Dopaminergic drug treatment remediates exaggerated cingulate prediction error responses in obsessive-compulsive disorder

Craig, Kevin 
Abbot, Sanja 

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Rationale: Patients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function. Objective: In this study we investigate potential dopaminergic dysfunction during reward processing in the context of OCD. Methods: We studied OCD patients (n=18) and controls (n=18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of: a dopamine receptor agonist, pramipexole 0.5mg; a dopamine receptor antagonist, amisulpride 400mg, and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest. Results: There were no significant group, drug or interaction effects in number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p=0.089, partial ƞ2=0.1). In the imaging results, there was a significant interaction of group by drug (p=0.013, partial ƞ2=0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p=0.014, partial ƞ2=0.26, 1-β error probability=0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD. Conclusions Our data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.

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Amisulpride, Anterior cingulate, Computational model, Nucleus accumbens, Obsessive-compulsive disorder, Pramipexole, Prediction error, Reward learning, Adult, Dopamine, Dopamine Agonists, Dopamine Antagonists, Double-Blind Method, Female, Forecasting, Gyrus Cinguli, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Nucleus Accumbens, Obsessive-Compulsive Disorder, Photic Stimulation, Reward
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Springer Verlag
Medical Research Council (G1000183)
Medical Research Council (G0001354)
Medical Research Council (G0701911)
Wellcome Trust (093875/Z/10/Z)
Wellcome Trust (104631/Z/14/Z)
Supported by an award from GSK to University of Cambridge (RG45422, Principal Investigator TWR), a Wellcome Trust Senior Investigator Award (104631/Z/14/Z) to TWR, by a MRC Clinician Scientist award (G0701911) to GKM, and by a Betty Behrens Research Fellowship of Clare Hall to KDE. The research was conducted in the University of Cambridge Behavioural and Clinical Neuroscience Institute which was supported by a joint award from the Medical Research Council (G1000183) and Wellcome Trust (093875/Z/10Z)