Inflammation-Induced Anhedonia: Endotoxin Reduces Ventral Striatum Responses to Reward

Abstract

Background Although inflammatory activity is known to play a role in depression, no work has examined whether experimentally induced systemic inflammation alters neural activity that is associated with anhedonia, a key diagnostic symptom of depression. To investigate this, we examined the effect of an experimental inflammatory challenge on the neural correlates of anhedonia—namely, reduced ventral striatum (VS) activity to reward cues. We also examined whether this altered neural activity related to inflammatory-induced increases in depressed mood. Methods Participants (n = 39) were randomly assigned to receive either placebo or low-dose endotoxin, which increases proinflammatory cytokine levels in a safe manner. Cytokine levels were repeatedly assessed through hourly blood draws; self-reported and observer-rated depressed mood were assessed regularly as well. Two hours after drug administration, neural activity was recorded as participants completed a task in which they anticipated monetary rewards. Results Results demonstrated that subjects exposed to endotoxin, compared with placebo, showed greater increases in self-reported and observer-rated depressed mood over time, as well as significant reductions in VS activity to monetary reward cues. Moreover, the relationship between exposure to inflammatory challenge and increases in observer-rated depressed mood was mediated by between-group differences in VS activity to anticipated reward. Conclusions The data reported here show, for the first time, that inflammation alters reward-related neural responding in humans and that these reward-related neural responses mediate the effects of inflammation on depressed mood. As such, these findings have implications for understanding risk of depression in persons with underlying inflammation.

In Sickness and in Health: The Co-Regulation of Inflammation and Social Behavior

“…This figure comes from a prior study (Inagaki et al, 2012) and shows amygdala activity (average of left and right sides) in response to viewing social and non-social, threatening and non-threatening images, displayed separately for endotoxin and placebo subjects. characterized by anhedonia or an inability to experience reward and (2) leads to a reduction in reward-related neural reactivity to monetary rewards (Eisenberger et al, 2010a). Although it seems logical to assume that inflammation would reduce reward-related neural reactivity to various types of positive experiences, a different picture emerges when we focus on positive social experiences.…”

Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?

“…For example, peripheral administration of LPS decreases verbal and nonverbal memory in humans (Reichenberg et al, 2001). Peripheral administration of different pro-inflammatory mediators reduces ventral striatum responses to reward (Capuron et al, 2012;Eisenberger et al, 2010). Peripheral administration of LPS potentiates amygdala activity in response to socially threatening stimuli (fear faces) (Inagaki et al, 2012), and typhoid vaccine reduces the connectivity of the subgenual anterior cingulate cortex (sACC) with the amygdala and increases the activity within the sACC during emotional face processing (Harrison et al, 2009; Box 2).…”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…More recent studies have used functional magnetic resonance imaging (fMRI) to further characterize the effects of inflammatory stimuli on the basal ganglia. The data indicate that administration of inflammatory cytokines (ie, IFN-α) or inducers of the inflammatory response (eg, typhoid vaccination or endotoxin) lead to decreased neural activity in basal ganglia nuclei, specifically the ventral striatum (nucleus accumbens), in response to reward anticipation or feedback (Brydon et al, 2008;Harrison et al, 2015a, b;Eisenberger et al, 2010a;Capuron et al, 2012;Dowell et al, 2015). Studies have also indicated that not only is neural activity reduced in response to these reward-based tasks, but also there is an increased response to aversive stimuli (ie, loss) (Harrison et al, 2015b).…”

“…Studies have also indicated that not only is neural activity reduced in response to these reward-based tasks, but also there is an increased response to aversive stimuli (ie, loss) (Harrison et al, 2015b). The reduced ventral striatal response to both IFN-α and endotoxin were correlated with depressive symptoms including anhedonia and fatigue as well as acute alterations in striatal microstructure as assessed by quantitative magnetization transfer (qMT) imaging (Eisenberger et al, 2010a;Capuron et al, 2012;Dowell et al, 2015). Of note, administration of typhoid vaccination has also been associated with alterations in neural activity in the substantia nigra (another basal ganglia nuclei) that was correlated with IL-6 and psychomotor slowing (Brydon et al, 2008).…”

“…Studies using IFN-α, typhoid vaccination, and endotoxin in humans have all identified motivational circuits and symptoms of anhedonia as being primary targets of inflammatory stimuli on the brain and behavior (Brydon et al, 2008;Harrison et al, 2009aHarrison et al, , b, 2015aEisenberger et al, 2010a;Capuron et al, 2012;Dowell et al, 2015). In addition, studies in patients with depression have also indicated strong relationships between peripheral inflammatory markers (eg, CRP) and changes in reward circuitry as well as alterations in glutamate metabolism in the basal ganglia, both of which were associated with symptoms of anhedonia Felger et al, 2016).…”