Fatigue and salivary cortisol in relapsing-remitting multiple sclerosis: an investigation in everyday life

Multiple sclerosis (MS) is a chronic autoimmune disease characterised by inflammatory attacks on the central nervous system. Fatigue is a common symptom in MS, yet its aetiology, exacerbating factors, and manifestation in everyday life are unclear. Given its role in regulating inflammation, energy metabolism and stress responses, cortisol is a relevant psychobiological target for MS fatigue research. The primary aims of this thesis were to examine diurnal fatigue patterns and contextual effects of daily stressors and mood in people with relapsing-remitting MS (RRMS); explore cortisol secretory activity in RRMS in everyday life; and investigate associations of cortisol with fatigue at baseline and change in fatigue 6 months later. Data were collected in an ecological momentary assessment study incorporating repeated real-time selfreports and salivary cortisol assessments over 4 consecutive weekdays in an RRMS group (n = 38) and healthy control group (n = 38), matched for age and sex.Statistical analysis was predominantly by multilevel modelling. The analysis presented in the first empirical chapter (Chapter 3) demonstrated that RRMS fatigue typically follows an increasing (but decelerating) within-day fatigue trajectory, distinct from linear trajectories in controls. Fatigue was sensitive to stressor and mood fluctuations within-subjects in both groups. The analysis presented in the second empirical chapter (Chapter 4) described larger cortisol awakening responses in RRMS compared to controls, but similar diurnal cortisol slopes. Cortisol reactivity to daily life stressors was apparent in both groups, mediated by self-reported distress. A systematic review was conducted (presented in Chapter 5) showing attenuated diurnal cortisol variability is most-frequently associated with fatigue across clinical populations; cortisol output appeared less relevant. However, the analysis presented in the final empirical chapter (Chapter 6) showed greater cortisol variability in the morning (larger cortisol responses to awakening) was associated with RRMS fatigue. Flatter diurnal cortisol slopes were associated with fatigue in controls. Chronic stress and depressive symptoms did not moderate associations, and there was no relationship between cortisol and change in fatigue 6 months later in either group. The original research presented confirms MS fatigue is not a stable symptom experience in everyday life, is sensitive to psychosocial contextual factors, and is associated with cortisol, potentially via pro-inflammatory immune mediators