tors, and moderators that may be involved in substance use
outcomes regardless of the treatment approach.
A call for a more nuanced understanding of behavior
change has resulted in research focused on identifying
potential mechanism candidates (52–54). It is thought that by
learning more about “how” or “why” treatment works,
researchers and clinicians can place stronger emphasis on
these mechanisms in developing new and improving existing
treatments. Accordingly, a cognitive neuroscience framework
for examining behavior change in the context of SUD treatment
(55–58) may be of value. However, only a handful of studies
have attempted to examine changes in functional brain activity
that may accompany changes in behavior during and after
SUD treatment (59–63). Most research related to treatment
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outcomes and neural processing has focused on identifying
biomarkers—measures of neural activity that appear to have
some predictive validity for treatment response (4)—rather than
indexing changes in cognitive and reinforcement processes in
conjunction with changes in substance use.
VALUE OF ERPs IN THE CONTEXT OF SUD
TREATMENT
Given the extensive findings emphasizing the significance of
reinforcement and cognition as treatment targets, a burgeoning
literature utilizing high-spatial-resolution imaging techniques
has explored various biomarkers for treatment outcomes
(29,64–71). While recognizing the value these studies have
added to our understanding of SUD treatment response, it is
imperative to note the inherent weaknesses of these tech-
niques for assessing brain activity in this context. In view of the
potential moment-to-moment variability of the key processes
that have been identified as critical to the development and
maintenance of addiction, low-temporal-resolution assess-
ment may limit our ability to accurately gauge the rapidly
unfolding sequence of neural activity that ultimately translates
to behavior (e.g., decision to use). Prior research has also
questioned the reliability of these high-spatial-resolution mea-
sures, particularly fMRI (72–74). Techniques such as fMRI and
positron emission tomography are expensive and lack mobility.
Functional near-infrared spectroscopy offers greater temporal
but lower spatial sensitivity than fMRI or positron emission
tomography (75). However, ERPs and magnetoencephalogra-
phy (MEG) are far superior in terms of temporal measurement.
The major drawback of MEG is the need for highly specialized
shielding, which results in higher cost and less portability.
High-temporal-resolution measures such as ERPs and MEG
are well suited to directly reflect the momentary fluctuations in
neural activity that characterize the key cognitive and reward
processes associated with addiction (76). ERPs are also more
cost-effective and portable than most other neuroimaging
measures. Studies have established the reliability of ERPs
(77–79) as well as comparatively demonstrating that reliability
can be achieved with fewer trials and subjects than with fMRI
(80). Thus, the advantages conferred by using ERPs may hold
important clinical implications (29,81,82).
First, as noted, development and maintenance of addiction
is characterized by rapidly occurring neurocognitive pro-
cesses. Although much has been gleaned from high-spatial-
resolution assessment regarding underlying neurocircuitry,
temporally sensitive measures offer a higher level of psycho-
metric accuracy. Although assessment during and after treat-
ment represents lengthy time intervals, reliable and precise
measurement of neurocognitive processes that occur on the
order of milliseconds at each assessment point is critical for
revealing changes in these processes over time. Moreover, it
has been clearly established that there are multiple processes
and pathways involved in the development and maintenance
of addiction (83) and considerable variability in terms of the
addiction phenotype (84). These variations suggest that
despite the end behavior (i.e., substance use), there are
different mechanisms and stages at play; in turn, this may
translate to a need for alternative therapeutic approaches.
While most measures of functional brain activity could be
31

Table 1. ERPs as Biomarkers for SUD Treatment Outcome Study Details
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Study
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Glenn et al.,1993 (109)
Bauer, 1997 (108)
Wan et al., 2010 (120)
Anderson et al., 2011 (115)
Versace et al., 2012 (118)
Cinciripini et al., 2017 (119)
(same sample)
Marhe et al., 2013 (117)
Petit et al., 2014 (112)
Sample Characteristics
89 inpatient alcohol treatment
residents (36 women)
49 cocaine-dependent participants
with and without antisocial
personality disorder (15 women)
32 at follow-up
41 substance-dependent patients
(8 women)
35 substance-dependent patients
(8 women)
180 cigarette smokers (63 women)
49 cocaine-dependent patients
(5 women)
27 patients with alcohol dependence
(7 women)
ERP Paradigm/Stimuli
Oddball dual-modality target selection
(neutral)
Visual selective attention (neutral)
Visual oddball (neutral)
Auditory perseveration (neutral)
Passive viewing of unpleasant, neutral,
pleasant, and cigarette-related
pictures
Eriksen flanker (neutral)
Visual go/no-go (neutral)
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ERP Results Related to
Design/Treatment SUD Outcomes
ERP: On discharge Longer N200 latency in those that
FU: 13 months postdischarge relapsed within 6 months prior to
Tx: NS-I retest.
