Journal of Head Trauma Rehabilitation:
3rd Federal Interagency Conference on TBI
Fatigue and Sleep Disturbance Following Traumatic Brain Injury—Their Nature, Causes, and Potential Treatments
Ponsford, Jennie L. PhD; Ziino, Carlo DPsych; Parcell, Diane L. DPsych; Shekleton, Julia A. DPsych; Roper, Monique DPsych; Redman, Jennifer R. PhD; Phipps-Nelson, Jo PhD; Rajaratnam, Shantha M. W. PhD
Section Editor(s): Bushnik, Tamara PhD; Gordon, Wayne PhD, ABPP/Cn
School of Psychology and Psychiatry, Monash University (Drs Ponsford, Ziino, Parcell, Roper, Redman, Rajaratnam, Shekleton and Phipps-Nelson), Monash-Epworth Rehabilitation Research Centre, Epworth Hospital (Drs Ponsford and Roper), Victoria, Australia.
Corresponding Author: Jennie L. Ponsford, PhD, School of Psychology and Psychiatry, Monash University, Clayton, 3800, Victoria, Australia (email@example.com).
The projects described in the article received funding from the National Health and Medical Research Council (Project ID 334002) and Monash University.
The authors declare no conflicts of interest.
Background: Although fatigue and sleep disturbance are commonly reported following traumatic brain injury (TBI), understanding of their nature and treatment remains limited.
Objectives: This article reviews a series of investigations of the nature and causes of fatigue and sleep disturbance following TBI.
Methods: A large cohort of community-based patients with TBI, recruited from a TBI rehabilitation program, completed measures of subjective fatigue and sleep disturbances, as well as attentional measures. A subgroup of participants completed polysomnography and assessment of dim light melatonin onset.
Results: Fatigue and sleep disturbance are common. Both are associated with anxiety, depression, and pain. However, fatigue is also associated with slowed information processing and the need for increased effort in performing tasks. Sleep disturbances contribute to fatigue. Objective sleep studies show reduced sleep efficiency, increased sleep onset latency, and increased time awake after sleep onset. Depression and pain exacerbate but cannot entirely account for these problems. There is increased slow-wave sleep. Individuals with TBI show lower levels of evening melatonin production, associated with less rapid-eye movement sleep.
Conclusions: These findings suggest potential treatments including cognitive behavior therapy supporting lifestyle modifications, pharmacologic treatments with modafinil and melatonin, and light therapy to enhance alertness, vigilance, and mood. Controlled trials of these interventions are needed.
MORE THAN 60% of patients with traumatic brain injury (TBI) report experiencing fatigue, which interferes with their rehabilitation and daily lifestyle. Sleep disturbance is also often reported following TBI.1–14 Brain regions and systems regulating arousal, alertness, attention, and sleep are vulnerable to TBI. However, there has been little empirical investigation into the nature, causes, or progression of fatigue and sleep disturbance following TBI, and no efficacious treatments for these problems have been established. This article describes a series of studies attempting to shed light on these issues.
WHAT IS FATIGUE?
Fatigue is a universal symptom and is also present in healthy individuals. Defining fatigue is difficult as it is a multidimensional construct. Aaronson and colleagues15 define fatigue 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 activity.”(p46) A distinction is drawn between physiological and psychologic resources. Physiologically, fatigue is defined as functional organ failure, generally caused by excessive energy consumption; depletion of essential substrates of physiological functioning, such as hormones or neurotransmitters; and/or a diminished ability to contract muscles. Central fatigue arises from impairment within the central nervous system (CNS) (eg, in the hypothalamus or reticular formation) or impaired transmission between CNS and peripheral nervous system. Peripheral fatigue results from malfunction of the peripheral nervous system, such as impaired neuromuscular transmission at the motor endplate and is not related to the CNS.16–18 This distinction means that motor tasks tapping into peripheral nervous system function may not be sensitive to fatigue originating in the CNS.18,19 This is supported by the findings of LaChapelle and Finlayson20 that performance on a thumb pressing task did not differentiate individuals with brain injury from healthy controls. Psychologic fatigue is defined as “A state of weariness related to reduced motivation, prolonged mental activity, or boredom that occurs in situations such as chronic stress, anxiety or depression.”21(p291) Because a high proportion of patients with TBI develop depression and anxiety,22 this aspect of fatigue is important to consider.
