Mental Fatigue after Mild Traumatic Brain Injury in Relation to Cognitive Tests and Brain Imaging Methods

Most people recover within months after a mild traumatic brain injury (TBI) or concussion, but some will suffer from long-term fatigue with a reduced quality of life and the inability to maintain their employment status or education. For many people, mental fatigue is one of the most distressing and long-lasting symptoms following an mTBI. No efficient treatment options can be offered. The best method for measuring fatigue today is with fatigue self-assessment scales, there being no objective clinical tests available for mental fatigue. The aim here is to provide a narrative review and identify fatigue in relation to cognitive tests and brain imaging methods. Suggestions for future research are presented.


Introduction
Traumatic brain injury (TBI) is a common health problem and can lead to temporary or permanent disabilities of cognitive or physical functioning [1][2][3], and approximately 70-90% of injuries are mild TBI (mTBI) [4]. Most people recover after an mTBI within one to three months, but those who suffer long-term symptoms experience a reduced quality of life with deterioration of general health, cognitive impairments, higher risk of depression, social isolation, behavioral problems, and an inability to maintain employment status or continue with education [5][6][7][8]. Thus, "mild" injury may be anything but mild [8].
After a traffic-related mTBI, 23% did not recover within a year [9]. An unfavorable outcome was reported for 30% of all mTBI patients [10]. A review reported that approximately half of the individuals with a single mTBI demonstrated long-term cognitive impairment [11]. A worse outcome can develop after recurrence of mTBI [12]. The assessment and definition of symptoms after an mTBI varies between studies, and symptoms are also common in the population irrespective of whether it is a case of an mTBI. The interaction between pre-and post-biological and psychological factors results in a complex model [13,14], and there is limited evidence for variables as predictors of fatigue [14]. However, in many studies, mental fatigue is not recognized as a separate factor, despite being one of the most distressing and long-lasting symptoms following mTBI [15,16], having an impact on well-being and quality of life [2]. Further research is warranted to better understand the associations between fatigue and pre-and post-morbid variables and for the development of adapted treatment options.
Pathological mental fatigue (not to be confused with non-pathological mental fatigue) is a reduced capacity to continue a mental activity repeatedly. It is a lack of mental energy and a reduced ability to restore the energy in response to performed activity. The mental energy varies depending on the activities performed, but it never returns to normal and is not restored after sleep or an extended rest [17]. Mental fatigue restricts the ability to perform daily activities with work, studies, and social activities, and there is a limited endurance over the course of the day and for weeks and months. The mental fatigue is unlike that normally experienced; rather, it persists as a profound exhaustion over months

Fatigue Self-Assessment Scales
The best method measuring fatigue today is self-assessment scales. Several scales exist, although there is no consensus regarding the assessment scales. Fatigue can be divided into state-or trait-fatigue. State-fatigue or fatigability is measured as a reduced performance or a worse perception of fatigue in relation to a specific activity performed. Visual analog scales (VAS) are commonly used for fatigability, but also cognitive tests or brain activation are used. Trait-fatigue is measured with assessment scales as the subjective perception of fatigue over a pre-defined period of time (weeks and months) [39]. In relation to the mental fatigue discussed here, both state-and trait-fatigue are valid. The mTBI individual suffering from long-term or chronic mental fatigue will have a long-lasting fatigue and will not be fully recovered, and the mental fatigue will vary over the course of the day and from one day or week to the next. When suffering from long-lasting mental fatigue, there is also a distinct fatigability in relation to performed mental activities, and it takes a long time to recover from the extra load on the brain. Physical activity has not been extensively investigated in terms of mental fatigue and mTBI, but patients commonly report a worsening of their mental fatigue following physical activity.

Emotional Distress and Fatigue
Emotional and psychological problems before the brain injury as well as stress add to the trauma, and personal coping abilities interact with psychological, biological, and genetic factors [13,40]. These need to be taken into account for a multifactorial interactive model for mental fatigue during clinical assessment. Clearly, factors such as depression or unemployment before the injury will persist during recovery. Long-lasting fatigue after an mTBI will affect everyday life, such as not managing work and social activities. This can result in an increase in psychological distress if adequate rehabilitation or helpful personal coping strategies are not in place. People suffering from depression and anxiety prior to a skull trauma more frequently experience long-term complications and psychiatric disorders after a brain injury [41][42][43]. With regard to executive function, self-report of executive function increased after mild to moderate TBI and was found to be a predictor for depressive symptoms, although this was not related to objective tests for executive function [44]. Fatigue was not measured in the study. Many authors have reported depression to be common after a brain injury, but they have seldom included fatigue in their analyses.
