This figure shows the core clinical symptoms of drug addiction — intoxication, bingeing, withdrawal and craving — as behavioural manifestations of the impaired response inhibition and salience attribution (iRISA) syndrome. Drug self-administration may lead to intoxication, depending on the drug, amount and rate of use, and individual variables. Bingeing episodes develop with some drugs, such as crack cocaine, and drug use becomes compulsive — much more of the drug is consumed and for longer periods than intended — indicating reduced self-control. Other drugs (for example, nicotine and heroin) are associated with more regimented drug use. After discontinuation of excessive or repeated drug use, withdrawal symptoms develop, including lack of motivation, anhedonia, negative emotion and enhanced stress reactivity. Excessive craving or drug wanting, or other, more automatic processes such as attention bias and conditioned responses, can then pave the way to additional drug use even when the addicted individual is trying to abstain (see for clinical characteristics of addiction in the context of iRISA and the role of the PFC in addiction). Figure is modified, with permission, from © (2002) American Psychiatric Association.

The areas of activation (measured using MRI, positron emission tomography (PET) or single-photon emission computed tomography (SPECT)) () are plotted in stereotaxic space, shown rendered on the dorsal and ventral surfaces (top part) and the lateral and medial surfaces (middle part and bottom part, respectively) of the human brain. a | Activity changes related to neuropsychological features in addiction. Prefrontal cortex (PFC) areas show differences in activity between individuals with addiction and healthy controls during tasks involving attention and working memory (shown in green), decision making (shown in light blue), inhibitory control (shown in yellow), emotion and motivation (shown in red), and cue reactivity and drug administration (shown in orange). In addition, in some PFC areas activity correlates with task performance or drug use (shown in dark blue). b | Activity changes related to clinical features in addiction, including intoxication and bingeing (shown in red; drugs were used within 48 hours of the study), craving (shown in pink; drugs were used 1–2 weeks before the study) and withdrawal (shown in purple; drugs were used more than 3 weeks before the study). Areas that showed activation in studies in which the stage of addiction was not specified or could not be determined are also indicated (shown in brown). These are the same studies as those depicted in a. Studies were included only if x, y and z coordinates were provided and if these coordinates were within PFC grey matter; studies in which x, y and z coordinates could not be located or were incorrectly labelled were not included. All x, y and z coordinates were converted to Talairach space (using GingerAle, a Cross-platform Java application for Meta-Analysis) before plotting. The Multi-Level Kernel Density Analysis toolbox^, was used (see the University of Colorado CANLab software Web site; see also ).

A model of how interactions between prefrontal cortex (PFC) subregions may regulate cognitive, emotional and behavioural changes in addiction. The model shows how changes in the activity of PFC subregions in addicted individuals relate to core clinical symptoms of addiction — intoxication and bingeing, and withdrawal and craving — compared to PFC activity in healthy, non-addicted individuals or states. The model focuses particularly on inhibitory control and emotion regulation. The blue ovals represent dorsal PFC subregions (including the dorsolateral PFC (DLPFC), the dorsal anterior cingulate cortex (dACC) and the inferior frontal gyrus; see ) that are involved in higher-order control (‘cold’ processes). The red ovals represent ventral PFC subregions (the medial orbitofrontal cortex (mOFC), the ventromedial PFC and rostroventral ACC) that are involved in more automatic, emotion-related processes (‘hot’ processes). Drug-related neuropsychological functions (for example, incentive salience, drug wanting, attention bias and drug seeking) that are regulated by these subregions are represented by darker shades and non-drug related functions (for example, sustained effort) are represented by lighter shades. a | In the healthy state, non-drug related cognitive functions, emotions and behaviours predominate (shown by the large light-coloured ovals) and automatic responses (emotions and action tendencies that could lead to drug taking) are suppressed by input from the dorsal PFC (shown by the thick arrow). Thus, if a person in the healthy state is exposed to drugs, excessive or inappropriate drug-taking behaviour is prevented or stopped (‘Stop!’). b | During craving and withdrawal, drug-related cognitive functions, emotions and behaviours start to eclipse non-drug related functions, creating a conflict regarding drug taking (‘Stop?’). Decreased attention and/or value is assigned to non-drug related stimuli (shown by smaller light-shaded ovals), and this reduction is associated with reduced self-control and with anhedonia, stress reactivity and anxiety. There is also an increase (shown by the larger dark-shaded ovals) in drug-biased cognition and cue-induced craving and drug wanting. c | During intoxication and bingeing, higher-order non-drug related cognitive functions (shown by the small light blue oval) are suppressed by increased input (shown by the thick arrow) from the regions that regulate drug-related, ‘hot’ functions (large dark red oval). That is, there is decreased input from higher-order cognitive control areas (shown by the thin dashed arrow), and the ‘hot’ regions come to dominate the higher-order cognitive input. Thus, attention narrows to focus on drug-related cues over all other reinforcers, impulsivity increases and basic emotions — such as fear, anger or love — are unleashed, depending on the context and individual predispositions. The result is that automatic, stimulus-driven behaviours, such as compulsive drug consumption, aggression and promiscuity, predominate (‘Go!’). This model does not take into account the challenge of localizing PFC functions or the evidence that some addicted individuals use drugs to ‘self-medicate’ in an attempt to normalize PFC functions (although part a could represent an approximation of the normalized PFC functions in these individuals).

Methylphenidate enhances functional MRI cingulate responses and reduces commission errors on a salient (remunerated cue reactivity) cognitive task in individuals with cocaine addiction. a | An axial map of the cortical regions that showed enhanced responses to methylphenidate (MPH) compared to a placebo in cocaine-addicted individuals. These regions are the dorsal anterior cingulate cortex (dACC; Brodmann areas 24 and 32) and the rostroventromedial ACC (rvACC) extending to the medial orbitofrontal cortex (mOFC; Brodmann areas 10 and 32). The significance levels (T scores) of the activations are colour-coded (shown by the colour scale). b | Correlation between BOLD signal (presented as % signal change from placebo) in the rvACC extending to the mOFC (x = –9, y = 42, z = –6; Brodmann areas 10 and 32) during processing of drug-related words and accuracy on the fMRI task (both are delta scores: MPH minus placebo). The subjects are 13 individuals with cocaine use disorders and 14 healthy controls. Figure is reproduced, with permission, from © (2011) Macmillan Publishers Ltd. All rights reserved.