Abnormal temporal difference reward-learning signals in major depression

Abstract

Anhedonia is a core symptom of major depressive disorder (MDD), long thought to be associated with reduced dopaminergic function. However, most antidepressants do not act directly on the dopamine system and all antidepressants have a delayed full therapeutic effect. Recently, it has been proposed that antidepressants fail to alter dopamine function in antidepressant unresponsive MDD. There is compelling evidence that dopamine neurons code a specific phasic (short duration) reward-learning signal, described by temporal difference (TD) theory. There is no current evidence for other neurons coding a TD reward-learning signal, although such evidence may be found in time. The neuronal substrates of the TD signal were not explored in this study. Phasic signals are believed to have quite different properties to tonic (long duration) signals. No studies have investigated phasic reward-learning signals in MDD. Therefore, adults with MDD receiving long-term antidepressant medication, and comparison controls both unmedicated and acutely medicated with the antidepressant citalopram, were scanned using fMRI during a reward-learning task. Three hypotheses were tested: first, patients with MDD have blunted TD reward-learning signals; second, controls given an antidepressant acutely have blunted TD reward-learning signals; third, the extent of alteration in TD signals in major depression correlates with illness severity ratings. The results supported the hypotheses. Patients with MDD had significantly reduced reward-learning signals in many non-brainstem regions: ventral striatum (VS), rostral and dorsal anterior cingulate, retrosplenial cortex (RC), midbrain and hippocampus. However, the TD signal was increased in the brainstem of patients. As predicted, acute antidepressant administration to controls was associated with a blunted TD signal, and the brainstem TD signal was not increased by acute citalopram administration. In a number of regions, the magnitude of the abnormal signals in MDD correlated with illness severity ratings. The findings highlight the importance of phasic reward-learning signals, and are consistent with the hypothesis that antidepressants fail to normalize reward-learning function in antidepressant-unresponsive MDD. Whilst there is evidence that some antidepressants acutely suppress dopamine function, the long-term action of virtually all antidepressants is enhanced dopamine agonist responsiveness. This distinction might help to elucidate the delayed action of antidepressants. Finally, analogous to recent work in schizophrenia, the finding of abnormal phasic reward-learning signals in MDD implies that an integrated understanding of symptoms and treatment mechanisms is possible, spanning physiology, phenomenology and pharmacology.

Regret and the negative evaluation of decision outcomes in major depression

“…A number of neuroimaging experiments have been designed to evaluate the fundamental aspects of reward and punishment processing. Reduced neural activation elicited by rewards in regions of the medial frontal cortex and striatum has been observed (Knutson et al, 2008;Kumar et al, 2008;Pizzagalli et al, 2009). Consistent with a negative bias, enhanced punishment or loss-related activity has also often been observed, particularly in studies employing event-related potentials (e.g., Chiu & Deldin, 2007;Holmes & Pizzagalli, 2008), but equally so has been attenuated loss-related activity (Steele et al, 2007).…”

Anorexia Nervosa and Obesity are Associated with Opposite Brain Reward Response

“…Some other studies investigated the dopamine model-related brain response in psychiatric disorders, such as depression (Kumar et al, 2008) or schizophrenia (Waltz et al, 2010), and tended to find reduced brain response in those disorders. Dopamine neuronal reward response can be captured in an algorithm that takes advantage of dopamine neurons responding to unexpected reward stimulus receipt or omission (Schultz, 2002).…”

Resting-State Connectivity Predictors of Response to Psychotherapy in Major Depressive Disorder

“…MDD is characterized by impaired cortico-limbic functioning, including dysfunction in (1) the cortical brain regions that mediate attention, reward-based decision making, and monitoring of emotional salience (Ressler and Mayberg, 2007;Seminowicz et al, 2004); (2) the subcortical brain regions that process affective stimuli (Kumar et al, 2008;Pizzagalli et al, 2009) and that modulate emotional memory formation and retrieval (Dillon et al, 2013); and (3) the coordinated interactions of distributed networks of limbiccortical pathways during processing of cognitive and affective information (Drevets et al, 2008;Northoff et al, 2011). Neuroimaging treatment outcome research has shown that MDD remission is associated with decreased activity in orbitofrontal and medial prefrontal cortex Kennedy et al, 2007), increased activity in hippocampus and dorsal cingulate cortex , and increased subcortical circuits involved in responses to rewards Stoy et al, 2012) and emotion regulation (Ressler and Mayberg, 2007).…”