Neuropsychological and physiological correlates of fatigue following traumatic brain injury

Abstract

Background:
Fatigue is a common and debilitating phenomenon experienced by individuals with traumatic brain injury (TBI) that can negatively influence rate and extent of functional recovery by reducing participation in brain injury rehabilitation services and increasing maladaptive lifestyle practices. The underlying mechanisms of TBI-related fatigue are not entirely understood and focused research on symptom reduction or prevention is limited.

Review:
The current review of the literature suggests that the aetiology of TBI-related fatigue can be viewed as a multifactorial and complex model impacting physiological systems (i.e. endocrine, skeletal muscle and cardiorespiratory) that can be directly or indirectly influenced by neuropsychological correlates including cognitive and psychological impairment. Distinguishing central from peripheral fatigue is helpful in this regard. Potential therapeutic strategies and pharmacological agents to help alleviate fatigue in this patient population are discussed.

Full text

2014
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Brain Inj, 2014; 28(4): 389–397
!2014 Informa UK Ltd. DOI: 10.3109/02699052.2014.884242
REVIEW
Neuropsychological and physiological correlates of fatigue following
traumatic brain injury
Dennis J. Zgaljardic
1,2
, William J. Durham
2
, Kurt A. Mossberg
2
, Jack Foreman
1
, Keta Joshipura
2
, Brent E. Masel
1,2
,
Randall Urban
2
, & Melinda Sheffield-Moore
2
1
Transitional Learning Center, Galveston, TX, USA and
2
University of Texas Medical Branch, Galveston, TX, USA
Abstract
Background: Fatigue is a common and debilitating phenomenon experienced by individuals
with traumatic brain injury (TBI) that can negatively influence rate and extent of functional
recovery by reducing participation in brain injury rehabilitation services and increasing
maladaptive lifestyle practices. The underlying mechanisms of TBI-related fatigue are not
entirely understood and focused research on symptom reduction or prevention is limited.
Review: The current review of the literature suggests that the aetiology of TBI-related fatigue
can be viewed as a multifactorial and complex model impacting physiological systems
(i.e. endocrine, skeletal muscle and cardiorespiratory) that can be directly or indirectly
influenced by neuropsychological correlates including cognitive and psychological impairment.
Distinguishing central from peripheral fatigue is helpful in this regard. Potential therapeutic
strategies and pharmacological agents to help alleviate fatigue in this patient population are
discussed.
Keywords
Cardiorespiratory capacity, fatigue, growth
hormone deficiency, hypopituitarism,
neuropsychology, rehabilitation, skeletal
muscle dysfunction, traumatic brain injury
History
Received 11 October 2013
Accepted 13 January 2014
Published online 12 February 2014
Introduction
Traumatic brain injuries (TBI) contribute to a substantial
number of deaths and cases of permanent disability in the
US annually. The Center for Disease Control (CDC) estimates
that at least 5.3 million Americans, 2% of the US popula-
tion, are dependent on the care of another to perform activities
of daily living as a result of TBI [1]. Fatigue is a common
phenomenon experienced by patients with TBI, with preva-
lence rates ranging from 50–80% [2–5], which is considerably
greater than prevalence rates for neurologically intact indi-
viduals (lifetime prevalence ¼24% [6]). Fatigue has been
previously defined by Aaronson et al. [7] as ‘the awareness of
a decreased capacity for physical and/or mental activity due
to an imbalance in the availability, utilization and/or restor-
ation of resources needed to perform an activity’ (p. 46).
Despite the rather high occurrence of fatigue in patients with
TBI there has been limited investigation of the underlying
aetiological factors and potential treatment options.
Fatigue is a multidimensional construct that can be present
in individuals with or without neurological disorder and can
be categorized as either Peripheral or Central fatigue [8].
Peripheral fatigue typically refers to impaired muscle
performance secondary to physical exertion. Certain disease
processes or disorders of the muscle and/or neuromuscular
junction may increase one’s susceptibility to the development
of peripheral fatigue or peripheral fatigability. Central
fatigue, on the other hand, can be viewed from a neuropsy-
chological standpoint, as a subjective percept of one’s fatigue
symptoms at the level of the central nervous system described
by Chaudhuri and Behan [9] as ‘the failure to initiate and/or
sustain attentional tasks and physical activities requiring self-
motivation’ (p. 35). Central fatigue is typically viewed as a
subjective phenomenon that can be expressed in several
different ways such as experiencing a lack of energy or
motivation, weakness, fatigability, sleepiness, weariness,
lassitude, boredom, adynamia, anhedonia and/or abulia [10]
and has been reported to greatly impact patients’ lifestyles by
limiting participation in social and leisure activities [11, 12],
which can in turn negatively influence quality-of-life.
