Fatigue and brain arousal in patients with major depressive disorder.

Fatigue is considered a key symptom of major depressive disorder (MDD), yet the term lacks specificity. It can denote a state of increased sleepiness and lack of drive (i.e., downregulated arousal) as well as a state of high inner tension and inhibition of drive with long sleep onset latencies (i.e., upregulated arousal), the latter typically found in depression. It has been proposed to differentiate fatigue along the dimension of brain arousal. We investigated whether such stratification within a group of MDD patients would reveal a subgroup with distinct clinical features. Using an automatic classification of EEG vigilance stages, an arousal stability score was calculated for 15-min resting EEGs of 102 MDD patients with fatigue. 23.5% of the patients showed signs of hypoarousal with EEG patterns indicating drowsiness or sleep; this hypoaroused subgroup was compared with remaining patients (non-hypoaroused subgroup) concerning self-rated measures of depressive symptoms, sleepiness, and sleep. The hypoaroused subgroup scored higher on the Beck Depression Inventory items "loss of energy" (Z = - 2.13, p = 0.033; ɳ2 = 0.044, 90% CI 0.003-0.128) and "concentration difficulty" (Z = - 2.40, p = 0.017; ɳ2 = 0.056, 90% CI 0.009-0.139), and reported higher trait and state sleepiness (p < 0.05) as compared to the non-hypoaroused group. The non-hypoaroused subgroup, in contrast, reported more frequently the presence of suicidal ideation (Chi2 = 3.81, p = 0.051; ɳ2 = 0.037, 90% CI 0.0008-0.126). In this study, we found some evidence that stratifying fatigued MDD patients by arousal may lead to subgroups that are pathophysiologically and clinically more homogeneous. Brain arousal may be a worth while target in clinical research for better understanding the mechanisms underlying suicidal tendencies and to improve treatment response.

Corrigendum to "EEG revealed improved vigilance regulation after stress exposure under Nx4 - A randomized, placebo-controlled, double-blind, cross-over trial" [IBRO Neurosci. Rep. 11C (2021) 175-182].

[This corrects the article DOI: 10.1016/j.ibneur.2021.09.002.].

EEG revealed improved vigilance regulation after stress exposure under Nx4 - A randomized, placebo-controlled, double-blind, cross-over trial.

OBJECTIVES: Vigilance is characterized by alertness and sustained attention. The hyper-vigilance states are indicators of stress experience in the resting brain. Neurexan (Nx4) has been shown to modulate the neuroendocrine stress response. Here, we hypothesized that the intake of Nx4 would alter brain vigilance states at rest. METHOD: In this post-hoc analysis of the NEURIM study, EEG recordings of three, 12 min resting-state conditions in 39 healthy male volunteers were examined in a randomized, placebo-controlled, double-blind, cross-over clinical trial. EEG was recorded at three resting-state sessions: at baseline (RS0), after single-dose treatment with Nx4 or placebo (RS1), and subsequently after a psychosocial stress task (RS2). During each resting-state session, each 2-s segment of the consecutive EEG epochs was classified into one of seven different brain states along a wake-sleep continuum using the VIGALL 2.1 algorithm. RESULTS: In the post-stress resting-state, subjects exhibited a hyper-stable vigilance regulation characterized by an increase in the mean vigilance level and by more rigidity in the higher vigilance states for a longer period of time. Importantly, Nx4-treated participants exhibited significantly lower mean vigilance level compared to placebo-treated ones. Also, Nx4- compared to placebo-treated participants spent comparably less time in higher vigilance states and more time in lower vigilance states in the post-stress resting-state. CONCLUSION: Study participants showed a significantly lower mean vigilance level in the post-stress resting-state condition and tended to stay longer in lower vigilance states after treatment with Nx4. These findings support the known stress attenuation effect of Nx4.

Fatigue in Cancer and Neuroinflammatory and Autoimmune Disease: CNS Arousal Matters.

The term fatigue is not only used to describe a sleepy state with a lack of drive, as observed in patients with chronic physical illnesses, but also a state with an inhibition of drive and central nervous system (CNS) hyperarousal, as frequently observed in patients with major depression. An electroencephalogram (EEG)-based algorithm has been developed to objectively assess CNS arousal and to disentangle these pathophysiologically heterogeneous forms of fatigue. The aim of this study was to test the hypothesis that fatigued patients with CNS hyperarousal score higher on depressive symptoms than those without this neurophysiological pattern. METHODS: Subjects with fatigue (Multidimensional Fatigue Inventory sum-score > 40) in the context of cancer, neuroinflammatory, or autoimmune diseases were drawn from the 60+ cohort of the Leipzig Research Center for Civilization Diseases. CNS arousal was assessed by automatic EEG-vigilance stage classification using the Vigilance Algorithm Leipzig (VIGALL 2.1) based on 20 min EEG recordings at rest with eyes closed. Depression was assessed by the Inventory of Depressive Symptomatology (IDS-SR). RESULTS: Sixty participants (33 female; median age: 67.5 years) were included in the analysis. As hypothesized, fatigued patients with CNS hyperarousal had higher IDS-SR scores than those without hyperarousal (F1,58 = 18.34; p < 0.0001, η2 = 0.240). CONCLUSION: hyperaroused fatigue in patients with chronic physical illness may be a sign of comorbid depression.