Primary fatigue encapsulates both central and peripheral fatigue processes and is thought to be caused by diseases or disorders, such as multiple sclerosis or chronic heart failure. Secondary fatigue is said to result from exacerbation of primary fatigue in circumstances such as physiological distress, sleep disturbance, and pain.23 With this in mind, postulated causes of primary fatigue following TBI could be related to mechanical brain changes such as diffuse axonal injury, impaired excitability of the motor cortex, and hypopituitarism, whereas causes for secondary fatigue include sleep disorders, pain, and depression.10 Fatigue may be a symptom of depression, and depression may result in early morning wakening. Anxiety may also disturb sleep, more commonly resulting in difficulty falling asleep. Thus, emotional distress may contribute to sleep disturbances and exacerbate fatigue. In reality, the experience of fatigue most probably represents a combination of all these influences.
Numerous measures of fatigue have been developed. No single valid and reliable measure exists. Many fatigue scales have been developed in relation to particular conditions, such as cancer or multiple sclerosis. Existing scales address differing aspects of fatigue—its characteristics, its consequences, and/or the associated subjective feelings. Aaronson et al15 recommended assessment of fatigue from various perspectives, including subjective quantification of fatigue levels, subjective distress because of fatigue, the impact of fatigue on activities of daily living, other associated factors (eg, sleep and depression) and biological parameters.
Over the past decade, we have conducted a series of studies investigating the measurement, characteristics, time course, predictors, and interrelationships of fatigue and sleep disturbance following TBI. Findings from some of these studies have already been published and some have yet to be reported in detail. This article summarizes and synthesizes the findings from the studies, as a basis for recommendations regarding potential treatments.
SUBJECTIVE FATIGUE: ITS FREQUENCY AND ASSOCIATED FACTORS
The first study aim of the series of studies by our research group investigated the magnitude, self-reported causes, and impact of subjective fatigue in a consecutive sample of individuals with TBI, relative to demographically similar controls, and examined the relationships between subjective fatigue and demographic and injury-related variables, orthopedic injury, medication use, pain, depression, and anxiety. Preliminary findings on a smaller sample than this study have been reported by Ziino and Ponsford.24 In the subsequently expanded study of subjective fatigue, we recruited 139 consecutive English-speaking people with mild to severe TBI (74% male) who had returned to the community, aged 16 to 67 years (mean = 34.72, median = 31, SD = 13.2 years), with a mean education of 12.15 (median = 12, SD = 2.6; range = 7-23 years). They had a mean lowest preintubation Glasgow Coma Scale score of 9.19 (median = 9, SD = 4.23, range = 3-15) and a mean duration of posttraumatic amnesia (PTA), measured prospectively using the Westmead PTA scale,25 of 22.63 days (median = 16, SD = 22.48, range = 0-119 days). They were recruited and had completed assessments at a mean of 295.68 days postinjury (median = 278, SD = 156.38, range = 20-870 days). They had no prior head injury, no preinjury neurologic or psychiatric illness requiring treatment, and no preinjury sleep disturbance (eg, sleep apnea); sufficient cognitive ability, visual acuity, and physical ability to complete the study tasks; no obesity based on body mass index; not traveled across more than 1 time zone in the preceding 3 months; no nightshift work in preceding 3 months; not recently used psychotropic medication known to cause fatigue or affect sleep; and not used illicit drugs. They were compared with a group of controls recruited from the general community, fulfilling the same criteria, except that they had no history of TBI. The healthy control group for the subjective fatigue study comprised 78 participants, of which 71% were male. Their mean age was 33.38 years (median = 32.5, SD = 11.87, range = 16-67 years), and the mean years of education was 12.67 (median = 12, SD = 2.12, range = 8-18 years). The TBI and healthy control groups did not differ significantly on age, gender, or education. However, a higher proportion of the control participants were currently working (81.8%) than individuals with TBI (40.4%).
