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. 2016 Feb 15;79(4):320-8.
doi: 10.1016/j.biopsych.2015.05.015. Epub 2015 Jun 4.

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

Free PMC article

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

Nicholas G Dowell et al. Biol Psychiatry. .
Free PMC article


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.

Keywords: Depression; Fatigue; Imaging; Inflammation; Insula; Interferon; Striatum.


Figure 1
Figure 1
Cytokine response to interferon (IFN)-alpha injection. Mean plasma cytokine concentrations before (Base) and 4 hours after the first subcutaneous injection of pegylated interferon-α-2a. Error bars represent standard error of the mean. IL1, interleukin-1; IL1Ra, interleukin-1 receptor antagonist; IL6, interleukin-6; IL10, interleukin-10; n.s., nonsignificant; TNF, tumor necrosis factor.
Figure 2
Figure 2
Interferon-alpha (IFN-α)-induced changes in fatigue and mood. (A) Change in global fatigue (fatigue visual analog scale [fVAS]) and fatigue subcomponents of tiredness and vigor (Profile of Mood States [POMS] subscales) and sleepiness (Epworth Sleepiness Scale [ESS]) during the 24 weeks of treatment with INF-α. (B) Change in depression (Hamilton Depression Rating Scale [HAMD]) and state anxiety (State and Trait Anxiety Inventory [STAI]) during the 24 weeks of treatment with INF-α. Base denotes baseline scores. Error bars show the standard error. Stars denote associated p values: *p < .05, **p < .01, ***p < .005, ****p < .001. Numbers below denote associated effect sizes (η2).
Figure 3
Figure 3
Interferon-alpha-induced changes in quantitative magnetization transfer parameters. Changes in quantitative magnetization transfer parameters kf and T2f 4 hours after commencing interferon-alpha-based treatment compared with baseline. Voxels showing a significant increase in forward exchange rate constant (kf) are shown in yellow and voxels showing a significant decrease in T2 of free water component (T2f) are shown in cyan. (A) Whole brain analysis showing the left striatal clusters surviving stringent familywise error correction at p < .05. (B) A priori region of interest analysis showing changes in kf and T2f for all voxels within the striatal region of interest at p < .05.
Figure 4
Figure 4
Left side shows voxels where acute changes in T2f significantly predict the increase in fatigue at 4 weeks and the right side voxels where acute changes in kf significantly predict the increase in fatigue at 4 weeks. Slices illustrate changes across the whole of the ventral striatum region of interest (from posterior to anterior). Blue to light blue denotes negative correlation and red to yellow positive correlation with associated t-scores denoting equivalent p values (p = .05 to p = .0004).

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