According to Cantor et al. [16], overlapping symptoms between fatigue and depression can give misleading results if the core symptoms are not carefully evaluated. When considering fatigue after a TBI, it is suggested to be related to the brain injury itself [2] rather than as a consequence of anxiety and depression [45], even though emotional distress can aggravate the symptoms of fatigue. Fatigue was also found to uniquely contribute to disability after TBI, measured with the Mayo-Portland Adaptability Inventory, after controlling for injury severity, executive functions, and depression status [46]. Fatigue decreased during the first year after mTBI and depression, insomnia, cognitive difficulties, and work status were related to the fatigue [47]. Adjustment for the overlapping items in the Mental Fatigue Scale (MFS) and Comprehensive Psychopathological Rating Scale (CPRS-depression and anxiety) removed the differences in depression and anxiety between participants with an acquired brain injury (mTBI, stroke) and healthy controls, but not for the mental fatigue [48]. It is important to acknowledge the increased risk for depression and suicide after a TBI [49] and also to understand the significance of this within the context of fatigue. Mental fatigue cannot be explained within the context of emotional distress alone. However, treatments for depression and anxiety are essential, and these can reduce mental fatigue and improve well-being [50,51].

Cognitive Function in Relation to Fatigue
From the book by Lezak et al.,p 177 [52], the effort to accomplish ordinary activities after a brain injury is exemplified.
"Activities that are normally automatic but become effortful after the injury include many that are performed frequently throughout a normal day, such as concentrating, warding off distractions, reading for meaning, doing mental calculations, monitoring ongoing performance, planning the day's activities, attending to conversations at once, or conversing with background noise, etc. It is by little wonder that by late afternoon, if not by noon, many of these patients are exhausted".
Despite the awareness of these problems, it has been difficult to detect such cognitive complaints after mTBI using standard neuropsychological tests, with the result that cognitive difficulties can go undetected [53][54][55]. In the clinic, many patients who suffer from long-term difficulties after an mTBI may perform within a normal range on cognitive tests, although they may still report mental fatigue, including distractibility and difficulties with reading as well as executive function. Executive function is a broad over-reaching term for cognitive and emotional functions and is suggested to have one of the greatest effects on functional outcomes after a TBI [56], irrespective of TBI severity, having a negative impact on daily living and the ability to go back to work and studies [31]. Executive function is important for the ability to respond adaptively to novel situations and manage emotional and social skills, including verbal reasoning, problem solving, attention control, sustained attention, planning, judgment, decision-making, motivation, impulsivity, resistance to interference, utilization of feedback, multi-tasking, and cognitive flexibility [52,54,55]. From a large-scale study including mild to severe TBI subjects, information processing speed was identified as the domain most strongly associated with daily functioning [57]. Neuropsychological tests have been developed to identify focal and diffuse brain damage rather than to predict how a patient would function in his or her environment [58].