O: Self- and/or collateral report P300 and N100 amplitude along with
N200 latency resulted in a 63%
predictive rate for relapse status.
ERP: During long-term residential Discriminant function analysis
treatment indicated that P300 amplitude solely
FU: 6 months while in treatment predicted 70.6% of relapsers vs.
Tx: NS-I 53.3% of abstainers.
O: Urinalysis P300 amplitude was positively
correlated with length of abstinence.
ERP: During residential treatment; Reduced target P300 amplitude
abstinent $21 days among treatment noncompleters
FU: N/A compared with completers.
Tx: NS-I
O: Program completion
ERP: During residential treatment; Reduced P3a amplitude among
abstinent $21 days treatment noncompleters compared
FU: N/A with completers.
Tx: RP, LS Discriminant function analysis
O: Program completion indicated P3a amplitude accurately
predicted 72.7% of completers and
76.9% of noncompleters.
ERP: Prior to a 10-week smoking- Smokers with reduced LPP amplitude
cessation intervention to pleasant stimuli less likely to
FU: 24 weeks successfully abstain after the quit
Tx: BP, VR, BC date.
ERPs and Behavior Change in SUD Treatment
O: Self-report; CO levels Varenicline had better treatment
efficacy for smokers with enhanced
LPP amplitude for cigarette stimuli
(compared with pleasant).
Smokers with larger LPP amplitudes
for pleasant vs. cigarette stimuli had
similar efficacy rates for varenicline
and bupropion.
ERP: On entry to inpatient Reduced ERN was a significant
detoxification unit predictor of cocaine use in the 3
FU: 3 months months postdetoxification.
Tx: CBT; P
O: Self-report; urinalysis
ERP: After 3 weeks of detoxification Larger P300 difference amplitude in
FU: 3 months relapsers compared to nonrelapsers.
Tx: NS-I P300 difference amplitude was a
O: Self- and/or collateral report (full significant predictor of odds of
relapse only) relapse and sooner relapse.

Table 1. Continued
Study Sample Characteristics
Petit et al., 2015 (113) 39 patients with alcohol dependence
(11 women)
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Fink et al., 2016 (116) 98 substance-dependent prisoners
(63 women) who completed therapy
protocol
Luijten et al., 2016 (111) 66 nicotine-dependent cigarette
smokers (32 women)
Matheus-Roth et al., 2016 (114) 30 alcohol-dependent patients (5
women)
Parvaz et al., 2017 (63) 19 cocaine use-disordered individuals
(8 women)
All samples included adult participants.
AC, addictions counseling; BC, behavioral counseling (smoking); BP, bupropion; CBT, cognitive behavioral therapy; CO, carbon monoxide; ERN, error-related negativity; ERP, timing of
event-related potential assessment; FU, approximate length of follow-up (outcome) period; LPP, late positive potential; LS, life skills training; N/A, not applicable; NR, nicotine replacement;
NS-I, treatment(s) not specified—inpatient and/or residential; NS-O, treatment(s) not specified—outpatient; O, outcome measure; P, psychoeducation; RP, relapse prevention; SET, substance
expectancy therapy; SUD, substance use disorder; Tx, treatment type(s); VR, varenicline.
