ReviewCommon and distinct neural targets of treatment: Changing brain function in substance addiction
Introduction
Addiction is characterized by continued drug-seeking and drug use despite reduced pleasure derived from the drug and often in the face of catastrophic social, emotional, and legal consequences. The recurrent nature of the disease poses a large economic burden to society and significant personal distress to the individual and their family (Volkow et al., 2011). Limited treatment options are available, and many are only effective in a subset of individuals. Thus, a critical step toward improving treatments for addiction is to clarify the neurobiological mechanisms of therapeutic interventions that are currently used or under investigation.
Addiction affects a distributed set of brain regions and neurotransmitter systems. Although different drugs of abuse have different mechanisms of action, they all increase dopamine release in what has traditionally been labeled as the brain's reward circuit to exert their reinforcing effects (Chen et al., 2010, Sulzer, 2011). Regions comprising this circuit include midbrain (ventral tegmental area and substantia nigra) and basal ganglia structures including the ventral (nucleus accumbens) and dorsal striatum. Chronic drug use modifies dopamine signaling in these regions, facilitating the transition from recreational to habitual use that characterizes addiction (Everitt and Robbins, 2005). These changes result in a state of impaired motivational drive and difficulty with inhibiting conditioned responses to drug-related cues, undermining more goal-directed behavior (Kalivas and Volkow, 2005). Following protracted use, exposure to drug-related cues activates the ventral striatum (among other regions like the cingulate cortices and amygdala) across substance addictions (Chase et al., 2011, Kuhn and Gallinat, 2011) in ways that may facilitate relapse to drug use (Grusser et al., 2004, Kosten et al., 2006). In addition to craving, the negative emotional state of withdrawal during periods of abstinence may also involve the reward circuit (Treadway and Zald, 2011), as well as the amygdala and autonomic structures (Koob and Volkow, 2010).
However, brain regions (and their corresponding functions) outside the reward system also appear affected by chronic drug use. In particular, drug addicted individuals exhibit alterations in the anterior cingulate, orbitofrontal, and dorsolateral prefrontal cortices, where abnormalities are linked to impaired emotion regulation and inhibitory control (Goldstein and Volkow, 2011). Thus, the ability of addicted individuals to achieve abstinence may be diminished both by pathologically strengthened drug-seeking behavior and impairments in the capacity to regulate such behavior (Everitt and Robbins, 2005, Kalivas, 2009). The effectiveness of therapeutic interventions may consequently depend on the ability of these interventions to target and normalize addiction-related deficits in reward regions to decrease motivation for drugs (e.g., craving and withdrawal) and in control regions to increase inhibitory control, respectively. Furthermore, while different drugs of abuse share common neurobiological substrates (e.g., in reward and cognitive control regions), differences also exist and these differences may have implications for addiction treatment. For example, the influence of contextual triggers on relapse to drug use, supported by the medial prefrontal cortex, appears to be more profoundly impacted by stimulant use than by opiate use (Badiani et al., 2011); similarly, visuospatial attention, supported by occipital, parietal, and medial temporal lobe regions, appears to be more profoundly impacted by alcohol use; impulsivity and cognitive flexibility, supported by the orbitofrontal cortex, striatum, and thalamus, by alcohol and stimulant use; and fluency and working memory, supported by inferior frontal and parietal regions, by opiate use than by use of other substances, respectively [for review, see (Crunelle et al., 2012, Fernandez-Serrano et al., 2011, van Holst and Schilt, 2011)]. Thus, therapeutic interventions for addiction may share a common neural mechanism across addictions, and/or a unique mechanism by specific addiction type.
