Development of Persistent Fatigue Following Moderate and Severe Traumatic Brain Injury - Exploration of General and Injury-specific Mechanisms.

1.0. Fatigue following Traumatic Brain Injury (TBI) - definitions, measurement and prevalence.

Fatigue has been defined as "the awareness of a decreased capacity for physical and/or mental activity due to an imbalance in the availability, utilization and/or restoration of resources needed to perform an activity". TBI represents "an alteration in brain function, or other evidence of brain pathology, caused by an external force", and is among the most severe, disabling neurological disorders, with post-TBI fatigue (PTBIF) being one of the most common and debilitating chronic symptoms, regardless of injury severity. A challenge in studying PTBIF is related to difficulties in operationalization and assessment. Estimates of PTBIF rates thus vary from 21% to 73% due to heterogeneity of study populations, assessment strategies and study designs, e.g. time since injury, sampling of patients and fatigue measures employed. The numbers however typically by far exceed rates of fatigue in the general population, with one Norwegian study estimating 23%. Although numerous measures of fatigue exist, there is a lack of "gold standard" tools. Self-report instruments, VAS-scales and single item questionnaires are most common, and the Fatigue Severity Scale (FSS) has been documented to have good psychometric properties. There is however considerable overlap between measures of fatigue and other symptoms such as sleepiness, depression, and distress, resulting in less than optimal construct validity. Most studies of fatigue after TBI have furthermore used cross-sectional designs. Although very limited longitudinal data is available, there is some evidence to suggest that PTBIF levels may decline over the first 6 to 12 months post-injury, but remain steady or rise slightly thereafter. A recent study identified fatigue as the most common somatic complaint five years after TBI, affecting more than half of the patients. In summary, despite study variability, fatigue is a common and often chronic symptom after TBI. However, little longitudinal work has investigated individual variability in patterns of fatigue, rendering a lack of knowledge regarding sub-groups and clinical trajectories.

1.1. Contributing factors and theoretical accounts of PTBIF. Fatigue following TBI may be caused directly by the nervous system injury, i.e., primary fatigue, which is associated with deficits in cerebral networks mediating attention, arousal, and response speed (reticular activating system, limbic system, anterior cingulate, mid frontal, and basal ganglia). Primary fatigue may in turn be exacerbated by common symptoms after TBI, such as insomnia, pain, emotional distress, and reduced tolerance for physical and/or mental activity, i.e. secondary fatigue. Additional physical causes of PTBIF have also been noted, such as increased body mass index (BMI) leading to deconditioning, reduced physical activity and posttraumatic pituitary hormone deficiencies. Of notice, PTBIF does not seem to be related to the severity of injury as assessed by the Glasgow Coma Scale (GCS) or duration of post-traumatic amnesia (PTA). Ponsford et al. (2014) tested a model of the interrelationships between fatigue and daytime sleepiness, vigilance (i.e., sustained attention), anxiety, and depression after TBI. The findings indicated that fatigue after TBI is the precursor of anxiety, depression, and daytime sleepiness, and that fatigue exacerbates cognitive problems. However, this model needs to be replicated, as factors such as pre-and comorbid risk factors, premorbid fatigue, and personality were not included in the model, and the study used a cross-sectional design. The "coping hypothesis" put forward by van Zomeren and colleagues (1984) proposes that cognitive impairment, particularly reduced processing speed and attention, leads to a compensatory increase in brain activity and effort, which in turn results in fatigue. Some studies support this hypothesis, as increased brain (functional MRI) and autonomic reactivity (i.e., heart rate variability) was seen during cognitive effort in individuals with TBI compared to normal controls. Individuals with TBI have also been shown to experience greater fatigue while performing cognitive tasks requiring divided attention or other demanding cognitive processes. In their cost-benefit model, Boksem & Tops (2008) propose a theoretical framework emphasizing the role of automatic attributions of costs and benefits of mental and physical effort and rest in contributing to experienced fatigue. Mediated by dopaminergic structures, with medial frontal cortices playing a central role, it is proposed that heightened sensitivity to the short-term rewards of resting, in combination with a decreased sensitivity to the delayed rewards of long term goals, may lead to decreased intrinsic motivation to exert energy. Reward-related behavior is proposed to be associated with three factors; positive emotion towards the reward, a motivation to act in order to achieve it, and a capacity for learning stimulus-reward contingencies. An inverse relationship between self-reported reward sensitivity and fatigue has been reported in persons with Multiple Sclerosis, but no studies have explored the role of reward sensitivity PTBIF, despite the fact that both positive emotionality, motivated behavior and learning of reward contingencies are at risk of being affected by injury.

1.2. Risk factors for fatigue in the general population. In the general population, associations with fatigue have been found with demographic variables such as gender and educational level. Personality factors, such as neuroticism, have been linked to fatigue. Being high on neuroticism and perfectionism, and low on extraversion, constitute risk factors for experiencing exertion and fatigue, while extraverted people seem to be protected against high fatigue. Neuroticism might also moderate the role of catastrophizing cognitions and emotional distress on fatigue severity. Recent studies have also demonstrated that optimal levels of conscientiousness are related to a broad range of favorable health related behaviors and health outcomes, even including longevity. To our knowledge, conscientiousness, and personality in general, has not been much investigated in the context of PTBIF, nor in twin studies of fatigue. Emotional distress, anxiety and depression are commonly associated with fatigue, and may serve as both predisposing and perpetuating factors. Similarly, musculoskeletal pain, mood and sleep disturbances are associated with experienced fatigue in community dwelling adults.

In summary, there is reason to believe that individuals with TBI will be predisposed or vulnerable to develop PTBIF to variable degrees, as pre- and comorbid characteristics may act as both risk- and protective factors. Surprisingly, individual and general risk factors that may potentially contribute or even account for PTBIF, have not been extensively studied in populations with brain injury. Personality traits have been reported to be significant in mediating outcome following TBI, but the relationship between personality traits and persistent PTBIF has not previously been investigated.