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ERP Paradigm/Stimuli
Visual (photos) oddball with alcohol
and nonalcohol targets
Visual distractor
Visual oddball
Visual go/no-go
(All neutral)
Cue reactivity (smoking and neutral
pictures)
Go/no-go (smoking and neutral
pictures)
Eriksen flanker (neutral)
Visual go/no-go task (alcohol and
nonalcohol beverage pictures)
Passive viewing of unpleasant, neutral,
pleasant, and cocaine-related
pictures
ERPs and Behavior Change in SUD Treatment
ERP Results Related to
Design/Treatment SUD Outcomes
ERP: After 3 weeks of detoxification Abstainers exhibited smaller P300
FU: 3 months amplitude to alcohol targets
Tx: NS-I compared with nonalcohol targets.
O: Self- and/or collateral report (full P300 difference amplitude was a
relapse only) significant predictor of odds of
relapse.
ERP: Prior to entering treatment study Noncompleters exhibited smaller P3a
FU: N/A amplitude in visual oddball task.
Tx: AC, RP, SET Noncompleters exhibited larger N200
O: Program completion amplitude in the visual distractor
task.
No effects for go/no-go task.
Support vector machine models
accurately classified 75% of
completers and noncompleters.
ERP: One week prior to participants’ Smaller go/no-go P300 difference
target quit date amplitude associated with relapse.
FU: 12 weeks Trends for smaller Pe and ERN during
Tx: BP, VR, NR, BC flanker task associated with greater
O: Self-reported number of smoked smoking.
cigarettes No effects for cue reactivity ERPs.
ERP: Postdetoxification Relapsers exhibited larger N170
FU: 3 months amplitude in response to alcohol-
Tx: N/A; detoxification only (included related no-go stimuli.
benzodiazepines)
O: Self-report (full relapse only)
ERP: Baseline and follow-up Reversal in LPP amplitude bias
FU: 6 months (drug . pleasant to pleasant .
Tx: NS-O/NS-I drug).
O: Self- and collateral report Reversal in LPP amplitude related to
decrease in craving.
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applied for this purpose, the time-sensitive assessment pro-
vided by ERPs has the ability to more precisely identify these
underlying processes that rapidly unfold.
Second, ERPs possess the necessary sensitivity to char-
acterize neurocognitive disturbances when no behavioral
impairment is detected. For example, numerous studies have
demonstrated that broad decrements in P300 amplitude
among individuals with alcohol use disorder (85,86) are
frequently accompanied by behavioral deficits, but more
recent work has reported enhanced P300 amplitude in
response to neutral stimuli in binge drinkers with no behavioral
performance deficits, suggesting that these individuals may
need to allocate more neural processing resources to produce
the same level of behavioral performance as nonbinge drinkers
(87–89). Thus, the use of ERPs in this context may be valuable
in terms of monitoring risk. While researchers must be cogni-
zant of the potential for false-positive findings in the absence
of behavioral effects, it is possible that ERPs may prove
valuable for monitoring improvement over the course of
treatment regardless of, or in concert with, behavioral perfor-
mance changes that occur. Indeed, prior studies have
demonstrated the recovery of ERPs and behavior with absti-
nence from alcohol, cocaine, and opioids (90,91).
It is also evident that the neurobiological processes asso-
ciated with addiction do not neatly map onto specific SUD
diagnostic criteria—a phenomenon common to most psychi-
atric disorders and part of the impetus for the National
Institutes of Health’s Research Domain Criteria (RDoC) project
(92,93). RDoC is a research framework that focuses on
domains and constructs that underlie psychopathological
behavior. Contrary to a symptom-based approach, RDoC
promotes investigation of these domains using multiple levels
of analysis ranging from biological to self-report. The Alcohol
Addiction RDoC has also been outlined (94). It is expected that
measures of functional brain activity may provide a more
accurate representation of the processes underlying addiction
beyond basic diagnostic symptomatology.
Despite the aforementioned advantages of ERPs, some
limitations and challenges to their application exist, particularly
in a clinical context (95,96). The most notable limitation is low
spatial resolution. Another critical challenge with ERPs is a lack
of methodological standardization across studies. This applies
to variations in tasks used to elicit ERPs, data collection, and
data processing. ERPs also have specific constraints on task
design with regard to the elicitation of certain ERP compo-
nents. Finally, as with any measure of cognition in an experi-
mental setting, ERPs elicited in a specific context (e.g., stop
task) may be somewhat limited in terms of ecological validity
(e.g., drug lapse). Many of these issues also apply to other
measures of functional brain activity. Even with these chal-
lenges, the advantages outlined above suggest that ERPs may
be ideal for examining changes in rapidly occurring neuro-
cognitive processes associated with substance use and SUD
treatment outcome.
