ReviewFactors modulating neural reactivity to drug cues in addiction: A survey of human neuroimaging studies
Introduction
Growing evidence suggests that drug cue reactivity, as assessed with functional MRI (fMRI), positron emission tomography (PET), and related neuroimaging techniques, as well as behavioral and autonomic measures, is strongly associated with a number of indices of drug use, including addiction severity and treatment success. However, factors that modulate cue reactivity remain incompletely understood and in some cases the direction of causal influence unclear, impeding a translation of this knowledge to clinical practice. Therefore, our goal in this review is to identify and characterize major factors that modulate brain reactivity to drug cues, which may inform future neuroimaging studies as well as the design, selection, and tailoring of treatment and prevention programs. Toward that goal, we survey published fMRI and PET studies on drug cue reactivity in cocaine, alcohol, and tobacco cigarette users, with the focus on identifying and characterizing specific factors that modulate this reactivity. We first describe cue reactivity paradigms used in human neuroimaging research and outline the brain circuits that underlie drug cue reactivity. We then discuss major factors that have been shown to modulate cue reactivity and review specific evidence as well as outstanding questions related to each factor. In light of recent findings, we highlight the importance of implicit and explicit cognitive regulation over drug cue reactivity and the conditioned drug-seeking behavioral responses that these cues engender. Building on previous model-based reviews (Field and Cox, 2008, Franken, 2003, Wilson et al., 2004), we then provide a simplified model that includes the key modulatory factors and offer a tentative ranking of their relative impact on neural drug-cue reactivity in drug users. We conclude with a discussion of outstanding challenges and future research directions.
Section snippets
Drug cue reactivity paradigms in human neuroimaging research
A number of different neuroimaging paradigms have been used to investigate the neural correlates of drug cue reactivity in human drug users. The shared feature of these paradigms is that drug users are exposed to stimuli associated with their respective drug of abuse. These drug-related cues may be visual (seeing words, pictures or silent videos) (Janes et al., 2010, Luijten et al., 2011), auditory (e.g., listening to imagery scripts) (Kilts et al., 2001, Seo et al., 2011), audiovisual (
Mesocorticolimbic system and brain circuits of reward, motivation, and goal-directed behavior
A common characteristic, and arguably a shared neurobiological mechanism, of most if not all drugs of abuse is that they increase extracellular dopamine (DA) concentration in the mesocorticolimbic system, including the ventral striatum (VS), extended amygdala, hippocampus, anterior cingulate (ACC), prefrontal cortex (PFC), and insula, which are innervated by dopaminergic projections predominantly from the ventral tegmental area (VTA) (Hyman et al., 2006, Nestler, 2005). Such directly or
Addiction severity, craving, and treatment outcome
The clinical relevance of drug cue reactivity is well documented by behavioral studies (Field and Cox, 2008). Drug cue reactivity is associated with, and in some cases predictive of, a number of clinical measures of drug use and dependence, including length and intensity of drug use, addiction severity, risk of relapse, treatment outcomes, and use-associated problems. However, it should be emphasized that the direction of influence, or cause and effect, are less clear. On the one hand, chronic
Abstinence and withdrawal symptoms
Abstinence and associated withdrawal symptoms (including irritable, anxious, or depressed mood, difficulty concentrating, motor disturbances, disturbances in appetite and sleep, as well as changes in heart rate, blood pressure, and body temperature) are also likely to modulate neural reactivity to drug cues in drug users. Craving for a drug is sometimes considered a symptom of drug withdrawal as well. In fact, drug seeking during abstinence-induced withdrawal has been postulated to be at least
Sensory modality and length of presentation of drug cues
The sensory modality of the cues can also influence the behavioral and brain cue reactivity itself. Behavioral experiments have demonstrated pronounced differences in the ability of drug cues to elicit behavioral and psychophysiological reactions depending on the sensory modality (Johnson et al., 1998, Reid et al., 2006, Shadel et al., 2001, Wray et al., 2011). For instance, a recent fMRI study revealed that haptic smoking cues activate the DS more strongly than visual smoking cues (Yalachkov
