Neuropsychobiological Fingerprints of Chronic Fatigue in Sarcoidosis

Sarah Kettenbach, Sina Radke, Tobias Müller, Ute Habel, Michael Dreher, Sarah Kettenbach, Sina Radke, Tobias Müller, Ute Habel, Michael Dreher

Abstract

Background: Chronic fatigue is a prominent symptom in many sarcoidosis patients, affecting quality of life and interfering with treatment. This study investigated neuropsychobiological mechanisms and markers of chronic fatigue in sarcoidosis.

Methods: Thirty patients with a histological diagnosis of sarcoidosis were included. The Multidimensional Fatigue Inventory was used to define patients with and without chronic fatigue. All patients were then characterised using several depression, quality of life questionnaires, and executive functioning. Cognitive functioning and underlying neural correlates were assessed using an n-back task measuring working memory and (sustained) attention during functional magnetic resonance imaging. Sarcoidosis disease activity was determined using lung function, laboratory parameters, and exercise capacity.

Results: Nineteen patients had chronic fatigue and 11 did not; both groups had similar demographic and disease activity characteristics. Chronic fatigue patients showed more symptoms of depression and anxiety, and lower quality of life. During the n-back task, chronic fatigue was associated with a smaller increase in brain activation with increasing task difficulty versus the group without fatigue, especially in the angular gyrus.

Conclusion: Inadequate adjustment of brain activation with increasing demands appears to be a potential neurobiological marker of chronic fatigue in sarcoidosis patients. The angular gyrus, which plays an important role in the working memory system, was the major area in which fatigue patients showed smaller increase of brain activation compared to those without fatigue. These findings might be relevant for a deeper understanding of chronic fatigue mechanisms in sarcoidosis and future clinical treatment of this disabling syndrome.

Trial registration: ClinicalTrials.gov, Trial registration number: NCT04178239Date of registration: November 26, 2019, retrospectively registeredURL: https://ichgcp.net/clinical-trials-registry/NCT04178239.

Keywords: angular gyrus; chronic fatigue; functional magnetic resonance imaging; rare lung diseases; sarcoidosis.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Kettenbach, Radke, Müller, Habel and Dreher.

Figures

FIGURE 1
FIGURE 1
n-back task. Targets of each condition of the n-back task are circled. The 0-back, 1-back, and 2-back conditions were repeated five times, alternating with the baseline condition. For 0-back, a response on a certain target letter is required (button press for X); for 1-back, the response is required for a repetition of a target letter (e.g., second F); for 2-back, the response has to be on the last but one repetition of the target letter (e.g., L, J, L; response to the L).
FIGURE 2
FIGURE 2
Study flow chart. MFI: Multidimensional Fatigue Inventory; MRI: magnetic resonance imaging.
FIGURE 3
FIGURE 3
Hit rates and response times in n-back task. Hit rates (in proportions) (A) and response times (in milliseconds) (B) on the n-back task in sarcoidosis patients with versus without chronic fatigue presented as box–whisker plots. Horizontal lines denote (from bottom to top) minimum, third quartile, median, first quartile, and maximum. Crosses indicate arithmetic means; points denote statistical outliers.
FIGURE 4
FIGURE 4
Brain activation corresponding to the main effect of condition in n-back task: 2-back > 0-back. Highlighted areas are those that demonstrate more activation in the cognitively more challenging 2-back condition versus the cognitively less challenging 0-back condition.
FIGURE 5
FIGURE 5
Interactions for fatigue > no fatigue in n-back task. Highlighted areas show brain regions that show more activation in the chronic fatigue (CF) versus no chronic fatigue (NCF) group in the contrasts 0-back > 2-back (A) and 0-back > 1-back (B). Box–whisker plots show brain activation of the major cluster’s maximum voxel in arbitrary units. Horizontal lines denote (from bottom to top) minimum, third quartile, median, first quartile, and maximum. Crosses indicate arithmetic means; points denote statistical outliers.

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