Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression

Abstract

Depression is associated with alterations in corticostriatal reward circuitry. One pathophysiological pathway that may drive these changes is inflammation. Biomarkers of inflammation (for example, cytokines and C-reactive protein (CRP)) are reliably elevated in depressed patients. Moreover, administration of inflammatory stimuli reduces neural activity and dopamine release in reward-related brain regions in association with reduced motivation and anhedonia. Accordingly, we examined whether increased inflammation in depression affects corticostriatal reward circuitry to lead to deficits in motivation and goal-directed motor behavior. Resting-state functional magnetic resonance imaging was conducted on 48 medically stable, unmedicated outpatients with major depression. Whole-brain, voxel-wise functional connectivity was examined as a function of CRP using seeds for subdivisions of the ventral and dorsal striatum associated with motivation and motor control. Increased CRP was associated with decreased connectivity between ventral striatum and ventromedial prefrontal cortex (vmPFC) (corrected P<0.05), which in turn correlated with increased anhedonia (R=-0.47, P=0.001). Increased CRP similarly predicted decreased dorsal striatal to vmPFC and presupplementary motor area connectivity, which correlated with decreased motor speed (R=0.31 to 0.45, P<0.05) and increased psychomotor slowing (R=-0.35, P=0.015). Of note, mediation analyses revealed that these effects of CRP on connectivity mediated significant relationships between CRP and anhedonia and motor slowing. Finally, connectivity between striatum and vmPFC was associated with increased plasma interleukin (IL)-6, IL-1beta and IL-1 receptor antagonist (R=-0.33 to -0.36, P<0.05). These findings suggest that decreased corticostriatal connectivity may serve as a target for anti-inflammatory or pro-dopaminergic treatment strategies to improve motivational and motor deficits in patients with increased inflammation, including depression.