A number of therapeutic interventions for addiction have been put forth and some have been tested in clinical trials with the goal of reducing the amount or frequency of drug use, or extending time to relapse. These interventions can be broadly divided into pharmacological and cognitive-based (psychosocial) strategies [for review, see (Potenza et al., 2011)]. Briefly, pharmacological interventions are proposed to primarily target the reward circuit and influence neural processes that mediate negative mood and craving. Most pharmacological interventions for addiction block or mimic the reinforcing effects of drugs (Potenza et al., 2011). For example, among others, studies have tested the efficacy of nicotinic receptor agonists (e.g., varenicline, nicotine patch) and antagonists (e.g., bupropion) for nicotine addiction (Cahill et al., 2010, Eisenberg et al., 2008), opioid receptor agonists (e.g., methadone, buprenorphine) and antagonists (e.g., naltrexone) for opioid (Johansson et al., 2006) and alcohol (Srisurapanont and Jarusuraisin, 2005) addiction, and dopamine and norepinephrine agonists (e.g., psychostimulants including modafinil and methylphenidate) for stimulant addictions (Anderson et al., 2009, Castells et al., 2010, Dackis et al., 2005, Dackis et al., 2012, Longo et al., 2010). Cognitive-based interventions are proposed to primarily target executive control processes dependent on the prefrontal cortex. These interventions aim to help addicted individuals recognize and implement strategies to change cognitions and behaviors associated with drug use, and to increase motivation for change (Carroll and Onken, 2005). Interventions that have been tested in their efficacy for motivating change include motivational interventions (e.g., smoking cessation messages), psychoeducation (e.g., health-related information), and contingency management (e.g., receiving monetary incentives) (Burke et al., 2003, Dutra et al., 2008). Interventions that provide strategies for change include cognitive behavioral therapy (CBT) and its active components (e.g., self-regulation strategies, exposure therapy) (Dutra et al., 2008, Magill and Ray, 2009). Interventions that motivate individuals to quit and remain abstinent after quitting may involve the reward circuit and regions such as the ventromedial prefrontal cortex, anterior and posterior cingulate cortex, and insula that are involved in delay discounting (Luhmann, 2009), or the drive for immediate at the expense of delayed yet larger rewards, and effort (Prevost et al., 2010, Treadway et al., 2012). Taken together, pharmacological interventions may primarily target brain reward regions, while cognitive-based interventions may target both reward and control regions.
Neuroimaging offers an opportunity to examine the neurobiological mechanisms through which treatments for addictions might exert their effects, which is of fundamental interest to both basic and clinical neuroscience. A focus on studies using functional neuroimaging is important because, given what is known about the brain changes accompanying addiction in humans, it provides an appropriate context for evaluating changes with treatment beyond what can be gleaned from self-report or behavior alone. Indeed, neural activity has been shown to be a good predictor of relapse following treatment [e.g., (Brewer et al., 2008, Grusser et al., 2004, Janes et al., 2010, Jia et al., 2011, Paulus et al., 2005)]. Here, we quantitatively summarize studies that evaluated the neural correlates of therapeutic interventions for addiction using activation likelihood estimation (ALE) meta-analysis (Eickhoff et al., 2009, Laird et al., 2005, Turkeltaub et al., 2002). Meta-analysis offers the chance to aggregate data across studies to identify the most reliable patterns. Such an analysis can provide a synthesized and unbiased account of the neural mechanisms of therapeutic interventions, further revealing novel information about specific coordinates (not just anatomical boundaries) of localization of effects and statistical significance (not just a qualitative evaluation of presence/absence) in the convergence across studies of these effects. Meta-analysis can also be used for comparisons which were not or could not be feasibly performed in a single study, such as a direct comparison between pharmacological and cognitive-based interventions, or of their effects in specific populations and experimental paradigms. We therefore first examined the neural correlates of all interventions versus a non-intervention comparison condition. Conjunction and difference contrasts were then used to identify the common and distinct neural correlates of pharmacological and cognitive-based interventions, respectively. Lastly, more exploratory analyses contrasted subgroups of studies based on study (single-dose versus repeated administration interventions and use of a drug-related versus non-drug related task) and sample (primary drug of use) characteristics.