The current review of the literature posits that TBI-related
fatigue (central or peripheral) may manifest (directly or
indirectly) from a number of circumstances resulting from
neurological insult including neuropsychological impairment
(cognitive deficits and/or mood disorder including chronic
pain and sleep disorder, etc.), pituitary dysfunction, inflam-
matory processes, oxidative stress, skeletal (mitochondrial)
muscle changes and cardiorespiratory dysfunction with
resulting increases in sedentary lifestyle and inactivity
(Figure 1).
Neuropsychological correlates of central
fatigue in TBI
Psychological symptoms (e.g. anxiety and depression) may
occur as a reaction to the brain injury itself and/or as a result
Correspondence: Dennis J. Zgaljardic, PhD, ABPP, Director,
Department of Neuropsychology, Transitional Learning Center, 1528
Postoffice Street, Galveston, TX 77550, USA. Tel: 409-797-1472. Fax:
409-797-1490. E-mail: dzgaljardic@tlc-galveston.org
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of the experience of hospitalization, including loss of
independence and separation from loved ones following a
TBI. Pain and disruption of sleeping patterns, for instance,
are common in this patient population and can exacerbate
psychological symptoms. In addition, patients with TBI
must learn to cope with cognitive as well as physical
limitations and the very real possibility that their lives may
not return to pre-morbid levels of functioning [13].
Psychological symptomatology can also be the direct
result of underlying neurological impairment. For instance,
patients with left frontal cortical lesions or those localized
to sub-cortical areas of the brain may experience an
‘organic depression’ [14]. Alternatively, damage to specific
frontal regions of the brain may result in behavioural
disturbances such as disinhibition, impulsivity, apathy,
abulia and emotional lability [15].
The association between psychological symptoms and
fatigue post-TBI is not entirely clear. The consensus from
prior work indicates a consistent, but not necessarily causative
association between subjective fatigue and psychopathology
in this patient population [8]. In their study assessing potential
correlates of fatigue in patients with TBI, Ponsford et al. [4]
discovered that patients with symptoms related to anxiety
and depression were more likely to report significant levels
of fatigue; however, so were patients who also experienced
heightened levels of pain and cognitive dysfunction (e.g.
reduced speed of information processing). Schnieders et al.
[16] found that disrupted sleeping patterns, vitamin D
deficiency and symptoms related to anxiety explained
approximately two-thirds of the variance in the subjective
fatigue scores in patients with TBI. Similarly, Englander et al.
[17] discovered that 42–60% of the variance discovered
across two separate fatigue rating scales were explained by
gender of the patient, depression severity, pain and perceived
memory or motor dysfunction. Bushnik et al. [2] assessed
and monitored fatigue, as well as other cognitive and
behavioural symptoms in patients with moderate-to-severe
TBI, over a 2-year period. Despite a lack of statistically
significant findings across all time-points, fatigue severity
in their sample varied with scores highest during the
first 6 months, declining by 12 months post-injury and
increasing somewhat by 18–24 months post-injury. The
declines in fatigue reported in their sample of patients with
TBI appeared to coincide with improvements in patients’
experience of pain, sleep quality, cognition and participation
in productive activities. Conversely, those patients who
continued to experience heightened levels of fatigue reported
worsening sleep quality and lack of functional or cognitive
gains over time.
Cognitive impairment is common following TBI and
predominantly impacts domains such as memory, attention,
executive functioning and speed of information processing
[10, 18, 19]. van Zomeren and Brouwer [20] attributed the
relationship between fatigue and cognitive impairment to
the heightened level of resource utilization required in order
to establish and maintain pre-injury levels of mental func-
tioning in the presence of cognitive deficits (i.e. coping
hypothesis). As a consequence, patients with TBI may
typically identify their fatigue symptoms as a cognitive
phenomenon and experience exhaustion following certain
mental tasks [21].