The results reported here include both mTBI and TBI patients, the subject of few studies (Table 1). Fatigue in a group with mild to severe TBI was related to the speed subscales included in the Cambridge Neuropsychological Test Automated Battery (CANTAB) [59]. A worsening of performance after severe TBI on a dual-task with load on working memory and/or executive control was related to increased mental effort. Mental effort was not related to task difficulty or to performance, and it was suggested that fatigue interferes with performance even in simple and automatic tasks [60]. Patients with severe TBI who have a high baseline fatigue performed less well on the selective attention test with a longer reaction time and more omissions compared to controls. Significant correlations were found in the TBI group between attention performance, mental effort, and subjective fatigue. Depression did not correlate with fatigue [61]. Reduced processing speed (digit symbol-coding, reading speed, trail making test) correlated with mTBI and TBI participants all suffering from mental fatigue. Those participants with mTBI working full-time rated their mental fatigue on a similar high level as participants with mTBI and TBI on sick leave. Unlike in the case of those on sick leave, objective cognitive tests did not differ between controls and those with mTBI who were also working full-time. This was suggested to be related to the mental demands during the day. Those suffering from mental fatigue after an mTBI but who are also working full-time might need to devote more time and effort to mental work [34]. Slower performance on a complex selective attention task was associated with fatigue for mild to severe TBI participants in comparison with controls. It was suggested that tasks with a higher order of attentional demand in everyday life are associated with subjective fatigue, this being irrespective of the effects of mood [62]. In contrast, a group including TBI participants reported increased fatigue after the test session having a slower reaction time compared to controls, although the reaction time remained constant for both groups during the session [25]. A vigilance test with a total duration of approximately 45 min was performed by participants with mild to severe TBI. The TBI group was slower and remained at a similar slower speed throughout the duration of the task. Higher state-fatigue was associated with more omissions for TBI participants. A subgroup of these participants showed a decline in performance, which the authors suggested was associated with the greater psychophysiological cost of striving to maintain a stable performance over time, and this cost was associated with a reported increase in fatigue [63]. Reaction time was longer and increased during a 20-min vigilance task for mTBI group, while the reaction time remained stable for the controls [26]. Decreased performance (fatigability) was reported for an mTBI group who described more fatigue than controls in more demanding cognitive tests with simultaneous activation of several cognitive domains (Digit Symbol Substitution Test-DSST) and executive functions (Color Word Test). However, fatigability was not found to be present for less demanding tests involving simple automatic attention [64]. Using the Barrow Neurological Institute (BNI) Fatigue Scale and BNI Screen for Higher Cerebral Functions, the TBI group reported significantly higher levels of fatigue compared to controls. Fatigue was unrelated to injury severity, number of days since injury, cognitive impairment, and gender. The authors suggested regular rest during the day for inpatients in rehabilitation units [65]. During a subacute period, no differences between mTBI and controls in simple reaction time tasks was found, but with increased task complexity, the mTBI group performed more slowly than controls. However, no relation between cognition and fatigue was found [66]. Fatigue and relations to saccadic eye movements and attention in mTBI patients and patients with minor orthopedic injuries early after an mTBI was investigated. The mTBI group reported higher self-rated change in fatigue compared with levels prior to the mTBI and showed more fatigability/state-fatigue measured with cognitive tests. Their state-fatigue correlated with prosaccade latency and cognitive fatigability. In contrast, mTBI trait-fatigue correlated with anxiety and antisaccade latency and variability [67].   When combining endurance and cognitive function among people suffering from mental fatigue after a TBI, no change was found when tests were repeated, while improvement was achieved for healthy controls [24,59,68,69]. A 30-min computerized neuropsychological test battery using the Cambridge Neuropsychological Test Automated Battery with three repetitions, with the second and third repetition separated by approximately 2 h of interviews and self-report measures, was compared between TBI and control groups. Fatigue was associated with poor performance in speed for the TBI group, but this was not associated with an objective decline in cognitive tests. On the contrary, improvement on speed and accuracy was found in the control group [59]. A five-minute computer test with five repetitions, including task repetitions with simultaneous load on processing speed and working memory, showed an overall slower speed for the mTBI group. During the test, the controls became significantly faster when they repeated the task, while this was not found for the mTBI group, who remained on a similar slower speed [69]. After a 2.5-h test session, there was no change in test performance for the mTBI group (processing speed, working memory, attention), but a significantly reduced mental energy compared to the controls was reported after the test session. In contrast, the control group improved their processing speed (Digit symbol coding, WAIS-IV) when the test was repeated [24]. Repetition (three times) of a working memory and wordlist memory test, with 60 sec. rest between trials, revealed no difference between control and mTBI groups after the first trial. However, a significant difference was reported between groups in working memory after trial three, and a significant difference was also found between groups for word-list learning after trials two and three, with the controls performing better with a greater improvement in word-list learning. It was suggested that repetition of tests can be useful for distinguishing cognitive fatigue [70].