After informed consent and provision of demographic and medical details, participants completed the following measures: The Fatigue Severity Scale (FSS)26 is a 9-item general fatigue scale used to assess the behavioral consequences of fatigue and the impact of fatigue on daily functioning. The FSS has acceptable internal consistency, stability over time, sensitivity to clinical changes, and the ability to distinguish patients with brain injury from healthy controls.20,26 The Visual Analogue Scale for Fatigue (VAS-F)21 was used as a measure of subjective quantification of fatigue levels at one point in time. It requires the subject to respond to descriptors on two subscales: (1) an Energy subscale, for example, “not at all active” versus “extremely active”(6 items) and (2) a Fatigue subscale. for example, “not at all worn out” versus “extremely worn out” (12 items). This scale has demonstrated reliability and validity as a measure of fatigue, and the vigor subscale of the VAS-F has differentiated individuals with head injury from healthy controls.20,21 The Causes of Fatigue Questionnaire (COF) developed by Ziino and Ponsford24 contains 12 statements of activities of a cognitive (eg, reading, having a conversation) or physical nature (eg, having exercise). Participants rated the extent to which these activities cause fatigue on a 5-point scale. The COF items were categorized to create two subscales reflecting whether activities primarily involved mental effort or physical effort. Items comprising the Mental Effort Causes of Fatigue subscale (COF-ME) included (a) watching television, (b) mental effort, (c) reading, (d) having a conversation in person, (e) concentrating, and (f) having a conversation over the telephone. Items comprising the Physical Effort Causes of Fatigue subscale (COF-PE) included (a) walking, (b) exercising, (c) physical effort, and (d) showering. Two items (shopping and participating in social activities) were excluded because these items were not easily categorized as being primarily physical or cognitive in nature. The Hospital Anxiety and Depression Scale (HADS)27 is a 14-item self-report questionnaire assessing anxiety and depression symptoms. It is relatively unaffected by concurrent physical illness. It has been used in TBI follow-up studies and has demonstrated sensitivity to anxiety and depression in individuals with TBI.28 The National Adult Reading Test29 is a reading test of 50 irregularly spelled words used as a measure of premorbid IQ. The Brief Pain Inventory (BPI)30 was used as a measure of pain levels.
Ethics approval was obtained from relevant hospital and university ethics committees, and all participants (and/or their legal guardians) provided informed consent. Medical details including all injuries were obtained from hospital records. Participants completed a questionnaire documenting their demographic details and medical history, followed by the study measures.
In terms of data analyses, Student t tests were used to examine differences between participants with TBI and healthy controls on the measures of subjective fatigue, depression, anxiety, and sleep disturbance, as well as changes over time. Pearson correlations were used to examine the association between variables. Multiple regression analyses were used to examine the predictors of subjective fatigue. Mann-Whitney U tests were conducted—due to extremely skewed distributions—when comparing use of medication between groups, as well as exploring the relationship between orthopedic injuries, pain, and fatigue.
COMPARISON BETWEEN TBI AND HEALTHY CONTROL PARTICIPANTS ON SUBJECTIVE FATIGUE MEASURES
From Table 1, it can be seen that individuals with TBI showed significantly higher scores on the FSS and COF subscales, reporting a significantly greater impact of fatigue on their lifestyle. They reported that activities requiring both COF-ME and COF-PE more frequently caused fatigue. Differences in scores on the VAS-F subscales only approached significance in the expected direction.
As reported by Ziino and Ponsford,24 the fatigue scales showed good internal consistency. The FSS also showed significant correlations with both the VAS-F (r = 0.51) and VAS-E (r = −0.42), and the VAS-F fatigue subscale correlated significantly with the VAS-F energy subscale (r = −0.63) (P < .001).
PREDICTORS OF FATIGUE SEVERITY FOLLOWING TBI
To investigate predictors of subjective fatigue in the TBI sample (as measured on the FSS), a multiple regression analysis was conducted, with age, gender, education, time since injury, and injury severity (as measured by PTA duration) as independent variables. Preliminary analyses indicated no significant intercorrelations between these variables, so multicollinearity was not deemed a problem. As shown in Table 2, time since injury was the only significant predictor of FSS scores, with FSS scores increasing over time. The effect of female gender approached significance. Only 8% of variance in FSS scores was explained by all variables (P = .09). Injury severity, as measured by PTA duration, was not a significant predictor of FSS scores.
