Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue

BACKGROUND: Interferon-alpha (IFN-alpha) is a key mediator of antiviral immune responses used clinically for hepatitis C treatment. Though effective, IFN-alpha induces marked behavioral changes that, when severe, can appear indistinguishable from major depression. Curiously, fatigue and motivational impairment evolve rapidly, suggesting acute engagement of immune-brain communicatory pathways, yet mood impairments typically emerge later, after weeks of treatment. Whether this reflects prolonged modulation of motivational processes underpinning fatigue or separate neurobiological mechanisms is currently unclear. METHODS: Here, we used quantitative magnetization transfer (qMT) imaging, an advanced microstructural neuroimaging technique sensitive to effects of inflammation, in a prospective study design to measure acute brain changes to IFN-alpha and relate these to later development of discrete behavioral changes. Twenty-three patients initiating IFN-alpha treatment for hepatitis C underwent qMT imaging and blood sampling at baseline and 4 hours after their first IFN-alpha injection. Comprehensive behavioral and psychological assessments were completed at both scanning sessions and at treatment weeks 4, 8, 12, and 24. RESULTS: IFN-alpha injection stimulated an acute inflammatory cytokine response and evoked fatigue that peaked between 4 and 12 weeks, preceding mood change by 4 weeks. In the brain, IFN-alpha induced an acute change in striatal microstructure that additionally predicted development of fatigue but not mood symptoms. CONCLUSIONS: Our findings highlight qMT as an in vivo biomarker of central effects of peripheral inflammation. We demonstrate exquisite sensitivity of the striatum to IFN-alpha, implicate striatal perturbation in IFN-alpha-induced fatigue, and dissociate this from mechanisms underlying IFN-alpha-induced mood symptoms, providing empirical support for distinct neural substrates mediating actions on motivation and mood.