Abstract
RationalePatients 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.ObjectiveIn this study, we investigate potential dopaminergic dysfunction during reward processing in the context of OCD.MethodsWe 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 0.5 mg; a dopamine receptor antagonist, amisulpride 400 mg; 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.ResultsThere were no significant group, drug, or interaction effects in the 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.ConclusionsOur 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.
Highlights
Obsessive-compulsive disorder (OCD) has been associated with deficits in learning and decision making (Gillan and Robbins 2014; Nielen et al 2009)
Bonferroni corrected post hoc tests revealed that participants independently of group reacted to the reward trials significantly slower under pramipexole (845.29 ms ± 29.22) compared with placebo (770.93 ms ± 23.66; p = 0.016), or amisulpride (757.86 ms ± 26.41; p = 0.002)
There were no correlations between placebo COPE values in the nucleus accumbens and rating scales (Y-BOCS, selfregulation including subscales, all p > 0.5). In this pharmacological fMRI study of reinforcement learning, we found that OCD patients exhibited abnormally increased signaling of prediction errors to omitted rewards in the anterior cingulate cortex under placebo treatment, which was reduced by acute dopaminergic drug treatment using either pramipexole or amisulpride
Summary
Obsessive-compulsive disorder (OCD) has been associated with deficits in learning and decision making (Gillan and Robbins 2014; Nielen et al 2009). Neural mechanisms underlying decision making and learning involve fronto-striatal networks generating reward prediction errors which are highly sensitive to dopaminergic modulation (Frank et al 2004; Kehagia et al 2010; Schultz and Dickinson 2000). Studies in healthy human volunteers have shown dopaminergic modulation of the brain response to a reward prediction error response using fMRI (Bernacer et al 2013; Eisenegger et al 2014; Pessiglione et al 2006). Evidence from human molecular imaging studies of patients with OCD suggests a possible role for dopaminergic pathology in OCD (Denys et al 2004; Hesse et al 2005; Moresco et al 2007; Olver et al 2009, 2010; Perani et al 2008; Sesia et al 2013; Van Der Wee et al 2004). Whilst dopaminergic medications are not first-line treatments for OCD, dopamine receptor antagonists are often used to augment first-line treatment in refractory cases (Hirschtritt et al 2017) and the efficacy of this strategy is confirmed by meta-analyses (Dold et al 2015; Veale et al 2014)
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