Exposure to attachment narratives dynamically modulates cortical arousal during the resting state in the listener.

BACKGROUND: Affective stimulation entails changes in brain network patterns at rest, but it is unknown whether exogenous emotional stimulation has a prolonged effect on the temporal dynamics of endogenous cortical arousal. We therefore investigated differences in cortical arousal in the listener following stimulation with different attachment-related narratives. METHODS: Resting-state EEG was recorded from sixteen healthy subjects for ten minutes each with eyes closed: first at baseline and then after passively listening to three affective narratives from strangers about their early childhood experiences (prototypical for insecure-dismissing, insecure-preoccupied, and secure attachment). Using the VIGALL 2.1 algorithm, low or high vigilance stages in consecutive EEG segments were classified, and their dynamic profile was analyzed. Questionnaires assessed the listeners' emotional response to the content of the narrative. RESULTS: As a general effect of preceding affective stimulation, vigilance following the stimulation was significantly elevated compared to baseline rest, and carryover effects in dynamic vigilance profiles were observed. A difference between narrative conditions was revealed for the insecure-dismissing condition, in which the decrease in duration of high vigilance stages was fastest compared to the other two conditions. The behavioral data supported the observation that especially the insecure narratives induced a tendency in the listener to affectively disengage from the narrative content. DISCUSSION: This study revealed carryover effects in endogenous cortical arousal evoked by preceding affective stimulation and provides evidence for attachment-specific dynamic alterations of brain states and individual differences in emotional reactivity.

Coupling and dynamics of cortical and autonomic signals are linked to central inhibition during the wake-sleep transition.

Maintaining temporal coordination across physiological systems is crucial at the wake-sleep transition. As shown in recent studies, the degree of coordination between brain and autonomic arousal influences attention, which highlights a previously unrecognised point of potential failure in the attention system. To investigate how cortical and autonomic dynamics are linked to the attentive process we analysed electroencephalogram, electrocardiogram and skin conductance data of 39 healthy adults recorded during a 2-h resting-state oddball experiment. We related cross-correlations to fluctuation periods of cortical and autonomic signals and correlated obtained measures to event-related potentials N1 and P2, reflecting excitatory and inhibitory processes. Increasing alignment of cortical and autonomic signals and longer periods of vigilance fluctuations corresponded to a larger and earlier P2; no such relations were found for N1. We compared two groups, with (I) and without measurable (II) delay in cortico-autonomic correlations. Individuals in Group II had more stable vigilance fluctuations, larger and earlier P2 and fell asleep more frequently than individuals in Group I. Our results support the hypothesis of a link between cortico-autonomic coupling and dynamics and central inhibition. Quantifying this link could help refine classification in psychiatric disorders with attention and sleep-related symptoms, particularly in ADHD, depression, and insomnia.

CNS- and ANS-arousal predict response to antidepressant medication: Findings from the randomized iSPOT-D study.

Arousal systems are one of the recently announced NIMH Research Domain Criteria to inform future diagnostics and treatment prediction. In major depressive disorder (MDD), altered central nervous system (CNS) wakefulness regulation and an increased sympathetic autonomic nervous system (ANS) activity have been identified as biomarkers with possible discriminative value for prediction of antidepressant treatment response. Therefore, the hypothesis of a more pronounced decline of CNS and ANS-arousal being predictive for a positive treatment outcome to selective-serotonin-reuptake-inhibitor (SSRI) treatment was derived from a small, independent exploratory dataset (N = 25) and replicated using data from the randomized international Study to Predict Optimized Treatment Response in Depression (iSPOT-D). There, 1008 MDD participants were randomized to either a SSRI (escitalopram or sertraline) or a serotonin-norepinephrine-reuptake-inhibitor (SNRI-venlafaxine) arm. Treatment response was established after eight weeks using the 17-item Hamilton Rating Scale for Depression. CNS-arousal (i.e. electroencephalogram-vigilance), ANS-arousal (heart rate) and their change across time were assessed during rest. Responders and remitters to SSRI treatment were characterized by a faster decline of CNS-arousal during rest whereas SNRI responders showed a significant increase of ANS-arousal. Furthermore, SSRI responders/remitters showed an association between ANS- and CNS-arousal regulation in comparison to non-responders/non-remitters while this was not the case for SNRI treatment arm. Since positive treatment outcome to SSRI and SNRI was linked to distinct CNS and ANS-arousal profiles, these predictive markers probably are not disorder specific alterations but reflect the responsiveness of the nervous system to specific drugs.