New insights on the multidimensionality of fatigue and on its relationship with cognitive impairments in multiple sclerosis

Multiple Sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), and it represents the most common cause of irreversible impairment in young adults, affecting about 2.5 million individuals worldwide. In MS, acute attacks of inflammation, leading to demyelination and axonal loss, determine the accumulation of disabilities, varying in number, nature, and severity. Indeed, motor, sensory, cognitive, and behavioral symptoms may manifest at different times during the disease's variable clinical course. Fatigue is a complex and multifaceted phenomenon and one of the most prevalent and disabling symptoms of MS, affecting 75%–90% of patients. Despite its prevalence, MS- related fatigue is still poorly understood. The absence of a well-validated definition and of clear insights into its pathophysiological causes makes fatigue a hybrid symptom, approached within the context of different disciplines, each with their own methods and tools. As a result, the scientific literature abounds with irreconcilable data, leaving fatigue in a dark shadow zone, at the expense of MS patients still lacking adequate therapies and strategies of management. The main topic of this thesis relates to the multidimensional nature of fatigue, to its variability, and its effects on attentional processes, most commonly affected in MS patients. Specifically, studies presented in the current thesis address four research issues: (i) are physical and mental fatigue two distinct constructs? (ii) how do physical and mental fatigue vary within a short (within a day) and long (within a year) period? (iii) how do induced physical and mental fatigue impact the attentional functions of alerting, orienting, and conflict resolution in MS? The main results of the studies are reported: a) A clear distinction between physical and mental fatigue has been psychometrically documented in MS patients. b) MS patients reported experiencing more overall fatigue than Controls. c) A gradual increase in overall fatigue from the morning to the evening was reported by MS participants. d) Across experiments physical fatigue was significantly more pronounced in MS patients as compared to Controls. e) Both MS patients and Controls reported having experienced more overall fatigue in the past (one year ago) than in the present (the last 24 hours). f) MS patients were slower as compared to Controls in performing attentional tasks; however, inconclusive results have emerged regarding the effects of physical and mental fatigue on attentional processes. g) Sleep quality and depression were both associated with fatigue across the experiments. The relationship between self-efficacy, general cognitive functioning, functional deterioration, and physical and mental fatigue is fragmented, thus preventing a clear conclusion