While research assessing cognitive impairment and sub-
jective fatigue following TBI is limited, prior work has been
able to demonstrate significant associations between self-
reported symptoms of fatigue and performance on select tests
of neuropsychological functioning. Using various neuropsy-
chological tests that assess selective attention, divided
attention, working memory and speed of information pro-
cessing, Ziino and Ponsford [22] reported significant,
although modest correlations between three separate self-
report measures of fatigue and test performance declines in a
sample of patients with TBI. After controlling for symptoms
related to depression and anxiety associations between fatigue
measures and performance on a test of selective attention
and working memory remained stable, whereas associations
between fatigue measures and performances on tests of
divided attention and speed of information processing were
no longer statistically significant. In another study, Ziino and
Ponsford [23] assessed the association between subjective
and objective fatigue following administration of a computer-
based vigilance task. Measures of subjective fatigue and
selective attention were administered along with a registration
of a change in blood pressure (i.e. objective fatigue) before
and after administration of the vigilance task. Patients with
TBI performed worse than neurologically intact individuals
with regard to reaction time and number of errors on the
vigilance task; however, the TBI group performance levels
remained unchanged across the duration of the task. Ziino and
Ponsford [23] discovered that subjective reports of fatigue
reported by their TBI sample were related to the number of
Traumatic Brain Injury
Neuropsychological
impairment, Pain,
Sleep disorders, etc.
Endocrine
Dysfunction
Inflammation,
Oxidative
stress
Hormone
Levels
Peripheral
Fatigue
inactivity
Central
Fatigue
Mitochondrial
Dysfunction
Cardiorespiratory
Dysfunction
Figure 1. Proposed mechanism of TBI-related central and peripheral
fatigue. TBI induces neuropsychological impairment, pain, sleep
disorders and, in some individuals, endocrine dysfunction. In addition,
TBI elicits inflammation and oxidative stress, initially at injury foci,
later possibly in additional tissues through indirect effects, such as
TBI-induced physical inactivity or mitochondrial impairment secondary
to hormone deficiencies. Mitochondrial and cardiovascular dysfunction,
as well as oxidative stress, may contribute to peripheral fatigue.
Notably, central fatigue-induced reductions in physical activity may
initiate a self-reinforcing cycle of central fatigue and peripheral fatigue.
Well-established relationships are designated by solid lines, whereas
those less certain, particularly in the setting of TBI, are indicated by
dashed lines. Brain mitochondrial function, blood flow, inflammation
and oxidative stress may also influence central fatigue but were omitted
for the sake of simplicity.
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errors on the vigilance task (but not the selective attention
task), as well as an increase in diastolic blood pressure. While
they were unable to replicate previous findings [22], their
overall findings appear to lend support to van Zomeran and
Brouwer’s [20] coping hypothesis in that patients with TBI
may exert greater mental effort and physiological cost on
cognitive demanding tasks in order to maintain stable levels
of performance over time that results in heightened levels
of subjective fatigue.
Chaudhuri and Behan [9, 24] proposed that the basal
ganglia plays a vital role in central fatigue, as neurological
disorders with hallmark symptoms of central fatigue appear
to have a strong association with basal ganglia dysfunction
(e.g. Parkinson’s disease [25]). Lesions and/or neurodegen-
eration of the basal ganglia can disrupt neural transmission to
regions such as the prefrontal cortex (dorsolateral, anterior
cingulate and ventromedial regions) and thalamus, which can
in turn negatively impact limbic system function including
initiation of movement, emotion and cognition [26–30]. Kohl
et al. [31] investigated the neural correlates of fatigue in
patients with TBI and neurologically intact individuals using
a sustained attention and processing speed task paradigm
while undergoing functional magnetic resonance imaging
(fMRI). Task performance did not differ between patients
with TBI and neurologically intact individuals; however,
patients with TBI demonstrated greater neural activation in
brain regions including the basal ganglia, middle frontal
gyrus, superior parietal cortex and the anterior cingulate.
These increases in neural activation in the TBI group were
purported to represent an increase in resource utilization
necessary to perform at a level analogous to neurologically
intact individuals that may result in greater subjective fatigue.
On the other hand, neurologically intact individuals were
reported to rely more on increased activation in the striatal
and prefrontal regions early on during task performance, with
steady decreases in activation with continued task perform-
ance [31]. Dobryakova et al. [26] provide an argument for the
association between central fatigue and the ‘non-motor
functions of the basal ganglia’ (e.g. reinforcement/reward
schedules [for review, see 30]) by suggesting the existence
of a disparity between an individual’s perception of the
reward in performing a given task and the amount of effort
(i.e. energetic cost) exerted in doing so. This imbalance may
be attributed to a disruption of cortico-strial (dopaminergic)
circuitry, connecting the basal ganglia and the prefrontal
cortex.
Relationship between central fatigue and
skeletal muscle fatigue in TBI
Skeletal muscle fatigue is a type of peripheral fatigue and is
defined as a decline in skeletal muscle force or power pro-
duction resulting from muscle activity [32]. In addition to the
definition of central (subjective or perceptual) fatigue
described above, ‘central fatigue’ is also often used to
describe skeletal muscle fatigue secondary to impaired neural
activation of muscle [33]. In this review, central fatigue refers
to the perceptual experience of fatigue rather than sub-optimal
motor drive, while acknowledging the two are potentially
related.