On the HADS, relative to healthy controls, participants with TBI showed higher levels of anxiety (TBI mean HADS anxiety score = 7.4, SD = 5.2; control mean anxiety score = 6.14, SD 3.53; P = .04) and depression symptoms (TBI mean HADS depression = 6.03, SD = 4.49; control = 2.92, SD = 2.55, P < .001). Forty-three percent of participants with TBI obtained HADS scores indicative of clinically significant anxiety (13.7% mild, 16.5% moderate, and 12.9% severe), and 40% showed clinically significant depression (20.1% mild, 16.5% moderate, and 2.9% severe). Sixty-four percent of participants with TBI showed clinically significant fatigue (FSS >4) as compared with 35.1% of healthy controls. The HADS anxiety and depression scores correlated significantly with each other and with scores on the FSS and VAS-F scales, with correlations ranging from 0.48 to 0.59 (all P < .001). That is, people with anxiety and depressive symptoms were more likely to show clinically significant fatigue. Correlations were lower or absent in the healthy control group. A regression analysis, including gender, time postinjury and anxiety and depression symptoms showed that anxiety and depression were both significant predictors of FSS mean scores in the TBI sample, despite their intercorrelations, with the model being significant (P < .001) and accounting for 30% of the variance, with 26% accounted for by HADS anxiety and depression scores (Table 3)
Relationship between fatigue and employment
A 2-way analysis of variance was conducted to investigate the impact of involvement in employment or study of participants with TBI and healthy controls on FSS scores. There was, however, no significant difference in fatigue scores between those involved in employment or study and those who were not, F1,209 = 0.09, P = .77. There was also no significant interaction between group and employment status, F1,209 = 0.30, P = .59.
MEDICATION USE AND FATIGUE
In the TBI group, 39.3% were taking some form of medication at the time of testing, with 15.6% taking antidepressant medication, 13.3% taking analgesic medication regularly and 18.5% occasionally, 11.1% anticonvulsant medication, 3.0% anti-inflammatory medication, 3.0% antispasmodic medication, and 11.9% taking other forms of medication (eg, herbal medicines). Mann-Whitney U tests revealed no significant association between scores on the FSS and medication use (P = .12). However, patients with TBI who had high VAS-F fatigue scores were more likely to take analgesics regularly (P = .04). Very few of the healthy control participants were taking any medication, apart from occasional analgesics.
ORTHOPEDIC INJURIES, PAIN, AND FATIGUE
Of the participants with TBI, 70.8% had an orthopedic injury. There was no significant association between the presence/absence of orthopedic injuries and scores on the fatigue scales (Mann-Whitney U tests). Participants with TBI showed significantly higher pain severity ratings on the BPI than healthy controls (all P < .001). There were moderate significant associations between pain severity and rating on the FSS (range = 0.29-0.36) and the VAS-F fatigue subscale (range = 0.22-0.31). The VAS-F Energy subscale showed lower, although still significant, correlations with pain severity (range = −0.12 to −0.21).
Changes in fatigue levels over time
Eighty-eight participants with TBI and 63 healthy controls were followed up 6 months after their initial assessment. Participants with TBI only showed a significant increase in fatigue on VAS-F Fatigue subscale (t80 = −3.425, P = .001). However, no significant changes were found on the COF-ME subscale, COF-PE subscale, VAS-F Energy subscale, or the FSS. Healthy controls showed no significant changes over time.
Summary of subjective fatigue studies
The FSS is a sensitive measure of fatigue because it impacts on daily lifestyle. Our studies showed that individuals with TBI experience greater subjective fatigue, caused by both physical and mental activities, which impacts on their lifestyle and does not decrease over time. This fatigue was not significantly associated with injury severity, age, or orthopedic injury, but it was moderately associated with pain, taking analgesic medication, female gender, and depression and anxiety, as well as greater time postinjury. If fatigue were a direct result of injury, a dose-response relationship between severity of TBI and fatigue might be expected. However, such an association was not evident in this study. It is possible that increased reporting of fatigue over time may reflect increasing activity levels. The lack of significant association of fatigue with employment status is inconsistent with this hypothesis; however, individuals who had most impairment were also less likely to be employed. It may also be that increasing fatigue reflects increasing emotional distress with a growing awareness of functional limitations over time. However, the direction of the association of fatigue with mood is unclear. It is possible that the experience of fatigue over an extended period may cause depression and anxiety. It is of interest that the association between fatigue and emotional distress was not evident in healthy controls, which supports the view that injury-related factors are influential. These findings are consistent with those of other recent studies9,11–13 and confirm that a complex range of factors need to be considered by the clinician in assessing causes of fatigue and addressed as needed. In addition to those already mentioned, the subjective experience of fatigue is likely to be determined by the complex interaction of functional disability with lifestyle demands, which is difficult to quantify and idiosyncratic.