Explicit and implicit regulation of drug cue reactivity
Current theories of addiction posit that, with repeated drug use and associated DA processes in the mesocorticolimbic and nigrostriatal circuits, drug-related cues acquire incentive-motivational salience, which gives them the capacity to trigger craving and drug seeking (Robinson and Berridge, 1993). In the process, drug cues also acquire attentional salience, which is manifested as a powerful attentional bias for drug cues in drug-dependent individuals (Field and Cox, 2008, Franken, 2003; see
Stressor exposure
Stressor exposure is known to interact with drug-related cues as a potent trigger of craving and relapse to drug-taking behavior following abstinence (for reviews, see Koob, 2008, Sinha, 2008). Stressors and drug-related cues also engage partially overlapping brain systems, including the mesocorticolimbic system (for review, see Sinha and Li, 2007). Therefore, stressor exposure would be expected to impact neural reactivity to drug cues in drug users. Consistent with this view, when a
Toward an integrative model of neural reactivity to drug cues
As discussed in the sections above, human neuroimaging literature strongly suggests that the neural reactivity to drug cues is modulated by a number of both individual-specific and study-specific factors. Furthermore, these factors are likely to have both main and interactive effects, although the direction and magnitude of this modulation is not always well understood. To facilitate progress toward such understanding, we present a table summarizing our findings (see Table 1) and outline a
Outstanding challenges and future directions
Neural reactivity to drug cues has been proposed to be a key manifestation of addiction processes and may constitute a biomarker of addiction severity, treatment outcome, and risk of relapse. Yet considerable variability in the extensive neuroimaging literature on drug-cue reactivity has hindered translation of this knowledge to diagnosis, treatment, and prevention. This variability suggests that neural cue reactivity in drug users may be modulated by other factors, including both
Acknowledgements
A.J.J. and E.A.S. are supported by the National Institute on Drug Abuse Intramural Research Program (NIDA-IRP). M.J.N., J.K. and Y.Y. are supported by the Hessisches Ministerium für Wissenschaft und Kultur (LOEWE Forschungsschwerpunkt Neuronale Koordination Frankfurt).
References (155)
- et al.
Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum
Neuron
(2008) - et al.
Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction
Behav. Brain Res.
(2009) - et al.
Neural systems and cue-induced cocaine craving
Neuropsychopharmacology
(2002) - et al.
Neural substrates of resisting craving during cigarette cue exposure
Biol. Psychiatry
(2007) - et al.
Left inferior parietal representations for skilled hand-object interactions: evidence from stroke and corticobasal degeneration
Cortex
(2007) - et al.
Seeing or doing? Influence of visual and motor familiarity in action observation
Curr. Biol.
(2006) - et al.
Representation of manipulable man-made objects in the dorsal stream
Neuroimage
(2000) - et al.
The neural basis of drug stimulus processing and craving: an activation likelihood estimation meta-analysis
Biol. Psychiatry
(2011) - et al.
Autoradiographic evidence for nicotine receptors on nigrostriatal and mesolimbic dopaminergic neurons
Brain Res.
(1985) - et al.
Bringing the real world into the laboratory: personal smoking and nonsmoking environments
Drug Alcohol Depend.
(2010)
Neural representations of graspable objects: are tools special?
Brain Res. Cogn. Brain Res.
An acute psychosocial stress enhances the neural response to smoking cues
Brain Res.
Ventral striatum/nucleus accumbens activation to smoking-related pictorial cues in smokers and nonsmokers: a functional magnetic resonance imaging study
Biol. Psychiatry
Haemodynamic responses to sensory stimulation are enhanced following acute cocaine administration
Neuroimage
Cocaine preferentially enhances sensory processing in the upper layers of the primary sensory cortex
Neuroscience
Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior
Neuropsychopharmacology
A core system for the implementation of task sets
Neuron
Neural substrates of smoking cue reactivity: a meta-analysis of fMRI studies
Neuroimage
Addiction, compulsive drug seeking, and the role of frontostriatal mechanisms in regulating inhibitory control
Neurosci. Biobehav. Rev.