ERPs AS BIOMARKERS FOR SUD TREATMENT
OUTCOME
ERPs have been used to examine key processes involved in
drug addiction from a variety of perspectives (86,97–101). A
34 Biological Psychiatry: Cognitive Neuroscience and Neuroimaging January 2018; 3:30–40 www.sobp.org/BPCNNI
ERPs and Behavior Change in SUD Treatment
large body of research has examined the neurocognitive
consequences of chronic substance use [e.g., P300 decre-
ments in response to neutral stimuli (86,100) or enhanced P300
in response to drug-related stimuli (98)]. Numerous studies
have suggested an endophenotype, indexed by ERPs, that
signifies a vulnerability for substance use and related exter-
nalizing behaviors (85,100,102). Development of SUDs is
complex and includes genetic and environmental contribu-
tions, making it difficult to completely separate these
influences on cognition (and hence ERP measurement). At the
same time, prior studies demonstrate the versatility of ERPs in
assessing cognition and affective processes as they relate to
SUDs. For example, the use of neutral versus drug-related
(salient) stimuli or other variations in task design can elicit a
specific ERP (e.g., P300), but depending on task demands, this
component might reflect varying aspects of neurocognition.
This versatility further supports the application of ERPs as a
potentially valuable tool for understanding the key processes in
successful SUD treatment.
Like other neuroimaging methods, ERPs have been
explored for their predictive validity in substance use treatment
outcomes. Findings based on a review of published English-
language studies that have examined ERPs in relation to
treatment outcomes are summarized below (see Table 1 for
study details). Review was limited to longitudinal research in
treatment-seeking participants and involved either treatment
completion or posttreatment relapse as outcomes. Though
alternative treatment approaches such as biofeedback
(103,104) and neuromodulation (20,27) appear to hold promise,
findings summarized here focus on first-line SUD treatments
(105); though P300 neuromodulation effects have been
explored (106,107).
Review indicated multiple studies highlighting the signifi-
cance of the P300 in response to neutral (i.e., nondrug) stimuli
for predicting relapse among alcohol and/or cocaine users
(108–110) and cigarette smokers (111). Recent studies
(112,113) have also demonstrated that individuals whose P300
amplitude was reduced in response to alcohol-related pictures
compared with nonalcohol-related pictures at detoxification
were abstinent 3 months later; notably, the abstinent and
relapse groups did not differ in terms of behavioral perfor-
mance. A larger occipital no-go N170 to alcohol cues (114) and
longer N200 latency (109) have been shown to be predictive of
alcohol relapse. In fact, discriminant analyses in multiple
studies have suggested strong predictive value for the early
negativities and P300 (108,109,115,116). Several studies have
also suggested that error-related brain activity (i.e., error-
related negativity [ERN]) may serve as a useful biomarker for
SUD relapse (29,117). Smoking-cessation studies involving
pharmacological treatment and counseling have demonstrated
attentional bias as indexed by late positive potential (LPP)
amplitude, suggesting that salience of nondrug reward is
related to ability to abstain (118,119). Similarly, in individuals
with cocaine use disorder, increases in LPP amplitude in
response to pleasant stimuli (compared with drug-related
stimuli) were related to decreased drug craving 6 months
posttreatment (63). Finally, other studies have examined the
utility of ERPs for predicting treatment completion rather than
posttreatment relapse (115,116,120). These studies all report
reduced P3a/P3b in individuals characterized as treatment

ERPs and Behavior Change in SUD Treatment
noncompleters. In sum, ERPs reflecting impaired cognitive
and/or reward processing or heightened attention and/or
motivation toward drug cues appear to be predictive of poorer
treatment outcome. With the advantages outlined above, these
studies emphasize the usefulness of ERPs in predicting SUD
outcomes and suggest a role for ERPs in subsequent research
on treatment development and improvement (81).
