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From: Long-Lasting Mental Fatigue After Traumatic Brain
Injury – A Major Problem Most Often Neglected
Diagnostic Criteria, Assessment, Relation to Emotional
and Cognitive Problems, Cellular Background, and
Aspects on Treatment

a cellular level corresponds to the long time it takes for the TBI victims to restore mental
activity.
One way to restore this dysfunction is to stimulate Na+/K+-ATPase along the dopaminergic
circuits which regulate attention and executive functions. Possible candidates are methylphenidate
and the dopaminergic stabilizer OSU6162 (see below under the heading, ‘Treatment’).
3. Assessment of mental fatigue
There is an abundance of scales for assessing fatigue in general and several of these scales are
designed for use in different diseases [21, 22]. The scales include questions relating to feelings
of fatigue, perceived impact on activities, affective feelings and mental or cognitive effects.
Many of the scales are self-reported on a Likert or an ordered scale, with the following response
alternatives: Never, Sometimes, Regularly, Often or Always.
We have developed and used the Mental Fatigue Scale (MFS) during the last five years. We
decided to construct this scale since we were not able to find an assessment scale adapted to
mental fatigue. The MFS is a multidimensional questionnaire containing 15 questions. It
incorporates affective, cognitive and sensory symptoms, duration of sleep and daytime
variation in symptom severity. The questions concern the following: fatigue in general, lack
of initiative, mental fatigue, mental recovery, concentration difficulties, memory problems,
slowness of thinking, sensitivity to stress, increased tendency to become emotional, irritability,
sensitivity to light and noise, decreased or increased sleep as well as 24-hour symptom
variations. The questions in the scale are based on common activities and we have related the
estimation to exemplified alternatives. It is also possible to provide estimations in-between
two alternatives. The intention was to make the scale more consistent between individuals and
also between ratings for the same individual. The exemplified alternatives can help the person
to respond in a similar way despite the present state of fatigue or emotional state. The MFS is
designed in a similar way as The Comprehensive Psychopathological Rating Scale (CPRS). The
CPRS also includes exemplified alternatives and it is used to record changes in psychopathology
over a comparatively short period [23]. The questions included in the MFS are based on
symptoms described following longitudinal studies of patients with TBI, brain tumours,
infections or inflammations in the nervous system, vascular brain diseases, and other brain
disorders, which indicates that an acquired brain injury or disorder can result in similar
symptoms [24-26]. The scale is free to use and can be downloaded at www.mf.gu.se (both in
Swedish and English). We have transcribed one of the questions in the MFS, below:
Mental fatigue
Does your brain become fatigued quickly when you have to think hard? Do you become
mentally fatigued from things such as reading, watching TV or taking part in a conversation
with several people? Do you have to take breaks or change to another activity?

this, we found, with the use of the CPRS/MADRS, that there was an elevation in the rating of
depression items for TBI subjects compared to controls. The CPRS scale includes both a
depression and an anxiety scale [23, 38]. The CPRS depression scale is also called the Montgomery-
Åsberg Depression Rating Scale (MADRS) [39].
However, there are overlapping items in the MFS and CPRS. The overlapping items include
the following: lack of initiative, concentration difficulties, irritability and decreased sleep. With
a factor analysis, the items were separated into a mental fatigue component and a depression
and anxiety component. Irritability was placed in the depression-anxiety component and the
other three items in the mental fatigue component. With an analysis using the new components,
we found that by adjusting the mental fatigue component this removed the difference
observed between the brain injured subjects and controls in the depression-anxiety component.
However, by removing the depression-anxiety component this did not have an effect on
the difference observed between the brain injured subjects and controls in the mental fatigue
component.
In this subject sample, we were able to demonstrate that a significant effect on the difference
observed between the brain injured subjects and controls in the scores for depression can result
in an overestimation if the effect of the mental fatigue component is not taken into consideration.
This indicates that mental fatigue and depression must be treated as separate constructs
and it is also important to make this distinction for the purposes of therapeutic strategies.
6. Definition and diagnostic criteria for long-lasting mental fatigue
The diagnostic criteria for posttraumatic brain syndrome include most of the symptoms that
are often present along with mental fatigue. However, we suggest mental fatigue to be a central
symptom after a brain injury reflecting an inefficient support to the neuronal networks.
Mental fatigue is a lack of mental energy with impaired cognitive, emotional and sensory
functioning. Mental fatigue is characterized by an unusual feeling of fatigue or malaise. There
is a drain on the person’s mental energy upon mental activity. The result is a diminished
attention and concentration capacity. Situations which involve high levels of external cues and
an overload of impressions are strenuous. Failing energy levels and excessively long recovery
times are the result of over-exertion. The condition impairs the person’s ability to function in
their work, studies and gatherings with family and friends.