IS SUBJECTIVE FATIGUE ASSOCIATED WITH INJURY-RELATED ATTENTIONAL AND INFORMATION PROCESSING PROBLEMS?
Having established that fatigue is a significant problem following TBI, the question then arises, what is its cause? Is it a primary disorder, associated with the injury and its cognitive consequences, or is it the result of secondary factors such as depression, anxiety, and pain? From the findings already discussed, fatigue seems to be associated with anxiety, depression, and pain. However, according to the coping hypothesis, put forward by van Zomeren and Brouwer,31 fatigue may also result from the additional compensatory effort expended in meeting the demands of everyday life in the presence of cognitive deficits, including impaired attention. To examine this possibility, we have investigated the relationship between the subjective experience of fatigue and selective attention deficits. Ziino and Ponsford32 tested this hypothesis in a group of 46 participants with mild to severe TBI and 46 healthy controls. They completed the subjective fatigue scales mentioned earlier, including the VAS-F, FSS, and COF, and attentional measures including the Telephone Search and Telephone Search while Counting subtests from the Test of Everyday Attention and a Complex Selective Attention Task (C-SAT), which required the participants to hold instructions in working memory to guide responses. In addition to reporting greater subjective fatigue on the FSS and COF, participants with TBI, performed more slowly on attentional measures, and made more errors on the C-SAT. After controlling for anxiety and depression, fatigue ratings were significantly correlated with indices of performance on the C-SAT, which requires higher-order attentional processes, but not with attentional measures that placed fewer demands on controlled processing and working memory. This finding suggested a relationship between subjective fatigue and impairment on more demanding tasks, which arguably require greater mental effort.
Ziino and Ponsford33 investigated the association between subjective and objective fatigue and vigilance performance in the same 2 groups of participants. Measures of subjective fatigue (VAS-F), selective attention (C-SAT), and blood pressure were completed before and after a 45-minute vigilance task, which required selective responding to stimuli on a computer screen. Results showed that participants with TBI performed at a lower level in terms of response speed and errors on the vigilance task, but performed at a similar level across the duration of the task. Greater subjective fatigue on the VAS-F was associated with increased misses on the vigilance task in TBI participants. Greater increases in diastolic blood pressure were evident in participants with TBI while they were performing the vigilance task, and these were associated with greater increases in subjective fatigue on the VAS-F. Some participants with TBI exhibited a decline in vigilance performance over time, and they also showed disproportionate increases in subjective fatigue. These results supported the coping hypothesis, suggesting that individuals with TBI expend greater effort in maintaining performance over time (reflected in increased diastolic blood pressure), which is in turn associated with increased subjective fatigue. It is possible that expending this increased effort results in stress, which, in turn, leads to anxiety and depression. This hypothesis has been supported by the finding of a significant association between errors on the earlier-mentioned vigilance task and the presence of anxiety (r = 0.40; P < .01) and depression (r = 0.43; P < .001) on the HADS.
SUBJECTIVE SLEEP CHANGES FOLLOWING TBI
Another factor that may contribute to fatigue following TBI is sleep disturbance. Reported sleep complaints following TBI include insomnia, hypersomnia, excessive daytime somnolence, and altered sleep-wake cycles.34 Excessive daytime sleepiness (EDS) is manifested as tiredness or drowsiness during the daytime after insufficient sleep or sleep disruption. People with EDS commonly feel the need to nap when they want to be awake. EDS is associated with sleep disturbances such as sleep apnoea, narcolepsy, and circadian rhythm sleep disorders, including advanced and delayed sleep phase disorders. There is a theoretical distinction between EDS and fatigue, although in practice, patients may not differentiate between the symptoms. As mentioned earlier, sleep disturbances may also be associated with depression and anxiety.8
Parcell and colleagues35 explored subjective sleep reports in 63 community-based participants with TBI recruited following discharge from rehabilitation and 63 age- and gender-matched healthy controls from the general community. They completed a 7-day self-report sleep-wake diary assessing sleep and wake times, sleep onset latency, frequency and duration of nocturnal awakenings and daytime naps, a general sleep questionnaire evaluating subjective sleep change and quality, and the Epworth Sleepiness Scale (ESS), as a measure of EDS. Participants with TBI showed a significantly higher frequency of reported sleep changes following TBI (80%) relative to the healthy control group (23%), who responded retrospectively. The TBI group reported more nighttime awakenings and longer sleep onset latency. Increased levels of anxiety and depression were associated with increased reporting of sleep changes.