Although the aforementioned studies have expanded our
knowledge base on potential neurobiological underpinnings of
treatment response, this literature is also limited in several
ways. There are challenges with the application of biomarkers
for psychiatric disorders broadly speaking (121), and there are
specific challenges for the application of ERPs as biomarkers
(122). These range from methodological and logistical factors
affecting precision of measurement to individual variation.
However, in the case of SUD treatment research, another
significant issue is use of a categorical, typically binary,
outcome variable. The vast majority of studies related to bio-
markers for SUD treatment outcomes are based solely on
abstinence versus relapse. Classification for this distinction
may be based on self-report or biochemical verification (or
both). However, this categorical approach is problematic for
several reasons: 1) maintaining abstinence and/or cessation is
an ongoing process and categorical outcome measures do not
adequately capture the change process; 2) an indication of
abstinence or relapse is not theoretically related to the pro-
posed mechanisms that have been implicated in the devel-
opment and/or maintenance of addiction; 3) given the
fluctuating change processes, some relapse indicators (e.g., a
positive urine) may not truly reflect treatment failure or a
treatment nonresponder; and 4) for some substances such as
alcohol, moderation, rather than abstinence, is the treatment
goal (123,124). These limitations, along with the capability of
ERPs to accurately reflect the time-sensitive nature of key
neurocognitive processes underlying addiction, and the recent
shift in the treatment literature to focus on mechanisms of
behavior change point to the fact that high-temporal-resolution
neurophysiological measures, ERPs in particular, should be an
ideal approach to characterize neurophysiological mecha-
nisms underlying behavior change during SUD treatment.
ERPs AS AN INDEX OF BEHAVIOR CHANGE
Recent years have seen an exponential increase in research
delineating mechanisms of behavior change in response to
SUD treatment. Given this trend and the RDoC and Alcohol
Addiction RDoC initiatives, it is not surprising that researchers
are exploring these mechanisms from a cognitive neurosci-
ence framework (55–58,60). Accordingly, a small set of studies
have examined changes in functional brain activity as a
potential mechanism of behavior change over the course of
SUD treatment and posttreatment (60,125). Not surprisingly,
these studies generally implicate activation and connectivity in
brain regions responsible for cognitive control and reward
processing as a result of cognitive behavioral therapy and MI
approaches (57,59,61,62,126). It is worth noting that although
these studies aim to identify neural mechanisms associated
with behavior change, most still take a predictive biomarker
approach. In other words, with few exceptions (59,61,63),
these studies did not necessarily assess changes in neural
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activity in concordance with changes in substance use
behavior. In addition, most of these studies employ high-
spatial-resolution techniques, with the exception of an MEG
study on MI-related change talk (62) and an LPP study of
individuals with cocaine use disorder during treatment and 6
months posttreatment (63). Although the cost and logistics of
multiple assessments using these neuroimaging techniques
can be challenging, it is imperative that studies applying a
cognitive neuroscience approach include design features
similar to other research on mechanisms of behavior change—
that is, changes in purported mechanisms need to be
assessed concurrently with assessments of behavior change.
This translates into multiple assessments before, during, and
after treatment. Again, ERPs may be advantageous in this
regard given their lower cost and ease of acquisition.
As noted, ERPs are also particularly well suited for accu-
rately assessing the key cognitive and reinforcement pro-
cesses that have consistently emerged as potential treatment
targets. The underlying neural activity involved in reward,
inhibition, working memory, and attention are all characterized
by moment-to-moment fluctuations that may require the high
temporal sensitivity of ERPs. Taking a page from the RDoC
framework, we suggest that several of the purported active
components of psychosocial treatments (127) can be aligned
with these proposed key cognitive processes, many of which
can be indexed via ERPs. For example, reward processing is a
critical aspect of addiction that can change over the various
stages of addiction. There is evidence to suggest that each of
these stages can be indexed by specific ERP components. The
motivational salience of the drug eventually contributes to the
experience of craving (12). The cue-elicited P300 and contin-
gent negative variation, among others, can reflect relative
reward value and reward anticipation, respectively (128,129).