The aetiology of both central and peripheral fatigue is likely
multifactorial, although the contribution of skeletal muscle
properties to the experience of central fatigue is poorly
understood. For example, skeletal muscle afferents contribute
to the perception of fatigue during muscle contractions [34, 35]
and the effort required to perform a task increases in response
to skeletal muscle fatigue [36–39] or damage [40–42]. Neural
feedback from fatiguing skeletal muscles can reduce motor
activation of contraction and increase breathing rate and
perceived exertion [43, 44]. In addition, specific regions of the
brain are activated as skeletal muscle fatigue develops [45].
Conversely, when central fatigue is pre-induced by a task
associated with activation of at least one of those regions
(e.g. prefrontal cortex), time to exhaustion during subsequent
exercise (e.g. cycling) is reduced and perceived exertion is
increased relative to exercise without pre-induced central
fatigue [46]. Notably, these responses occur despite near-
identical physiological parameters (e.g. heart rate, cardiac
output, oxygen consumption and lactate concentration) [46].
Intriguingly, compelling proof-of-concept studies in dys-
trophic mouse models suggest that reduced skeletal muscle
capillary perfusion, secondary to reduced nitric oxide (NO)
signalling through cyclic guanine monophosphate (cGMP),
reduces exercise capacity, exacerbates sarcolemmal (mem-
brane enclosing a striatal muscle fibre) damage and contributes
to central fatigue [47–50]. Further, augmentation of NO-cGMP
signalling with a phosphodiesterase 5 inhibitor (PDE5 inhibi-
tor, e.g. sildenafil or tadalafil) ameliorates these responses
while increasing skeletal muscle perfusion [49–51]. These
findings suggest that changes in muscle perfusion could
contribute to both skeletal muscle fatigue and central fatigue
and could be reduced by PDE5 inhibitors, a drug class with
proven efficacy to safely improve tissue perfusion in multiple
tissue beds [49, 52–55].
Evidence suggests that impaired skeletal muscle mito-
chondrial functioning could also be involved in central
fatigue experienced by individuals with TBI, although to the
authors’ knowledge this has not been thoroughly investigated.
Reduced content or function of skeletal muscle mitochondria
has been described in other patients in which fatigue is
common, including chronic fatigue syndrome [56, 57],
individuals undergoing statin treatment [58–62], HIV/AIDS
[63, 64] and ageing [65]. Notably, skeletal muscle mitochon-
drial function is depressed by inactivity [65–67] and individ-
uals with TBI typically have low levels of physical activity,
both during early recovery from the injury, when rest is
recommended by consensus panels [68, 69], as well as later
in the chronic phase of recovery [69, 70]. Although not a
direct measure of skeletal muscle mitochondrial function, the
reduction in maximal oxygen uptake (VO
2
max) in individ-
uals with TBI [71, 72] is consistent with impaired skeletal
muscle mitochondrial function. Likewise, the reduced venti-
latory threshold, characterized by relative hyperventilation
at submaximal exercise intensities, observed in individuals
with TBI [71, 72], may be reflective of reduced oxygen
extraction by skeletal muscle mitochondria and increased
reliance on non-mitochondrial metabolism, although other
factors, such as altered processing of afferent signals from
skeletal muscle or altered activity of specific brain regions
cannot be ruled out.
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Debility, cardiorespiratory capacity and
fatigue following TBI
Aerobic capacity and the ability to do sustained work are
estimated to be reduced in 25–35% of patients with TBI
[72–74], which may have a considerably negative impact on
fatigue in this patient population. Among the likely causes are
the deleterious effects of inactivity or bed rest (i.e. debility),
particularly during the acute phase of recovery. It is well
documented that debility has a negative effect on muscle
oxidative capacity, which is specifically related to decreased
capillary density and decreased mitochondrial numbers and
enzyme capacities [75, 76]. Becker et al. [77] were the first
to document the reduced physical work capacity of patients
recovering from TBI by means of assessing ventilatory
capacity. Decreased ventilatory capacity has also been
reported in the form of increased submaximal ventilatory
equivalents of oxygen and carbon dioxide [72], which are
indicators of decreased breathing efficiency. During bed rest
and the sedentary lifestyle that a majority of patients with
TBI experience, ventilatory muscles atrophy and lose their
endurance capacity, which contribute to decreased breathing
efficiency. The sensation of shortness of breath is also a result
of the combination of cardiac and pulmonary changes
(e.g. deconditioning) and may play a major role in fatigue
symptomatology during physical work or exercise. The
myocardium (muscular tissue of the heart) also undergoes
changes, including the diuresis that takes place during bed
rest, that result in decreased stroke volume and ultimately
cardiac output. This constellation of factors can severely limit
the delivery and utilization of oxygen by the working muscle,
suggesting they may play a significant role in the reduced
cardiorespiratory capacity that has been documented in
patients with TBI.