To investigate whether sleep disturbance was contributing to fatigue and daytime sleepiness, we subsequently examined, in an expanded study involving 140 participants with TBI (70% males), with median age 30 years (SD = 13.5; range = 16-65 years), median Glasgow Coma Scale score of 8 (SD = 4.3; range = 3-15), median PTA 15 days (SD = 20.5; range = 0.1-112 days), median time since injury = 272 days, (SD = 183.4; range = 21-1153 days), and 104 healthy controls of similar gender (64.4% male) and age (median = 27; SD = 11.9; range = 17-65 years), the interrelationships between self-reported sleep changes, as measured on the Pittsburgh Sleep Quality Index (PSQI), and subjective fatigue, as measured on the FSS and daytime sleepiness, as measured on the ESS. We found significantly greater reporting of sleep disturbance in the TBI group on the PSQI (TBI mean global score = 6.0, SE = 0.49; control mean global score = 4.0, SE = 0.34; t = 3.2, P = .002). We also found greater daytime sleepiness in participants with TBI on the ESS (TBI mean ESS total = 7.0, SE = 0.34; control mean ESS score = 5.6, SE = 0.32; t = 3.0, P = .003). HADS anxiety (r = 0.36) and depression (r = 0.40) and pain severity as measured on the Brief Pain Inventory (r = 0.50) were all significantly associated with PSQI scores in the TBI group. We found significant associations between scores on the FSS and VAS-F Fatigue and Energy subscales and scores on both the PSQI and the ESS (r = −0.31 to 0.36, P = .000-.009), confirming a relationship between sleep disturbance and subjective fatigue.
OBJECTIVE SLEEP STUDIES
From the studies of Parcell et al35 and others,34 it is clear that sleep disturbances are commonly reported following TBI; however, there is limited evidence as to the objective nature and pathophysiological basis of such complaints. Polysomnographic studies have generally utilized small samples and findings have been inconsistent. In individuals with TBI, there have been findings of reduced sleep efficiency,36 increased sleep fragmentation,8,37,38 and increased sleep onset latency,36,39 although some studies have reported no differences in sleep onset latency.8,37,40 Findings regarding sleep architecture have also been variable. Although some studies have shown no differences relative to healthy controls,36 others have shown increased stage 4 sleep,38 reduced rapid-eye movement (REM) sleep,38,40 increased REM sleep in the second half of the night,41 or decreased REM onset latency.8,36
These disturbances may be associated with injury-related damage to sleep-wake regulating centres.38,41,42 Circadian Rhythm Sleep Disorders and delayed circadian timing have been reported in patients with mild TBI and insomnia.43 The timing of sleep is regulated by the circadian (∼24-hour) pacemaker in the hypothalamic suprachiasmatic nuclei, which generate and maintain circadian rhythms including that of pineal melatonin synthesis. Melatonin plays a role in the circadian regulation of sleep-wakefulness.44 Given the high frequency of anxiety and depression following TBI, these should also be considered as potential etiologic factors.8,45
In a recent study by our group,46 23 patients with TBI and 23 age- and gender-matched healthy controls were compared on self-reported sleep quality on the PSQI, daytime sleepiness on the ESS, preferred sleep-wake time on the Morningness-Eveningness Questionnaire (MEQ), anxiety and depression symptoms on the HADS, polysomnographic sleep measures, and salivary dim light melatonin onset time, which is a marker of circadian phase of the sleep-wake cycle. The participants with TBI reported greater subjective sleep disturbance on the PSQI, with the difference remaining significant even after controlling for their significantly higher symptoms of anxiety and depression than healthy controls. On polysomnography, participants with TBI showed decreased sleep efficiency and increased time spent awake after sleep onset (WASO), and there was a trend for the TBI group to have less REM sleep and more slow-wave sleep. The difference in slow-wave sleep became significant after controlling for anxiety and depression scores. There was no group difference in REM sleep after controlling for anxiety or depression scores. The longer WASO and lower sleep efficiency remained after controlling for anxiety score, but weakened after controlling from depression, which was associated with WASO but not with sleep efficiency. More severe injuries were associated with longer WASO and poorer sleep efficiency in the TBI group, but there was no association between injury severity and subjective sleep disturbance reported on the PSQI.
