Impaired reward prediction error encoding and striatal-midbrain connectivity in depression

Abstract

Anhedonia (hyposensitivity to rewards) and negative bias (hypersensitivity to punishments) are core features of major depressive disorder (MDD), which could stem from abnormal reinforcement learning. Emerging evidence highlights blunted reward learning and reward prediction error (RPE) signaling in the striatum in MDD, although inconsistencies exist. Preclinical studies have clarified that ventral tegmental area (VTA) neurons encode RPE and habenular neurons encode punishment prediction error (PPE), which are then transmitted to the striatum and cortex to guide goal-directed behavior. However, few studies have probed striatal activation, and functional connectivity between VTA-striatum and VTA-habenula during reward and punishment learning respectively, in unmedicated MDD. To fill this gap, we acquired fMRI data from 25 unmedicated MDD and 26 healthy individuals during a monetary instrumental learning task and utilized a computational modeling approach to characterize underlying neural correlates of RPE and PPE. Relative to controls, MDD individuals showed impaired reward learning, blunted RPE signal in the striatum and overall reduced VTA-striatal connectivity to feedback. Critically, striatal RPE signal was increasingly blunted with more major depressive episodes (MDEs). No group differences emerged in PPE signals in the habenula and VTA or in connectivity between these regions. However, PPE signals in the habenula correlated positively with number of MDEs. These results highlight impaired reward learning, disrupted RPE signaling in the striatum (particularly among individuals with more lifetime MDEs) as well as reduced VTA-striatal connectivity in MDD. Collectively, these findings highlight reward-related learning deficits in MDD and their underlying pathophysiology.

Impaired Social Learning Predicts Reduced Real-life Motivation in Individuals with Depression: A Computational fMRI Study

“…Additionally, a range of studies have reported alterations in non-social learning in MDD. For instance, using decision-making tasks, it has been observed that depressed subjects display impaired reward learning (Blanco et al, 2013;Cooper et al, 2014;Herzallah et al, 2013;Kumar et al, 2018;Kunisato et al, 2012;Maddox et al, 2012;Pechtel et al, 2013;Robinson et al, 2012), while their punishment learning is either enhanced Maddox et al, 2012) or unchanged (Herzallah et al, 2013;Kumar et al, 2018;Kunisato et al, 2012;Robinson et al, 2012), when compared to controls.…”

Impact of pubertal timing and depression on error‐related brain activity in anxious youth

“…Conversely, it is possible that an enhanced ERN may protect early maturing anxious youth from developing depression. For instance, enhanced neural activity supporting the monitoring and salience of one’s performance could be an adaptive and compensatory response to the tendency of depressed individuals to exhibit reduced sensitivity to reward and reinforcement (Kumar et al, 2018). Future longitudinal designs would help to further unpack the emergence of internalizing symptom dimensions in relation to the neural changes occurring across the transition from pre- to post-pubertal status and in relation to the timing of when this transition occurs.…”

Family History of Depression is Associated with Alterations in Task-Dependent Connectivity between the Cerebellum and Ventromedial Prefrontal Cortex

“…In conjunction with structural changes, MDD appears to produce functional aberrations in systems associated with reward processing. Evidence of differences in activation and connectivity in healthy individuals relative to those with MDD typically implicate the OFC (Cheng et al, 2018;Ng et al, 2019), the ventral striatum (VS; Furman et al, 2011;Kumar et al, 2018;Robinson et al, 2012), and the vmPFC (Koenigs et al, 2008;Myers-Schulz & Koenigs, 2012). Together, this work suggests that we may be able to understand some of the canonical symptoms seen in MDD symptomatology by taking a closer look at the neural correlates that underlie them.…”