Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration

Abstract

Context: Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function.

Objectives: To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior.

Design: Cross-sectional and longitudinal studies.

Setting: Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia.

Patients: Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment.

Main outcome measures: Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa-induced depression, anhedonia, fatigue, and neurotoxicity.

Results: Patients with HCV receiving interferon alfa for 4 to 6 weeks (n = 14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n = 14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n = 12) exhibited significantly increased 18F-dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration.

Conclusions: These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release.

Figure 1

Group differences in striatal responses to a hedonic reward task. Neural activation in the ventral striatum was assessed by blood oxygen level–dependent (BOLD) responses in the win-lose condition of a gambling task using functional magnetic resonance imaging. A, Right and left regions of interest (ROIs) (depicted here) reflect maximal activation in the groups combined, and the average percentage of BOLD signal change corresponding to the win-lose contrast across all ROI voxels (right, left, or bilateral) was used for group comparisons and correlations with behavioral end points. B, The interferon alfa treatment group (IFN) had significantly decreased activation in the right, left, and bilateral ventral striatal regions compared with the untreated control group (CTL) (P<.01 for all comparisons). The color bar ranges from t=0 to t=8, with a group activation threshold of P<.005 uncorrected and a cluster size k≥19 voxels (P<.05 corrected).

Figure 2

Relationship between activation in the ventral striatum and reduced motivation. Neural activation in the ventral striatum was assessed by blood oxygen level–dependent (BOLD) responses in the win-lose condition of a gambling task using functional magnetic resonance imaging in patients with hepatitis C virus receiving interferon alfa for 4 to 6 weeks (white dots) and those awaiting interferon alfa treatment (black dots). Significant correlations were found between ventral striatal activation and reduced motivation as measured by the Multidimensional Fatigue Inventory (MFI) (P <.001 in all cases).

Figure 3

Mean fluorodopa F 18 (¹⁸F-dopa) uptake before and after interferon alfa therapy. Patients with chronic hepatitis C virus were administered ¹⁸F-dopa followed by positron emission tomography before and after 4 to 6 weeks of interferon alfa treatment. Mean images from the sample as a whole before and during interferon alfa administration indicate significantly higher uptake of ¹⁸F-dopa in caudate and putamen during interferon alfa treatment. The color bar represents the range of uptake values (Ki [1/min]) from 0 to 0.02.

Figure 4

Fluorodopa F 18 (¹⁸F-dopa) uptake and effective dopamine turnover before (black dots) and during (white dots) interferon alfa therapy. Patients with chronic hepatitis C virus were administered ¹⁸F-dopa followed by positron emission tomography before (visit 1) and after 4 to 6 weeks of interferon alfa treatment (visit 2). A, The ¹⁸F-dopa uptake (Ki [1/min]) was measured using the Patlak method (see the “Methods” section) in putamen and caudate. Significant increases in ¹⁸F-dopa uptake were found during interferon alfa administration compared with baseline (putamen: P <.005 for all; caudate: P <.05 for all) (Table 3), B, Effective dopamine turnover (EDT) was calculated by the method of Sossi et al (see the “Methods” section) in putamen and caudate. Significant decreases in EDT were found during interferon alfa administration compared with baseline (putamen: P <.005 for all; caudate: P <.05 for all) (Table 3).