Although the timing of salivary dim light melatonin onset did not differ significantly between the groups, participants with TBI showed significantly lower levels of evening melatonin production. Melatonin production was significantly correlated with REM sleep, but not sleep efficiency or WASO. These findings suggest the possibility of some disruption to the circadian regulation of melatonin synthesis. Overall, the study findings suggested that several factors may contribute to sleep changes following TBI. These include the presence of depression, which may reduce sleep quality, increased slow-wave sleep, which may be a response to mechanical brain damage, and circadian regulation of melatonin synthesis may be disrupted, reducing REM sleep, and possibly contributing to increased WASO. Although there was a significant association between injury severity and objectively measured WASO, as with subjectively reported fatigue, there was not a significant association between injury severity and self-reported sleep disturbance on the PSQI. This suggests that multiple factors, including emotional distress and patient self-awareness may contribute to self-reported sleep disturbances following TBI.
Other possible etiologic factors
The association of sleep disturbance and brain pathology has been supported by other researchers.1,11,13 Chaudhuri and Behan17 have argued that the cause of sleep change in case of brain injury is injury to ascending reticular activating system, limbic system, and the basal ganglia, affecting the striatal-thalamic-frontal cortical system. Kohl et al47 provided support for this hypothesis by showing increased brain activity in individuals with TBI in several regions including middle frontal, superior parietal, basal ganglia, and anterior cingulate regions during a speeded cognitive task (Symbol Digit Modalities Test).
It has also been postulated that fatigue may be associated with neuroendocrine abnormalities. Specifically, growth hormone deficiency (GHD) is thought to be associated with fatigue. Growth hormone deficiency is a common occurrence following TBI. However, studies to date have been unable to confirm this association.9,12
Baumann and colleagues1 have proposed a significant role of hypothalamic injury in post-TBI fatigue. They have made a case for lower levels of cerebrospinal fluid Hypocretin-1, caused by loss of hypocretin neurons, resulting in EDS in individuals with TBI. In a pathologic study of the brains of four deceased cases with TBI,48 significantly fewer hypocretin neurons were found in brains of the deceased cases with TBI than in matched uninjured healthy control cases.
The potential association of fatigue and sleep disturbance with lesions in specific neuroanatomical regions or systems clearly requires much further investigation. It raises the possibility that it is injury to certain structures rather than injury severity per se that underpins such disturbances, thereby providing an explanation for the lack of association between injury severity and fatigue or sleep disturbance.
TREATMENT OF FATIGUE AND SLEEP DISTURBANCE
The findings from these studies may be applied to inform the development of interventions for fatigue and sleep disturbance following TBI. Sadly, there has been little work done in this area to date, with no treatments shown to alleviate fatigue or sleep disturbance in individuals with TBI. In assessing patients who report these problems, the clinician needs to assess all possible contributing factors (eg, attention and processing speed, medications, pain, mood, sleep changes) and provide treatment of these accordingly. To minimize fatigue and manage stress, it is important to assist the injured person to regulate their lifestyle to live within cognitive and physical limitations. They may do this by reducing work hours, modifying the pace or demands of activities, reducing distraction and need for multitasking, and taking frequent rest breaks. It is likely to be necessary at the same time to address psychological issues related to making such changes in lifestyle, using cognitive behavior therapy techniques. Where there is sufficient self-awareness, strategies may be developed to manage information overload and associated social difficulties using techniques such as time pressure management.49 Physical conditioning programs can reduce physical fatigue and promote well-being, although they are not likely to alleviate fatigue of central origin.50,51
Where sleep disturbance is reported, it is important to investigate this objectively, as subjective reports make it difficult to accurately ascertain the source of the problem. Again, potential causative factors such as pain, anxiety, or depression need to be assessed and treated as necessary. Sleep hygiene techniques, including avoiding naps if this interferes with nighttime sleep, adhering to a regular schedule of being in bed, and avoiding time spent in bed awake may be taught in the manner recommended by Ouellet and Morin,52 who have demonstrated that such techniques can be effective in individuals with TBI.