In summary, several studies have demonstrated that fatigue is related to information processing speed, attention, and memory. More demanding cognitive tests are suggested to be related to fatigue, but also automatic and simple cognitive tests are suggested to be related to fatigue. This is not a simple relationship, and results can vary depending on which tests and study design are used. However, in no case has improved cognitive function been reported for those suffering from fatigue after an mTBI or TBI. The measurement of endurance, using the repetition of tests, is a promising means of assessment. Fatigability, namely a worsening of performance, is not an accurate means of assessment. The preferred method of assessment is altered performance over time or after repetition of tasks compared to controls.
It can be argued whether the injury per se is related to impaired cognitive function and, to a lesser extent, to mental fatigue. However, from a study including a recovered mTBI group, no difference was found in mental fatigue and reaction time between those who had recovered and the controls, while a significantly higher MFS and a slower reaction time were reported for those with persistent mTBI [71].

Brain Imaging in Relation to TBI and Fatigue
Brain imaging as an assessment tool for fatigue after TBI is in its infancy. A few recent studies have shown promising results ( Table 2). For participants with a moderate to severe TBI, increased brain activity was reported during a one-hour scanning, while controls showed decreased brain activity in a processing speed task, Symbol Digit Modalities Test -(SDMT), measured with functional magnetic resonance imaging (fMRI). Increased brain activity was suggested to represent increased effort and fatigue. No assessment of trait-or state-fatigue was performed [27]. In contrast, when the same processing speed test (SDMT) was performed, lower brain activity (fMRI) in the basal ganglia, primarily the caudate nucleus, thalamus, and anterior insula, was reported for the TBI group (ranging from mild to severe) compared to controls. The brain activity decreased across the 27-min test session for the controls, whereas the TBI group remained on a similar lower activity level and reported an increased state-fatigue after the session compared to controls [25]. A group of moderate to severe TBI patients reported increased fatigue during the test session compared to controls. Brain activation showed a positive relation between fatigue and fMRI for the more advanced 2-back working memory task and a negative relation for the simpler task (0-back task). Fatigue in relation to brain activation was related to the caudate nucleus [28]. Using functional near-infrared spectroscopy (fNIRS) to measure brain activity during a 2.5 h session, a lower event-related oxygenated haemoglobin (oxy-Hb) concentration was detected in the frontal cortex for the mTBI group, all of whom were suffering from mental fatigue compared to controls. The Stroop-Simon test was repeated once, and other cognitive tests and assessments scales were performed between these. The event activation remained on a similar lower level for the mTBI group and on a similar albeit higher level for the control group. An interaction was found, with the mTBI group having a similar lower oxy-Hb concentration for both congruent and incongruent trials, whereas the controls had a higher concentration of oxy-Hb in the more demanding incongruent trial compared to the congruent trial. Higher mental fatigue correlated with lower oxy-HB [24]. A group suffering from fatigue after mTBI used different brain networks compared to healthy controls during a 20-min vigilance task. There was a correlation between fatigue and functional connectivity in the thalamus and middle frontal cortex and changes in regional cerebral blood flow (rCBF). rCBF was related to fatigability with increased rCBF in the right middle frontal gyrus. Self-rated fatigue was related to increased rCBF in the left medial frontal and anterior cingulate gyri and decreases of rCBF in a frontal/thalamic network [26,29]. To evaluate mental fatigue associated with mTBI in acute and chronic phases, a 20-min psychomotor vigilance test was related to arterial spin labeling-fMRI. Sustained attention was impaired in mTBI patients both in acute and in chronic phases compared to controls, and with worse performance in the acute phase [72]. Brain activation associated with effort and fatigue did not differentiate the mTBI and controls, while functional connectivity did. Connectivity between the left anterior insula, rostral anterior cingulate cortex, and right-sided inferior frontal regions correlated with effort level and state-fatigue in mTBI participants. These connections also correlated with effort level in the controls. Left insula and superior medial frontal gyrus correlated with fatigue. The authors propose a complex link between effort and fatigue and that it may be related to an inefficient neuronal system [73]. Activation assessed with rCBF within the cerebellar cortex correlated with PASAT, measuring information processing and sustained and divided attention in controls, while mTBI participants with self-reported