Impact of Serum Cytokine Levels on EEG-Measured Arousal Regulation in Patients with Major Depressive Disorder and Healthy Controls

Abstract

Background: In major depressive disorder (MDD), findings include hyperstable regulation of brain arousal measured by electroencephalography (EEG) vigilance analysis and alterations in serum levels of cytokines. It is also known that cytokines affect sleep-wake regulation. This study investigated the relationship between cytokines and EEG vigilance in participants with MDD and nondepressed controls, and the influence of cytokines on differences in vigilance between the two groups. Methods: In 60 patients with MDD and 129 controls, 15-min resting-state EEG recordings were performed and vigilance was automatically assessed with the VIGALL 2.0 (Vigilance Algorithm Leipzig). Serum levels of the wakefulness-promoting cytokines interleukin (IL)-4, IL-10, IL-13 and somnogenic cytokines tumor necrosis factor-α, interferon-γ and IL-2 were measured prior to the EEG. Results: Summed wakefulness-promoting cytokines, but not somnogenic cytokines, were significantly associated with the time course of EEG vigilance in the MDD group only. In both groups, IL-13 was significantly associated with the course of EEG vigilance. In MDD compared to controls, a hyperstable EEG vigilance regulation was found, significant for group and group × time course interaction. After controlling for wakefulness-promoting cytokines, differences in vigilance regulation between groups remained significant. Conclusions: The present study demonstrated a relationship between wakefulness-promoting cytokines and objectively measured EEG vigilance as an indicator for brain arousal. Altered brain arousal regulation in MDD gives support for future evaluation of vigilance measures as a biomarker in MDD. Since interactions between cytokines and EEG vigilance only moderately differed between the groups and cytokine levels could not explain the group differences in EEG vigilance regulation, cytokines and brain arousal regulation are likely to be associated with MDD in independent ways.

Brain arousal regulation as response predictor for antidepressant therapy in major depression

“…In line with previous reports2425, the total group of MD patients showed a higher brain arousal level when compared with the healthy controls. Splitting groups according to the therapeutic response, differences were found in the subgroup of responders to AD only.…”

“…Splitting groups according to the therapeutic response, differences were found in the subgroup of responders to AD only. Extending the previous cross-sectional investigations2425, this raises the question whether or not upregulated arousal regulation separates a core group of depressed patients responding to AD from atypical depression with hypersomnia or fatigue. The latter often show signs of a downregulated arousal regulation and might respond to psychostimulants4344.…”

“…Such differences in EEG-vigilance regulation were observed in previous studies comparing patients with MD, mania and healthy subjects242542. This feature may be present amongst different entities of affective disorders but presumably may not be of enough penetrance to differ between sub-groups (responders vs. non-responders) within a sample of subjects suffering from the same disorder.…”

“…Also, it remains unclear if a recording period of two minutes is long enough to draw final conclusions on arousal parameters, as our exploratory analyses of a median vigilance index within three 1-min blocks to compare with the iSPOT-findings could not reveal any relation between response and the arousal regulation or level. Or if decisive information may be lost due to too short recording periods, as other studies2425 showed differences between groups to be enhanced in the later course of the recordings.…”

“…An EEG-based algorithm, the Vigilance Algorithm Leipzig (VIGALL), validated with simultaneous PET-22 and fMRI-analyses23, can be used for the objective classification of EEG-vigilances stages. Whereas healthy subjects usually show declines of their arousal level during a 15 minutes resting-EEG with appearance of drowsiness pattern or sometimes even signs of sleep onset, it is a replicated finding that patients with MD in comparison show a tonically high level and more stable regulation of arousal over the whole recording period2425. Within the arousal regulation model of affective disorders21, a variety of clinical and preclinical arguments have been presented indicating that the upregulation of arousal is a central pathogenic factor in MD.…”