Regarding pharmacologic interventions, hypnotic and benzodiazepine-like compounds (zolpidem and zopiclone) are not indicated for long-term use in treating insomnia. They are associated with adverse effects, including impaired cognitive function and reduced daytime alertness, hallucinatory behavior, sleepwalking, and altered sleep architecture.53
Modafinil is a wake-promoting drug approved in the United States for treating excessive sleepiness associated with narcolepsy, obstructive sleep apnoea/hypopnea syndrome, and shift-work disorder. It has been used in the treatment of fatigue in individuals with multiple sclerosis and TBI. A randomized controlled trial by Jha et al54 showed no evidence of a significant reduction in subjective fatigue measured on the FSS in a general TBI sample. There was a trend toward a reduction in daytime sleepiness evident at week 4 but not week 10 of treatment. A more recent RCT by Kaiser et al55 showed reduction in daytime sleepiness on ESS but no impact on fatigue (FSS) in 20 people with fatigue/sleepiness problems.
Melatonin has been reported to improve latency to sleep and sleep efficiency, in chronic and age-related insomnia.56,57 A prolonged-release melatonin preparation (Circadin) has been shown to improve sleep quality, reduce latency to sleep onset, improve morning alertness and quality of life and increase morning arousal after treatment in insomnia patients aged 55 years or more. These studies suggest that melatonin treatment is a safe and effective treatment of insomnia symptoms and improves daytime alertness. Only one RCT has evaluated the efficacy of melatonin to alleviate sleep disturbances in patients with TBI.58 Seven male TBI patients (mean age 39 years) with chronic sleep difficulties more than 6 months postinjury received either 5 mg of melatonin or 25 mg of amitriptyline (tricyclic antidepressant) for 1 month each followed by a 2-week washout period. No significant improvement was observed in subjective sleep parameters (latency, duration, quality, daytime alertness) for either melatonin or amitriptyline. However, effect sizes revealed that melatonin had a moderate effect on daytime alertness as compared with amitriptyline. These findings were limited by the small sample size. A larger RCT of melatonin for treatment of sleep disturbance following TBI is being conducted by our research group.
Bright light therapy
Bright light therapy also presents a potential treatment for fatigue and daytime sleepiness. Light exerts nonvisual effects on many biological functions. It has acute alerting effects that are distinct from its effects on circadian rhythms. In healthy and patient populations, light exposure results in reduced sleepiness, has arousing effects on a number of biological parameters, increases vigilance performance, and improves mood. Short wavelength (blue) light has been shown to be most effective,59–61 presumably due to the key role played in circadian photoreception by the blue light-sensitive photopigment melanopsin, expressed in intrinsically photosensitive retinal ganglion cells.62 On this basis, we suggest that daily, timed exposure to short wavelength light has the potential to reduce fatigue and daytime sleepiness and improve mood and possibly also aspects of attention. We are currently conducting an RCT of this therapy.
Fatigue and sleep disturbance are common and persistent problems following TBI. Fatigue and its impact on daily lifestyle may be assessed using the FSS. Our studies suggest that fatigue may be associated with impaired attention and information processing speed and the need to expend greater effort in performing tasks. Thus, assessment of these aspects of cognitive function is important. It may also be associated with depression, anxiety, and pain, which also require assessment, although the directions of these associations remain unclear. Sleep disturbances are also commonly reported and these contribute to fatigue. Objective sleep studies are important to verify the presence and/or causes of sleep disturbance. These studies may show reduced sleep efficiency, increased sleep onset latency, and/or increased time spent WASO. Depression and pain seem to exacerbate but not entirely account for these problems. There may be increased slow-wave sleep and a concomitant reduction in REM sleep. Individuals with TBI may also show lower levels of melatonin production in the evening, which is associated with less REM sleep.
These findings provide a foundation for development of treatments for fatigue and sleep disturbance following TBI. It is important to assess for and treat anxiety, depression, and pain. The injured person may be supported in making modifications to their lifestyle and daily activities to enable them to more effectively live within their cognitive and physical limitations. Sleep hygiene techniques may assist in minimizing sleep disturbance. Hypnotic medications are not generally effective in alleviating sleep disturbances in the longer term. However, there is some preliminary evidence that modafinil may reduce daytime sleepiness. Moreover, given the evidence of lower levels of melatonin production in the evening, trials of administration of melatonin to improve sleep quality and reduce sleep onset latency may be warranted. Of nonpharmacologic interventions, light therapy holds promise as a means of increasing daytime alertness as well as enhancing vigilance and mood. Controlled trials of all of these interventions are needed.
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attention; circadian rhythm; depression; fatigue; sleep disturbance; melatonin; polysomnography; treatments
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