Section snippets
Study selection
We searched Medline/Pubmed to identify relevant studies published between January 1, 2000 and July 31, 2013. In addition, several recently published reviews (Addolorato et al., 2012, Goldstein and Volkow, 2011, Newhouse et al., 2011, Potenza et al., 2011, Sharma and Brody, 2009, Sofuoglu, 2010, Spanagel and Vengeliene, 2012) and book chapters (Adinoff and Stein, 2011) were identified that specifically discussed the use of neuroimaging to evaluate therapeutic interventions for drug addiction.
Effects of any therapeutic intervention (all foci together)
Several networks of brain regions were identified in the analysis across all studies (Fig. 1, Table 2), that included regions involved in reward processing and associative learning [ventral striatum (caudate head), parahippocampal gyrus/amygdala, midbrain], executive functions (anterior cingulate cortex, superior and middle frontal gyrus), and sensory integration and attention (precuneus, cuneus/occipital lobe, cerebellum, thalamus). These results mostly held when the analysis was limited to
Discussion
Functional neuroimaging has informed much of what is known about neural abnormalities associated with human drug addiction. More recently, this tool has also allowed researchers to investigate whether and how these abnormalities can be targeted and potentially normalized by therapeutic interventions. Here, we used ALE meta-analysis to aggregate data across functional neuroimaging studies to examine the common and distinct neural targets of pharmacological and cognitive-based interventions for
Conclusion
In summary, our results provide novel, quantitative evidence that pharmacological and cognitive-based strategies target brain structures that are altered across substance addictions. In addition to common neural targets in the ventral striatum, inferior frontal gyrus, and orbitofrontal cortex, cognitive-based interventions were more likely to also target the anterior cingulate cortex, middle frontal gyrus, and precuneus/posterior cingulate cortex than pharmacological interventions. These
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
We would like to thank Brenda J. Anderson, Hoi-Chung Leung, and Christian C. Luhmann for their thoughtful comments on earlier versions of this manuscript. This manuscript was prepared in part with grant support from the National Institute on Drug Abuse (1R01DA023579 and R21DA034954 to R.Z.G. and 1F32DA030017-01 to S.J.M).
References (106)
- et al.
Modafinil for the treatment of cocaine dependence
Drug Alcohol Depend.
(2009) - et al.
Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction
Behav. Brain Res.
(2009) - et al.
Pretreatment brain activation during stroop task is associated with outcomes in cocaine-dependent patients
Biol. Psychiatry
(2008) - et al.
Smoking-induced change in intrasynaptic dopamine concentration: effect of treatment for Tobacco Dependence
Psychiatry Res.
(2010) - et al.
The neural basis of drug stimulus processing and craving: an activation likelihood estimation meta-analysis
Biol. Psychiatry
(2011) - et al.
Nicotine replacement in abstinent smokers improves cognitive withdrawal symptoms with modulation of resting brain network dynamics
NeuroImage
(2010) - et al.
Impulsivity, compulsivity, and top-down cognitive control
Neuron
(2011) - et al.
Neurobehavioral mechanisms of impulsivity: fronto-striatal systems and functional neurochemistry
Pharmacol., Biochem. Behav.
(2008) - et al.
The activation of attentional networks
NeuroImage
(2005) - et al.
What are the specific vs. generalized effects of drugs of abuse on neuropsychological performance?
Neurosci. Biobehav. Rev.
(2011)
Distribution of the dopamine innervation in the macaque and human thalamus
NeuroImage
Reduced grey matter in the posterior insula as a structural vulnerability or diathesis to addiction
Brain Res. Bull.
The neurocircuitry of impaired insight in drug addiction
Trends Cognit. Sci.
Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence
Biol. Psychiatry
An initial study of neural responses to monetary incentives as related to treatment outcome in cocaine dependence
Biol. Psychiatry
A double-blind, placebo-controlled trial of amantadine, propranolol, and their combination for the treatment of cocaine dependence in patients with severe cocaine withdrawal symptoms
Drug Alcohol Depend.
Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review
Neurosci. Biobehav. Rev.
Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients
Drug Alcohol Depend.
Neural correlates of hot and cold executive functions in polysubstance addiction: association between neuropsychological performance and resting brain metabolism as measured by positron emission tomography
Psychiatry Res.
Functional brain imaging of nicotinic effects on higher cognitive processes
Biochem. Pharmacol.
Neuroscience of behavioral and pharmacological treatments for addictions
Neuron
Neural substrates of cocaine-cue associations that trigger relapse
Eur. J. Pharmacol.
How addictive drugs disrupt presynaptic dopamine neurotransmission
Neuron
Reconsidering anhedonia in depression: lessons from translational neuroscience
Neurosci. Biobehav. Rev.
Meta-analysis of the functional neuroanatomy of single-word reading: method and validation
NeuroImage
Addiction: pulling at the neural threads of social behaviors
Neuron
Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation
Neuropsychopharmacol.: Off. Publ. Am. Coll. Neuropsychopharmacol.
Neuroimaging in Addiction
Methylphenidate normalizes resting-state brain dysfunction in boys with attention deficit hyperactivity disorder
Neuropsychopharmacology
Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial
JAMA: J. Am. Med. Assoc.
Opiate versus psychostimulant addiction: the differences do matter
Nat. Rev. Neurosci.
The orbitofrontal cortex, predicted value, and choice
Ann. N. Y. Acad. Sci.
The amygdala and reward
Nat. Rev. Neurosci.
The brain's default network: anatomy, function, and relevance to disease
Ann. N. Y. Acad. Sci.
The efficacy of motivational interviewing: a meta-analysis of controlled clinical trials
J. Consult. Clin. Psychol.
Nicotine receptor partial agonists for smoking cessation
Cochrane Database Syst. Rev.
Behavioral therapies for drug abuse
Am. J. Psychiatry
Efficacy of psychostimulant drugs for cocaine dependence
Cochrane Database Syst. Rev.
The precuneus: a review of its functional anatomy and behavioural correlates
Brain: J. Neurol.
Synaptic plasticity in the mesolimbic system: therapeutic implications for substance abuse
Ann. N. Y. Acad. Sci.
Effects of treatment for tobacco dependence on resting cerebral glucose metabolism
Neuropsychopharmacol.: Off. Publ. Am. College Neuropsychopharmacol.
Review. Context-induced relapse to drug seeking: a review
Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci.
Substrates of neuropsychological functioning in stimulant dependence: a review of functional neuroimaging research
Brain Behav.
A double-blind, placebo-controlled trial of modafinil for cocaine dependence
Neuropsychopharmacol.: Off. Publ. Am. College Neuropsychopharmacol.
A double-blind, placebo-controlled trial of modafinil for cocaine dependence
J. Subst. Abuse Treatment
Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement
Science
Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats
Proc. Natl. Acad. Sci. U. S. A.
Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats
J. Neurosci.: Off. J. Soc. Neurosci.
A meta-analytic review of psychosocial interventions for substance use disorders
Am. J. Psychiatry
Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty
Human Brain Mapp.
Cited by (61)
A review of functional brain differences predicting relapse in substance use disorder: Actionable targets for new methods of noninvasive brain stimulation
2022, Neuroscience and Biobehavioral ReviewsTime for a paradigm shift: The adolescent brain in addiction treatment
2022, NeuroImage: ClinicalEffects of 12-week aerobic exercise on cue-induced drug craving in methamphetamine-dependent patients and the moderation effect of working memory
2021, Mental Health and Physical ActivityDistinct patterns of prefrontal cortical disengagement during inhibitory control in addiction: A meta-analysis based on population characteristics
2021, Neuroscience and Biobehavioral Reviews