Preclinical studies have suggested that continuous, long-term opiate exposure may be neurotoxic. There is accumulating evidence for neural and neuropsychological abnormalities in diverse human drug addiction populations. However, the structural and behavioural correlates of human opiate dependency have been less studied than other drugs.

We investigated brain structure and neuropsychological functioning in opiate dependent, treatment-seeking patients receiving Methadone Maintenance Treatment, to test hypotheses of regional grey matter reductions correlating with methadone exposure and neuropsychological measures.

Cambridge Gambling Task (CGT) data were acquired from 47 patients receiving MMT and 51 controls. T1 weighted Magnetic Resonance Images were acquired from a representative subset of these volunteers.

MMT patients exhibited grey matter reductions in the orbito-medial prefrontal cortex and basal ganglia. Additionally, patients exhibited significant abnormalities on CGT behavioural measures; risk adjustment, risk taking and impulsivity. Both the initial titration dose of methadone at the commencement of MMT following protocolised tolerance testing, and methadone dose at the time of scanning, correlated with grey matter reductions in the globus pallidus. Abnormal risk adjustment behaviour correlated with reductions in globus pallidus grey matter, increased risk taking with orbitofrontal grey matter reductions, and increased impulsivity with cingulate cortex reductions.

These findings support an interpretation of heightened risk taking and impulsivity in patients receiving MMT. However, the anatomically restricted correlates with indices of methadone exposure suggest that most structural brain abnormalities are not opiate linked, with the possible exception of the globus pallidus.

Preclinical studies have suggested that continuous, long-term opiate exposure may be neurotoxic. There is accumulating evidence for neural and neuropsychological abnormalities in diverse human drug addiction populations. However, the structural and behavioural correlates of human opiate dependency have been less studied than other drugs.

We investigated brain structure and neuropsychological functioning in opiate dependent, treatment-seeking patients receiving Methadone Maintenance Treatment, to test hypotheses of regional grey matter reductions correlating with methadone exposure and neuropsychological measures.

Cambridge Gambling Task (CGT) data were acquired from 47 patients receiving MMT and 51 controls. T1 weighted Magnetic Resonance Images were acquired from a representative subset of these volunteers.

MMT patients exhibited grey matter reductions in the orbito-medial prefrontal cortex and basal ganglia. Additionally, patients exhibited significant abnormalities on CGT behavioural measures; risk adjustment, risk taking and impulsivity. Both the initial titration dose of methadone at the commencement of MMT following protocolised tolerance testing, and methadone dose at the time of scanning, correlated with grey matter reductions in the globus pallidus. Abnormal risk adjustment behaviour correlated with reductions in globus pallidus grey matter, increased risk taking with orbitofrontal grey matter reductions, and increased impulsivity with cingulate cortex reductions.

These findings support an interpretation of heightened risk taking and impulsivity in patients receiving MMT. However, the anatomically restricted correlates with indices of methadone exposure suggest that most structural brain abnormalities are not opiate linked, with the possible exception of the globus pallidus.

Depression is a disabling disorder that significantly impacts on the interpersonal functioning of individuals. However, little is known about the neural substrates of such difficulties. In the last few years neuroeconomics, which combines imaging with multiplayer behavioural economic paradigms, has been used to study the neural substrates of normal and abnormal interpersonal interactions.

This study used functional magnetic resonance imaging to investigate neural activity in unmedicated depressed participants (n = 25) and matched healthy controls (n = 25). During scanning, participants played a behavioural economic game, the Prisoner's Dilemma. In this game, the participant and a co-player independently choose either to cooperate or not cooperate with each other.

Depressed participants reported higher levels of negative feelings (betrayal, guilt) during the game than did controls. Neural activation was compared between ‘imbalanced’ events [when one of the players cooperated and the other defected (‘CD’ and ‘DC’)] and ‘draw’ events [when both players either cooperated or defected (‘CC’ and ‘DD’)]. Participants preferentially activated the anterior insula and the dorsolateral prefrontal cortex (DLPFC), a region implicated in cognitive control and regulation of emotions. Importantly, compared to controls depressed participants showed reduced activation in the left DLPFC, with the extent of signal reduction correlating with increased self-report feelings of guilt associated with DC outcomes.

Our findings suggest that depression is associated with reduced activation of the DLPFC during social events that involve unreciprocated cooperation. This abnormality may underlie anomalies in cognitive control and top-down regulation of emotions during challenging social exchanges.

Depression is a prevalent disorder that significantly affects the social functioning and interpersonal relationships of individuals. This highlights the need for investigation of the neural mechanisms underlying these social difficulties. Investigation of social exchanges has traditionally been challenging as such interactions are difficult to quantify. Recently, however, neuroeconomic approaches that combine multiplayer behavioural economic paradigms and neuroimaging have provided a framework to operationalize and quantify the study of social interactions and the associated neural substrates.

We investigated brain activation using functional magnetic resonance imaging (fMRI) in unmedicated depressed participants (n = 25) and matched healthy controls (n = 25). During scanning, participants played a behavioural economic paradigm, the Ultimatum Game (UG). In this task, participants accept or reject monetary offers from other players.

In comparison to controls, depressed participants reported decreased levels of happiness in response to ‘fair’ offers. With increasing fairness of offers, controls activated the nucleus accumbens and the dorsal caudate, regions that have been reported to process social information and responses to rewards. By contrast, participants with depression failed to activate these regions with increasing fairness, with the lack of nucleus accumbens activation correlating with increased anhedonia symptoms. Depressed participants also showed a diminished response to increasing unfairness of offers in the medial occipital lobe.

Our findings suggest that depressed individuals differ from healthy controls in the neural substrates involved with processing social information. In depression, the nucleus accumbens and dorsal caudate may underlie abnormalities in processing information linked to the fairness and rewarding aspects of other people's decisions.