title: Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue.
abstract: BACKGROUND
  Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used clinically for hepatitis C treatment. Though effective, IFN-α 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-α and relate these to later development of discrete behavioral changes. Twenty-three patients initiating IFN-α treatment for hepatitis C underwent qMT imaging and blood sampling at baseline and 4 hours after their first IFN-α injection. Comprehensive behavioral and psychological assessments were completed at both scanning sessions and at treatment weeks 4, 8, 12, and 24.
  
  
  RESULTS
  IFN-α 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-α 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-α, implicate striatal perturbation in IFN-α-induced fatigue, and dissociate this from mechanisms underlying IFN-α-induced mood symptoms, providing empirical support for distinct neural substrates mediating actions on motivation and mood.
authors.affiliation: Brighton and Sussex Medical School, University of Sussex.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Dowell
authors.affiliation: Brighton and Sussex Medical School, University of Sussex; Department of Gastroenterology, Brighton & Sussex University Hospitals, Brighton.
authors.forename: Ella A
authors.initials: EA
authors.lastname: Cooper
authors.affiliation: Department of Gastroenterology, Brighton & Sussex University Hospitals, Brighton.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tibble
authors.affiliation: Department of Psychiatry, University of Cambridge; Cambridge and Peterborough National Health Service Foundation Trust, Cambridge.
authors.forename: Valerie
authors.initials: V
authors.lastname: Voon
authors.affiliation: Brighton and Sussex Medical School, University of Sussex; Sackler Centre for Consciousness Science, University of Sussex, Falmer; Sussex Partnership National Health Service Trust, Brighton, United Kingdom.
authors.forename: Hugo D
authors.initials: HD
authors.lastname: Critchley
authors.affiliation: Brighton and Sussex Medical School, University of Sussex; Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Cercignani
authors.affiliation: Brighton and Sussex Medical School, University of Sussex; Sackler Centre for Consciousness Science, University of Sussex, Falmer; Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy. Electronic address: n.harrison@bsms.ac.uk.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Harrison
mesh_terms: D000328:Adult; D000339:Affect / Q000187:drug effects; D000998:Antiviral Agents / Q000009:adverse effects*; D000067290:Behavior Rating Scale; D016207:Cytokines / Q000187:drug effects; D003863:Depression / Q000139:chemically induced*; D005221:Fatigue / Q000139:chemically induced*; D005260:Female; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017072:Neostriatum / Q000187:drug effects*; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha
keywords: Depression; Fatigue; Imaging; Inflammation; Insula; Interferon; Striatum