Moreover, evidence of P300 normalization with abstinence
may also suggest disengagement of salience detection and/or
reward processing over time (90,91,130). Key processes in MI
and/or motivational enhancement therapy include fostering
motivation to change, identifying values-incongruent actions,
and increasing the pursuit of alternative, nondrug goal-directed
behavior. The LPP is thought to reflect motivated attention
(131) and has been examined across different SUDs
(63,118,119,132,133) to evaluate motivation toward drug cues.
The response-locked ERN is a neurophysiological measure of
an endogenous performance monitoring system that promotes
cognitive control and posterror compensatory behavioral ad-
justments (134,135). The feedback-related negativity is a
stimulus-locked ERP that evaluates performance outcomes
(136). Together, the ERN and feedback-related negativity index
essential characteristics of cognitive control, self-regulation,
and reinforcement learning, each of which are applicable to
facets of cognitive behavioral therapy, MI and/or motivational
enhancement therapy, contingency management, and 12-step
facilitation. For specific context, Figure 1 depicts examples of
proposed associations between a treatment ingredient, key
processes (RDoC constructs), and hypothesized relevant
ERPs that may be suitable for examining treatment-related
changes. Note that there may be overlap across treatments
(e.g., treatment ingredients in common) (127), across treatment
ingredients (e.g., key processes in common), and across key
processes (e.g., ERPs in common). The degree of overlap
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A Cognitive Behavioral Therapy B Contingency Management

Drug Refusal Reinforcement of Alternative Non-

Treatment Ingredient
drug Behaviors

Relevant Processes/ Action Selection, Cognitive Control: Reward Learning Action Selection,
RDoC Constructs Decision Making Response Inhibition Decision Making

Hypothesized Relevant
ERPs N200 P300 ERN N200 N450 ERN P300 ERN FRN N200 P300 ERN

Figure 1. Example hypothesized associations between “active” treatment ingredients of two common interventions for substance use disorder, relevant
processes/Research Domain Criteria (RDoC) constructs, and event-related potentials (ERPs). Cognitive behavioral therapy for substance use disorder
(A) emphasizes utilization of drug-refusal skills that are likely aided by complex higher-order processes that support the decision to engage in adaptive (e.g.,
nondrug) goal-directed behavior and successful inhibition of drug-use behaviors. Potential ERPs for reflecting changes in these self-regulatory processes
during and after treatment include the N200, N450, P300, and error-related negativity (ERN). Contingency management interventions for substance use
disorder (B) identify target behaviors (e.g., negative urine drug toxicology tests, therapy attendance) and provide tangible reinforcers upon demonstration of the
specified behavior (e.g., monetary incentives, treatment clinic privileges). Reinforcer valuation is modulated by the incentive salience of the reinforcer that is
acquired via the process of reward learning and the outcome of urine drug toxicology tests results from making the decision to use or abstain from drug use.
Changes in reward learning and processes that guide decision-making during and after treatment may be indexed by the N200, P300, ERN, or feedback-
related negativity (FRN).

underscores the importance of accurate assessment and may
also help to explain similarities in effectiveness of different
treatments. Though far from comprehensive, these examples
demonstrate the sensitivity of ERPs for monitoring fluctuations
in motivated states and self-regulation in the context of SUD
treatment-related behavior change. In addition, many of these
key processes able to be indexed by ERPs directly align with
RDoC domains (137–140). Although less well understood,
pharmacological treatments presumably also affect many of
these same key cognitive and reinforcement processes
(141,142). Given the status of the literature on the neural basis
of SUDs, mechanisms of behavior change in SUD treatment,
and the RDoC approach to understanding mental illness, we
are at a crucial point in terms of future research for ultimately
improving SUD treatment and preventative efforts. Based on
the theoretical, methodological, and logistical advantages, we
maintain that ERPs are ideally suited to significantly advance
subsequent work in this area and call for researchers to make
use of ERPs both independently and in conjunction with other
neuroimaging techniques as a means to examine underlying
mechanisms of behavior change in SUD treatment.
CONSIDERATIONS FOR FUTURE RESEARCH
We contend that ERPs are uniquely positioned to promote a
more nuanced understanding of mechanisms of behavior
change in SUD treatment, which should promote subsequent
research aimed at improving treatment and/or intervention.