cognitive fatigue showed significant correlations in the inferior frontal and superior temporal cortices [74]. MRI revealed grey matter (GM) and white matter (WM) brain lesions in a TBI group, but fatigue was not found to be related to brain lesions [75]. White matter hyperintensity lesions (WMH) were more common in mild-severe TBI patients compared to controls, but WMH lesions were not related to cognitive tests. Increased WMH lesions correlated with reduced fatigue, but the relation to fatigue was reported to be weak [76]. An mTBI group had a larger number of low diffusion tensor imaging measures (fractional anisotropy values) and more post-concussion symptoms (fatigue not measured separately but included in the PCS) compared to controls. No difference in neurocognitive tests was found [77]. In mild to moderate TBI participants, compared to controls, decreased white matter integrity of the left anterior internal capsule was associated with a greater level of fatigue [78]. A higher rating of fatigue in an mTBI group was associated with decreased right and left thalamic volumes [79]. From the Vietnam Head Injury Study registry, individuals with penetrating brain injuries (PBI) were assessed with a self-report questionnaire and computed tomography (CT) scans. Lesion location and volume were evaluated. PBI patients were divided into three groups according to lesion location: a nonfrontal lesion group, a ventromedial prefrontal cortex (vmPFC) lesion group, and a dorso/lateral prefrontal cortex group. Fatigue scores were compared between the three PBI groups and the healthy controls. Individuals with PBI with vmPFC lesion were significantly more fatigued than the other groups as well as the healthy controls. VmPFC volume correlated with fatigue scores showing that the larger the lesion volume, the higher the fatigue scores [80].   In summary, the brain imaging results are not consistent, although they show altered activity and connectivity in relation to fatigue after TBI. From the fMRI and fNIRS fatigue studies above, experimental block or event-related designs were used. Results need to be understood in relation to the study design used, as the results can vary depending on design. Discordance between study designs was reported for brain tumor patients [81].
No studies relating glucose metabolism (FDG-PET[(18)F]fluorodeoxyglucose-positron emission tomography) or magnetoencephalography (MEG) to fatigue in TBI were found, but it would be of interest to more deeply investigate energy metabolism in relation to fatigue after TBI and also to use MEG, a promising method for identifying mTBI [82].

Suggestions for Future Research
The heterogeneity was high between studies, with insufficient evidence to determine any cognitive or neuroimaging test to predict fatigue after TBI. However, the studies imply connections between cognitive function and brain activation in relation to fatigue after TBI. This is worth exploring further with an intention of being open-minded and considering explanations at many different levels.
Assessment of fatigue must be improved. Here, different fatigue assessment scales were used in the reports. The construction of the scale may have an impact on the results, depending on sensitivity and specificity. It is also important to differentiate between normal and pathological fatigue, as biological and psychological factors may have a different explanation for mental fatigue.
Mental fatigue and its relation to depression needs to be acknowledged after TBI, as it will be important for treatment strategies.
With regard to mental fatigue affecting everyday life, executive and cognitive function have not been explored adequately and it is important to reach a clearer understanding of these aspects in relation to fatigue.
On a group level, slower processing speed is encountered primarily in relation to mental fatigue. More demanding tests may be more sensitive in detecting fatigue, but there is no clear connection to fatigue. Endurance in everyday life is critical for those suffering from mental fatigue, and repetition of tests may be more valid for measuring fatigue.
Brain imaging methods show promising results, establishing an association between fatigue and brain activation, primarily in the frontal cortex, thalamus, caudate nucleus, and connectivity between these areas. Cognitive and physical functions can be related to focal brain injuries. When no single area is clearly affected and cognitive tests are performed within the spectrum of normality and yet debilitating mental fatigue persists, we need to investigate further. We need to better understand the impact of the neurochemical cascade that can induce inflammation, biochemical imbalance, oxidative stress, and an extended reduction of glucose metabolism in relation to mental fatigue [36]. Brain imaging is a growing research field along with other imaging methods such as PET and MEG, which also warrant investigation.
Mental fatigue is not a new phenomenon, and it is essential to acknowledge the debilitating fatigue that patients describe despite the limited availability of diagnostic criteria and the lack of a clear definition of mental fatigue after TBI or mTBI and its origins.