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

Abstract

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 0.5 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. Results There 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 ƞ 2 = 0.1). In the imaging results, there was a significant interaction of group by drug ( p = 0.013, partial ƞ 2 = 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 ƞ 2 = 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. Electronic supplementary material The online version of this article (10.1007/s00213-019-05292-2) contains supplementary material, which is available to authorized users.

An Experimental Medicine Investigation of the Effects of Subacute Pramipexole Treatment on Emotional Information Processing in Healthy Volunteers

“…The healthy volunteer assay we employed has been widely used, is well-validated, and has been shown to be sensitive to and specific for pharmacological manipulations using conventional antidepressants [ 15 ]. In contrast to previous studies on various cognitive effects of pramipexole (e.g., [ 13 , 35 , 36 , 37 , 38 , 39 , 40 ]), we used a subacute, rather than an acute dosing scheme including a comparatively high target dose. Compared to a single-dose challenge, subacute pramipexole treatment has higher clinical-ecological validity—especially considering that acute versus subacute dopaminergic challenges likely differ in their neuromolecular effects [ 8 , 10 , 16 , 41 , 42 ].…”

Social Cognition and Obsessive-Compulsive Disorder: A Review of Subdomains of Social Functioning

“…Other studies using probabilistic learning tasks have demonstrated increased prediction error-related activation in the ACC (122,127) and right putamen (122) during the omission of expected reward, while the unexpected receipt of reward has been associated with increased activity in the nucleus accumbens of patients (127). Studies on performance monitoring in OCD patients have also consistently shown enhanced amplitudes of the ERN during the commission of errors [see (13)], which may also be considered as aversive, negative stimuli or events.…”

Computational Predictions for OCD Pathophysiology and Treatment: A Review

“…In addition, a pharmacological fMRI study of RL has shown an abnormally increased signaling of prediction errors in the anterior ACC. This effect was reduced by both a D 2/3 agonist and an antagonist (30). Modeling results did not demonstrate the same effects but did show a marginally significant reduction in prediction error learning rates in OCD patients (30).…”

“…This effect was reduced by both a D 2/3 agonist and an antagonist (30). Modeling results did not demonstrate the same effects but did show a marginally significant reduction in prediction error learning rates in OCD patients (30).…”

“…Abnormally strong cingulate signaling was measured using fMRI during reward processing with OCD patients. Bidirectional re-mediation by dopaminergic modulation suggests that exaggerated cingulate error signals in OCD may be of dopaminergic origin (30).…”