6.1. How to recognize long-lasting mental fatigue
• The mental fatigue has persisted for at least 1 month;
• The sum of scores from the MFS is 10.5 points or above.
Typical symptoms include:
• An unusually rapid drain of mental energy upon mental activity;

activity;
500 Traumatic Brain Injury
• Impaired attention and concentration capacity over time;
• Following over-exertion, a long recovery time disproportionate to the exertion level;
• Diurnal variation of the fatigue symptom with the fatigue often being better in the mornings
and worse in the afternoons and evenings; variations from one day to the next;
• Usually one or several associated symptoms (see below):
The following additional or associated symptoms are common:
• Mood swings, irritability and stress intolerance;
• Trouble with memory;
• Sleep problems;
• Sensitivity to, or intolerance of light and loud noise;
• Headaches following over-exertion.
Sleep problems most often occur in the following way: either a shorter duration of sleep with
interrupted wake-ups or sleeping more than usual. If the person becomes more mentally
fatigued, the sleep will most often become worse, and if the person rests for some days the
sleep can become improved again. The emotional load may increase the severity of the fatigue,
but if mental fatigue exists, it will remain even once the emotional components, as depression
or anxiety have been treated. However, it is important to treat the emotional problems. In this
way, the mental fatigue may, to some extent be relieved.
6.2. If the fatigue is not acknowledged in time, this may result in the following
• A total and almost paralyzing fatigue;
• Longer periods of rest may be needed, often over several days;
• A worsening of symptoms over time;
6.3. Mental fatigue symptoms are often present in the following situations
• Situations in which there is an invasion of the senses with an overload of impressions, and
noisy and hectic environments such as crowded events, also the hustle and bustle of
shopping centers, and travelling by bus, etc.;
• Reading books and newspapers;
• Conversations with people – this becomes more of a struggle when more people are
involved;
• Unexpected events.

7.2. Treatment studies for alleviating mental fatigue
When mental fatigue becomes a prolonged problem, it is essential to be able to alleviate the
symptoms. We have reported on significantly reduced mental fatigue after treatment using
the mindfulness-based stress reduction (MBSR) program [40, 41]. We have also reported on
possible therapeutic strategies to reduce mental fatigue by means of pharmacological treatments,
using neurostimulant substances as methylphenidate [42] which affects dopamine and
norepinephrine signaling. We have also reported on a new substance not currently available
on the market, (-)-OSU6162, which is a dopamine and serotonin stabilizer [43].
7.2.1. Mindfulness
The MBSR program was tested on TBI and stroke victims suffering from long-term mental
fatigue [40]. MBSR is a clinically-effective
method for a wide range of conditions as stress, depression, pain, and fatigue after cancer,
with the potential to help individuals to cope with their difficulties [44-47]. MBSR is also
suggested to be linked to improvements in attention and cognitive flexibility [48] and also to
changes in brain neuronal connectivity [49].
MBSR includes a range of both formal and informal practices. The intervention is based on
Kabat Zinn’s MBSR program [50]. The formal practices in MBSR are described by M. Cullen
2011 [51] and these include gentle Hatha yoga with an emphasis on mindful awareness of the
body, a body scan designed to systematically, region by region, cultivate an awareness of the
body without the tensing and relaxing of muscle groups associated with progressive relaxation,
and sitting meditation with an awareness of the breath as well as a systematic widening
of the field of awareness to include all four foundations of mindfulness: awareness of the body,
feeling tone, mental states and mental contents. As such, the intention of MBSR is much greater
than simple stress reduction. The program consists of eight weekly group sessions which are
each approximately 2.5 hours long, one day-long silent-led retreat between sessions six and
seven and home practice of about 45 minutes, six days a week. The participants receive guided
instructions and CDs for home practice.
We found a significantly reduced mental fatigue after the MBSR program and participants
improved their processing speed significantly compared to control on waitlist [40]. Improvement
was independent of gender, time since injury and age. Another recent study with MBSR
for mild TBI patients showed a similar result with significant improvement in quality of life,
perceived self-efficacy, working memory and attention [52]. Furthermore, a small-scale study
of 10 mild TBI subjects included in the MBSR program over a 12-week period also showed a
significantly improved quality of life and decreased depression rating [53]. The effects were
maintained one year later among the seven contactable participants. They also noted an
improvement in reported energy levels at the follow-up [54]. However, after TBI, a short MBSR
program over a 4-week period did not result in any cognitive or emotional changes [55].