Attentional bias in addictive behaviors: a review of its development, causes, and consequences
Drug Alcohol Depend.
Drug craving and addiction: integrating psychological and neuropsychopharmacological approaches
Prog. Neuropsychopharmacol. Biol. Psychiatry
Differential brain response to alcohol cue distractors across stages of alcohol dependence
Biol. Psychol.
Dissociable executive functions in the dynamic control of behavior: inhibition, error detection, and correction
Neuroimage
Does visual perception of object afford action? Evidence from a neuroimaging study
Neuropsychologia
Nicotine preferentially stimulates dopamine released in the limbic system of freely moving rats
Eur. J. Pharmacol.
Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence
Biol. Psychiatry
Dopamine: a potential substrate for synaptic plasticity and memory mechanisms
Prog. Neurobiol.
Cue reactivity in cocaine-dependent subjects: effects of cue type and cue modality
Addict. Behav.
The neural bases of complex tool use in humans
Trends Cogn. Sci.
Memory and addiction: shared neural circuitry and molecular mechanisms
Neuron
A role for brain stress systems in addiction
Neuron
Common and distinct networks underlying reward valence and processing stages: a meta-analysis of functional neuroimaging studies
Neurosci. Biobehav. Rev.
Neurobiological substrate of smoking-related attentional bias
Neuroimage
Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas
Neuron
The neural basis of drug craving: an incentive-sensitization theory of addiction
Brain Res. Brain Res. Rev.
Exposure to smoking cues during an emotion recognition task can modulate limbic fMRI activation in cigarette smokers
Addict. Biol.
Decision making, impulse control and loss of willpower to resist drugs: a neurocognitive perspective
Nat. Neurosci.
Effect of brain structure, brain function, and brain connectivity on relapse in alcohol-dependent patients
Arch. Gen. Psychiatry
Alcohol-associated stimuli activate the ventral striatum in abstinent alcoholics
Journal of Neural Transmission (Vienna, Austria: 1996)
Brain metabolic changes during cigarette craving
Arch. Gen. Psychiatry
Does erotic stimulus presentation design affect brain activation patterns? Event-related vs. blocked fMRI designs
Behav. Brain Funct.
Nicotinic excitation of rate ventral tegmental neurons in vitro studies by intracellular recording
Br. J. Pharmacol.
Action observation and acquired motor skills: an FMRI study with expert dancers
Cereb. Cortex
Prelude to passion: limbic activation by “unseen” drug and sexual cues
PLoS One
Limbic activation during cue-induced cocaine craving
Am. J. Psychiatry
Identifying neurobiological phenotypes associated with alcohol use disorder severity
Neuropsychopharmacology
Neural responses associated with cue-reactivity in frequent cannabis users
Addict. Biol.
Interoception: the sense of the physiological condition of the body
Curr. Opin. Neurobiol.
Influence of alcohol use and family history of alcoholism on neural response to alcohol cues in college drinkers
Alcohol. Clin. Exp. Res.
Effects of acute nicotine abstinence on cue-elicited ventral striatum/nucleus accumbens activation in female cigarette smokers: a functional magnetic resonance imaging study
Brain Imaging Behav.
Cited by (382)
Risk-promoting effects of reward-paired cues in human sign- and goal-trackers
2024, Behavioural Brain ResearchBlunted Neurobehavioral Loss Anticipation Predicts Relapse to Stimulant Drug Use
2024, Biological PsychiatryDisrupted white matter structural networks in individuals with alcohol dependence
2023, Journal of Psychiatric ResearchAppetitive and aversive cue reactivities differentiate neural subtypes of alcohol drinkers
2023, Addiction Neuroscience
- 1
Equal contribution.