Further research is necessary to establish whether ERP
assessment itself may be a feasible tool for assisting clinicians
in tailoring treatment on an individual basis. With an aim toward
facilitating future research on mechanisms of change, we
outline a number of important theoretical and methodological
issues that should be considered when designing and con-
ducting studies in this area. First and foremost, research
utilizing ERPs should follow published guidelines and recom-
mendations for the acquisition, processing, analysis, and
reporting of ERP data (95,143), particularly those that address
the use of ERPs in clinical populations (96). To promote
standardization and reduce publication bias, it is imperative for
investigators to be transparent, open to replication of their
studies, and willing to communicate and/or collaborate.
Appropriate design, measurement, and statistical analyses in
the context of SUD treatment trials must also be applied (144).
Regarding treatment outcome measures, it is recommended
that researchers employ continuous (i.e., nonbinary) outcome
variables as well as multiple types of outcome measures (e.g.,
self-report, biochemical), when possible. Studies using ERPs
to examine mechanisms of behavior change should include
multiple assessments of both ERPs and outcome measures. In
addition, these concordant assessments should take place
prior to, during, and after treatment, ideally at least 6 to 12
months posttreatment. Another consideration that has not
been addressed in the current push to incorporate a cognitive
neuroscience framework into mechanisms of behavior change
research is variability in treatment goals. As noted earlier,
depending on the drug, not all clients have a goal of absti-
nence. Alcoholism treatment research has demonstrated that
controlled or moderated drinking may be a reasonable treat-
ment goal for some individuals (123,124). The use of contin-
uous outcome measures and multiple concordant ERP and/or
outcome assessments should provide a more fine-grained
approach, taking this difference in treatment goals into
account. In terms of measurement and analysis, it is worth
highlighting the importance of properly assessing treatment
adherence and/or attendance. Not all prior studies have
appropriately considered this critical element. Other consid-
erations include valid and specific measurement of substance
use and substance use severity, particularly for polysubstance
use, and ensuring sample diversity and statistical power to

36 Biological Psychiatry: Cognitive Neuroscience and Neuroimaging January 2018; 3:30–40 www.sobp.org/BPCNNI

ERPs and Behavior Change in SUD Treatment
allow examination of gender (145–147), age (e.g., adolescence,
advanced age) (148,149), and race, ethnicity, and/or culture
(150). Finally, researchers should pay considerable attention to
the purported active ingredients of the selected treatment
approach (127) and design ERP paradigms in light of the key
processes that align with these active ingredients. The RDoC
and Alcohol Addiction RDoC initiatives may provide guidance
and promote consistency regarding this aspect (82).
To conclude, we have suggested that ERPs provide an ideal
methodology for indexing mechanisms of behavior change in
the context of SUD treatment. Crucially, the high temporal
resolution that ERPs deliver, coupled with logistical and eco-
nomic value, make them an excellent choice for examining the
rapid changes in key neurocognitive processes related to SUD
behavior change. Given the significant public health concerns
associated with substance use, there remains a dire need for
improved treatment and intervention; we suggest that ERPs
hold unique scientific potential and clinical relevance for
advancements in this critically important area.
ACKNOWLEDGMENTS AND DISCLOSURES
This work was supported by National Institute of Alcohol Abuse and Alco-
holism Grant No. R21AA017113 (to RJH) and National Institute on Drug
Abuse Grant No. T32DA007209 (NJS).
We would like to thank four anonymous reviewers whose insightful
comments helped to improve and clarify this manuscript.
The authors report no biomedical financial interests or potential conflicts
of interest.
ARTICLE INFORMATION
From the Health and Addictions Research Center (RJH), Department of
Psychology, Rochester Institute of Technology, Rochester, New York; and
the Behavioral Pharmacology Research Unit (NJS), Department of Psychi-
atry and Behavioral Sciences, Johns Hopkins University School of Medicine,
Baltimore, Maryland.
Address correspondence to Rebecca J. Houston, Ph.D., Rochester
Institute of Technology, Department of Psychology, 18 Lomb Memorial
Drive, Rochester, NY 14623; E-mail: rjhgss@rit.edu.
Received Jun 5, 2017; revised Sep 15, 2017; accepted Sep 16, 2017.
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