Fatigue Following Moderate and Severe TBI
Condition: Traumatic Brain Injury; Fatigue
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Fatigue
Study type: Observational

Summary: 
      The subjective feeling of being periodically fatigued, tired, even exhausted is common in the
      general population, as well as in a large number of medical conditions, including
      neurological illness, such as traumatic brain injury (TBI), cerebrovascular accidents (CVA),
      multiple sclerosis (MS), and poliomyelitis. Fatigue typically results in compensatory
      behaviors such as spending extended time in bed, daytime napping, and restricted
      participation in activities of daily living, which in turn can have a profound negative
      impact on mental and physical health. Although fatigue is common and debilitating, there is a
      scarcity of knowledge concerning underlying biological, psychological and psychosocial
      mechanisms in the development and maintenance of persisting fatigue. There is also a general
      lack of theoretical accounts of potentially shared and etiology-specific mechanisms across
      conditions. The existence of clinical subgroups and diverse clinical trajectories is not well
      documented, resulting in a lack of evidence-based treatment opportunities. Diagnosis and
      management of fatigue is further challenged by difficulties in conceptualizing and defining
      the phenomenon itself, since fatigue is subjectively experienced and multifaceted. Thus, as
      fatigue often poses a chronic problem, health professionals in community based rehabilitation
      settings are faced with helping patients cope with this symptom without a clear understanding
      of causes or treatment options. The current project aims to map the occurrence of fatigue
      following moderate to severe TBI and achieve a better theoretical and clinical understanding
      of the mechanisms which may cause, exacerbate or protect against persisting fatigue following
      TBI. The study approach acknowledges that fatigue after neurological illness is the result of
      complex interplays between general individual predispositions and etiology-specific factors.
      A better understanding of these mechanisms is a prerequisite for personalized treatment and
      development of empirically based randomized controlled intervention studies. This approach
      has relevance to other clinical conditions as well. The long-term aim is to ensure accurate
      diagnosis, improve treatment and rehabilitation, and to contribute to knowledge based
      clinical decision-making both within specialized and community based rehabilitation settings.
    

Detailed description: 
      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.

      2.0. Research Aims and Hypotheses. The primary aim of this study is to establish the
      frequency and severity of PTBIF in a representative sample of patients with moderate to
      severe TBI during the first year and a half post-injury, including investigation of potential
      clinical subgroups and trajectories of fatigue. We expect to find that fatigue will be a
      substantial and persisting problem for a large proportion of TBI patients. We furthermore
      hypothesize that there will be distinct clinical subgroups where the role of intra-individual
      factors such as premorbid fatigue, personality, somatic complaints, resilience, emotional
      distress, reward sensitivity and injury-related cognitive deficit will contribute
      differentially to persistent fatigue.

      A secondary aim of the study is to explore the replicability of Ponsford´s (2014) model,
      wherein cognitive problems predicted fatigue, which in turn resulted in emotional distress.
      As we include a broader array of relevant individual factors, we hypothesize that the results
      will show multiple pathways to persistent fatigue, and expect to establish a more complex
      multidirectional model between the included factors.

      3.0, Methodology. This longitudinal study takes on a broad clinical and theoretical
      perspective in exploring factors that might be predictive of persistent fatigue in a
      representative sample of patients with moderate-to-severe TBI over the first year and a half
      after injury, including comparison with a non-clinical twin-sample. A prospective
      longitudinal design will be applied, where a representative sample of patients with moderate
      and severe TBI will be assessed at 6 and 12 months post injury.

      3.1. Statistical analyses and power. Analyses will be performed using the Statistical Package
      for the Social Sciences Version 22, with p<0.05 as level of significance. Change over time
      will be assessed using mixed models analysis at 3 time points: acute phase (T1), 6 months
      post-injury (T2), and 12 months post-injury (T3). Predictors of fatigue at 6 and 12 months
      post injury will be explored with linear regression analysis. The fatigue model presented by
      Ponsford et al. (2014) will be tested using path analysis, within a structural equation
      modelling framework. Based on previous reports, FSS scores ≥ 5 (on a scale ranging from 1-7)
      are interpreted as indicative of severe fatigue. According to the incident number of
      hospital-admitted adults with TBI in Eastern region of Norway, it is estimated that 130
      patients with moderate-to-severe TBI, aged 18 - 65 years, will be eligible for study
      inclusion within one year. With an expected dropout rate of 20 - 30 %, we assume that 91-104
      patients will be able to complete follow-ups. The statistical strength calculated with
      G*power 3.1.7 shows that a regression analysis with a correction for 10-13 predictors will
      yield a power of 81 % (effect size of 0.20, alpha of 0.05). One-point difference is a
      conservative indicator of an important change in individual FSS scores. Taking into account
      the total sample size, analysis of mean difference from T2 to T3 would permit a critical t of
      1.98-1.99 and effect size of 0.28-0.30.

      4.0. Plan for Activities, Visibility and Dissemination. Study results will be shared with the
      scientific community through scientific articles to be published in peer-reviewed
      international journals in the fields of neurology and rehabilitation, and through
      participation in scientific conferences. The PhD candidate will turn in his thesis containing
      three scientific articles addressing the study aims to the Department of psychology at the
      University of Oslo. Senior researchers in the group will publish additionally with him on the
      data set obtained in this study. Given the strong collaborative effort, the comprehensive
      data set, and the strong theoretical basis for this project, it has potential to result in
      high impact publications. Results will also be communicated through an ongoing dialogue with
      user organizations and central clinicians at Sunnaas Rehabilitation Hospital and Oslo
      University Hospital. A designated group of researchers and patient representatives within the
      project group will be responsible for planning of popularized presentation of results in
      order to communicate with society at large and to relevant patient groups. The research group
      will seek funding for hosting at least one large-scale scientific conference addressing
      mechanisms of fatigue in different clinical populations.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The study sample will be identified through the collaboration with the Neurosurgical
        department at Ullevål, Oslo University Hospital (OUH), where the majority of patients in
        the Eastern part of Norway with moderate to severe traumatic brain injuries are admitted.
        Patients within our eligibility criteria are referred to Department of Physical Medicine
        and Rehabilitation at Ullevål, OUH. Some eligible patients not admitted to the
        Neurosurgical department, are routinely referred from other hospitals to Sunnaas
        Rehabilitation Hospital or Department of Physical Medicine and Rehabilitation at Ullevål,
        OUH. Patients are informed about the project by clinicians, and if they consent, the
        primary investigator contacts them to inform more thoroughly about the project. Patients
        who have been identified, but who do not arrive at clinical appointments, are sent an
        informational letter with an invitation to the project, with contact information.
      
Biospecimen description: 
      Biological data will include standard blood test screening during hospitalization and 6
      months follow-up, including tests to rule out other causes of fatigue: kidney, liver,
      thyroidal and pituitary status, haemoglobin, cortisol, B-12, D-vitamins and C-reactive
      protein (CRP).
    
Keywords: persistent fatigue; traumatic brain injury