The results demonstrate that mindfulness practice may be a therapeutic method well-suited
to subjects suffering from mental fatigue after brain injury. One reason why MBSR was
effective may be that this treatment offers strategies to better handle stressful situations
504 Traumatic Brain Injury
appropriately and economize with mental energy. Despite the problem of ensuring that
participants stay awake, which is one of the fundamental aspects of meditation, it was possible
to adjust mindfulness to suit the needs of mental fatigue subjects and to improve their
wakefulness as well as reducing their mental fatigue levels.
7.2.2. Methylphenidate
Methylphenidate inhibits dopamine and noradrenalin reuptake resulting in increased
extracellular concentration of dopamine and noradrenalin [56]. Methylphenidate has been
used for many years in the treatment of ADHD in children, in the first instance to increase
wakefulness, attention and concentration capacity. Methylphenidate has also been tested on
TBI victims with positive effects on information processing speed and, to some extent on
working memory and attention [57-63]. Guidelines for use of methylphenidate for deficits of
attention and processing speed after TBI have been suggested [64], while no such guidelines
exist for fatigue following TBI.
In an open randomized study, methylphenidate significantly improved mental fatigue dosedependently
as assessed with the MFS [42]. The item, pain was also studied and we found that
this item was rated high by most of the subjects in our study as the participants were recruited
on the basis of the items, TBI and pain. However, no significant alleviation of pain was reported
as a result of methylphenidate treatment. However, it is important to note that pain can hide
posttraumatic brain injury symptoms or mental fatigue which is not always connected to the
actual pain. We also found that there was no interaction between the pain and the mental
fatigue in those participants treated with methylphenidate. These findings indicate that, not
only is it necessary to treat patients for the pain for which they are primarily referred to the
clinic, but also for the mental fatigue, if present.
Methylphenidate was well-tolerated by TBI subjects. However, tolerance of methylphenidate
differed between subjects and we therefore recommend starting treatment with an initial low
dose.
7.2.3. (-)-OSU6162
The monoaminergic stabilizer OSU6162 interacts with both dopaminergic and serotonergic
systems. It appears to act as an antagonist on a binding site of the D2 receptor. More recent
research has demonstrated that OSU6162 also exerts a stabilizing effect on serotonergic
neuronal circuits, acting as a partial 5-HT2A agonist [65, 66].
In two randomized, double-blind and placebo-controlled studies we found statistically
significant alleviation of mental fatigue after a stroke or TBI by OSU6162 during 4 weeks’
treatment with active drug [43]. However, the numbers of patients in these studies were small
(21 TBI and 19 stroke victims). Further studies are needed, with a larger number of patients
and, in particular longer treatment periods as mental fatigue may be long-lasting. Adverse
reactions were mild and could be avoided by dose adjustment. Several patients experiencing
such adverse reactions expressed the wish to receive continued treatment with the drug.
Long-Lasting Mental Fatigue After Traumatic Brain Injury – A Major Problem Most Often Neglected...
http://dx.doi.org/10.5772/57311
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Similar results were detected for methylphenidate and OSU6162. These drugs were shown to
have the effect of both alleviating mental fatigue and increasing information processing speed.
8. Conclusions
Mental fatigue can become a prolonged and distressing problem after TBI having considerable
effect on life and wellbeing. It is important to acknowledge and assess mental fatigue when
discussing the options regarding therapeutic methods as the mental fatigue has been the result
of a TBI.
After TBI, mental energy levels are failing, and the brain needs to rest. It is not possible to
improve the mental energy with training in order to perform more mental activities. In fact,
training with a view to resting the brain is what is important. Suitably-adapted and energysaving
strategies are important and most patients need support in order to achieve an enduring
balance between activities and rest as this is difficult, it takes a long time and may be frustrating.
The treatment studies we reported on are aimed at helping the person to manage their life
better. However, it is important to stress that there is a risk that the medication can compel the
person to do more than is appropriate. The reason for this is that, most often they want to carry
out activities in a similar way as before the injury and have been longing for the chance to be
able to do this. The problem is that, for most persons suffering from long-term mental fatigue
after TBI, the activity levels are close to the threshold of what they are able to sustain. This
makes them susceptible if they increase their activity levels too much. With mindfulness most
participants reported on more energy, but they also became more pleased and happy with life.
Mindfulness also gave them a tool to use and they could take command over their own lives;
how it is here and now, not longing for a better life or ruminating over what has been. This
also saves energy! A combination with neurostimulants and mindfulness may be a good
therapeutic strategy.
In the future, research is warranted for early treatment with the intention to reduce the
development of long-term mental fatigue. We also need to better elucidate and carry out an
in-depth analysis of mental fatigue.