The loss of control over drug intake that occurs in addiction was initially believed to result from disruption of subcortical reward circuits. However, imaging studies in addictive behaviours have identified a key involvement of the prefrontal cortex (PFC) both through its regulation of limbic reward regions and its involvement in higher-order executive function (for example, self-control, salience attribution and awareness). This Review focuses on functional neuroimaging studies conducted in the past decade that have expanded our understanding of the involvement of the PFC in drug addiction. Disruption of the PFC in addiction underlies not only compulsive drug taking but also accounts for the disadvantageous behaviours that are associated with addiction and the erosion of free will.
Neuroimaging studies have revealed an emerging pattern of generalized prefrontal cortex (PFC) dysfunction in drug-addicted individuals that is associated with worse outcome — more drug use, worse PFC-related task performance and greater likelihood of relapse.
Widespread PFC activation in drug-addicted individuals upon taking cocaine or other drugs and upon presentation of drug-related cues is replaced by widespread PFC hypoactivity during exposure to higher-order emotional and cognitive challenges and/or during protracted withdrawal when not stimulated.
The nature of the findings in PFC is different when abusers are studied during intoxication or craving and when they are studied during acute or protracted withdrawal, and this is to be expected considering the distinct role of the PFC in these processes.
PFC regions may be implicated in what seem to be opposite processes. This may reflect the limited temporal resolution of imaging technologies or methodological variability. Processes also reflect the function of networks rather than isolated regions, so that the output of a region will differ as it connects with different networks.
Although activity among PFC regions is highly integrated and flexible, such that any one region is involved in multiple functions, the dorsal PFC (including the dorsal anterior cingulate cortex, dorsolateral PFC and inferior frontal gyrus) has been predominantly implicated in top-down control and meta-cognitive functions (including awareness), the ventromedial PFC (including subgenual ACC and medial orbitofrontal cortex) in emotion regulation (including conditioning and assigning incentive salience to drugs and drug-related cues), and the ventrolateral PFC and lateral OFC in automatic response tendencies (for example, drug-related attention bias) and impulsivity.
Dysfunction of these PFC regions may contribute to impaired response inhibition and salience attribution (iRISA) in addiction, neuropsychological mechanisms that underlie the development of craving, compulsive use and impaired self-awareness (previously labelled 'denial' of illness and/or need for treatment), which are characteristic symptoms of drug addiction.
PFC dysfunction may in some instances precede drug use and confer vulnerability for (or protection against) developing substance use disorders.
Specific biomarkers could be targeted for intervention purposes. For example, PFC abnormalities could be used to identify the children and adolescents who would benefit most from intensive drug abuse prevention efforts.
The combination of targeted pharmacological interventions (for example, to enhance dopaminergic neurotransmission) with cognitive–behavioural exercises (for example, to enhance inhibitory control and non drug-related motivation, and reduce drug-related attention bias) could normalize select PFC functions. Ameliorating these deficits could help addicted subjects to engage in rehabilitation treatment.
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This study was supported by grants from the US National Institute on Drug Abuse (R01DA023579 to R.Z.G.), the Intramural NIAAA program and the Department of Energy, Office of Biological and Environmental Research (for infrastructure support). We are grateful for A. B. Konova's contribution to the design of figure 2. We are indebted to our reviewers whose comments were greatly appreciated and guided our revision of the original manuscript.
The authors declare no competing financial interests.
This table is a summary of the fMRI and PET studies in drug-addicted individuals vs. healthy control subjects conducted during 2000–2010 (articles published in 2011 have not been methodically reviewed), which were used to create (PDF 286 kb)
Functional neuroimaging studies (conducted during 2000–2010) comparing PFC activity during direct drug administration in addicted individuals and healthy controls. (PDF 218 kb)
Functional neuroimaging studies (conducted during 2000–2010) comparing brain activity during cue exposure in addicted individuals (S) and healthy controls (C) (PDF 235 kb)
Functional neuroimaging studies (conducted during 2000–2010) studying effects of abstinence and self-regulation on PFC activity. (PDF 215 kb)
Functional neuroimaging studies (conducted during 2000–2010) comparing PFC activity in addicted individuals (S) and healthy controls (C) during performance of selected emotion tasks. (PDF 247 kb)
Functional neuroimaging studies (conducted during 2000–2010) comparing PFC activity in addicted individuals (S) and healthy controls (C) during performance of inhibitory control tasks. (PDF 242 kb)
Functional neuroimaging studies (conducted during 2000–2010) comparing neurotransmitter systems in individuals with addiction (S) and healthy controls (C). (PDF 238 kb)
Recent neuroimaging studies of PFC activity in drug-addicted individuals. (PDF 3543 kb)
- 18Fluorodyoxyglucose PET
(18F-PET). Positron emission tomography (PET) with a radioligand to image regional glucose uptake, a measure of metabolic activity that can also be used to assess global brain function.
(MPH). A mild stimulant (approved for treatment of attention deficit hyperactivity disorder) with similar pharmacological effects to cocaine (it blocks the dopamine transporter) but with lower abuse potential owing to slower rates of clearance from the synapse.
- Non-contingent administration
Administration of a certain drug that is not dependent on the subject's behaviour.
- Fixed-rate self-administration
Self-administration of a certain drug on a ratio between drug delivery and behaviour that is fixed by an experimenter (for example, after emission of a certain number of responses or after a certain time has elapsed following the previous response).
- Arterial spin labelling
(Also known as arterial spin tagging). An MRI technique that is capable of measuring cerebral blood flow in vivo. It provides cerebral perfusion maps without requiring the administration of a contrast agent or the use of ionizing radiation, as it uses magnetically labelled endogenous blood water as a freely diffusible tracer.
- Masked cue
A cue that is presented below conscious processing level (that is, outside of conscious awareness). This is usually achieved with a very short duration of cue presentation followed by presentation of another cue that is consciously perceived (longer duration).
An NMDA receptor antagonist primarily used for the induction and maintenance of general anaesthesia. In addition, it can induce analgesia, elevated blood pressure and hallucinations, and it has been used as a recreational drug.
A positron emission tomography (PET) receptor radioligand that competes with endogenous opiates for binding to the mu opiate receptor.
- Affect matching
A neuropsychological test in which images of faces are matched based on their emotional facial expressions. This task can be used to assess impairments in emotional (or social) processing.
- Go/no-go task
A neuropsychological task that is commonly used to assess inhibitory control. Subjects are required to press a button when one stimulus type appears and withhold a response when another stimulus type appears.
- Stop signal reaction time task
(SSRT). A neuropsychological test that measures the ability to stop a response that has already been initiated. It is used clinically as an index of inhibitory control. Slower SSRT is associated with disruption of executive functions.
- Errors of omission and commission
Errors on a go/no-go task: a subject had to go but they did not go (omission of a response) or had to withhold a response but pressed a button instead (commission of an unnecessary response). The former is an index of inattentiveness while the latter is an index of impulsive (premature) responding.
- Stroop task
A neuropsychological task in which conflict is created between an automatic response (for example, reading) and a slower response (for example, colour naming), with both competing for the same processing resources. Impaired performance on Stroop tasks is associated with prefrontal cortex dysfunction.
A state of deficiency in understanding, processing or describing emotions, including the difficulty in identifying and/or describing one's own feelings and externally oriented thinking.
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