Post-traumatic hypopituitarism and fatigue
Post-traumatic hypopituitarism (PTH) accounts for 30% of
patients with moderate-to-severe TBI in the acute phase [78,
79] and 40% of individuals in the post-acute phase [79–81].
Due to its location within a densely packed sella turcica, the
pituitary gland is quite vulnerable to head trauma, resulting
in compression of the hypophysial portal system (vessels
that carry blood and regulatory hormones from the hypothal-
amus to the adenohypophysis) with damage leading to PTH.
Additionally, some studies have identified production of
antibodies targeting hypothalamic cells in the post-traumatic
period, suggesting the possibility of an autoimmune process
that may also contribute to pituitary dysfunction [82, 83].
Chronic PTH can result in hormonal dysregulation causing
several neuroendocrine disorders, including growth hormone
(GH) and gonadotropin deficiencies as well as hypothyroid-
ism [84]. Growth hormone deficiency (GHD) occurs in
15–20% of individuals with a history of TBI, including
blast-related injuries [79, 85–89], and is typically associated
with self-report of fatigue, decreased exercise tolerance,
depression, osteoporosis, hypercholesterolemia and athero-
sclerosis [90], all of which may negatively influence partici-
pation in brain injury rehabilitation services and potential for
functional gains. Perhaps the symptom of fatigue warrants
consideration of GHD in TBI, as GHD in the absence of TBI
is associated with fatigue [91–94]. Thomas et al. [95] reported
reduced aerobic capacity in patients with GHD but without
TBI that are similar in magnitude to those observed in
patients with TBI and GHD. GHD has also been reported in a
sub-set of patients with fibromyalgia [96–100], a group in
which fatigue is a cardinal characteristic. GHD may have
a direct impact on skeletal muscle mitochondrial function,
as GH stimulates skeletal muscle mitochondrial enzyme
activity and adenosine triphosphate (ATP) synthesis [101,
102]. Impaired skeletal muscle mitochondrial function may,
thus, be partially responsible for the reduced maximal aerobic
capacity in individuals with GHD but without TBI [94].
In patients with both TBI and GHD or GH insufficiency, VO
2
max is considerably worse relative to patients with TBI and
normal GH levels [103], which could reflect further impair-
ment of skeletal muscle mitochondrial function. These
findings suggest that GH replacement therapy may improve
cardiorespiratory capacity in TBI patients with GHD or GH
insufficiency. For instance, Bhagia et al. [104] reported on a
patient with mild TBI who received recombinant human
growth hormone (rhGH) over the course of 12 months. This
patient demonstrated improved cardiorespiratory fitness at a
6 month follow-up period and improved ventilatory equiva-
lents at 12 months. Other preliminary data suggest that
treatment with rhGH improves ventilatory equivalents and
breathing efficiency in patients with moderate-to-severe
TBI [105].
Potential therapeutic strategies and
pharmacological agents for treatment
of TBI-related fatigue
The development of treatment regimens are crucial to
mitigate symptoms of fatigue in patients with TBI [106],
yet, despite this recognition, few rehabilitation programmes
focus on fatigue reduction or prevention. The simple fact is
that patients with TBI could benefit both physically and
cognitively from receiving interventions targeting symptoms
of fatigue in the acute or post-acute period and there are
several potential therapeutic strategies and/or pharmaco-
logical agents that could be employed or administered to
effectively combat TBI-related fatigue.
Ponsford et al. [4] suggested that an interdisciplinary
rehabilitation treatment team should consider all possible
factors that may contribute to perceived fatigue (e.g. cognitive
changes, affective symptoms, prescription medications, sleep-
ing patterns, etc.) and address these symptoms accordingly.
Further, they suggest that the individual’s lifestyle practices
be monitored to ensure that they coincide with physical
and neuropsychological limitations attributed to the injury.
Borgaro et al. [107] suggested that having patients engage in
physical activities to help increase endurance, as well as
improve restful sleep, may help reduce fatigue and should be
considered a focus in the acute stage of injury. Continued
treatment for those individuals suffering from depression
(psychotherapy) or memory impairment (cognitive remedi-
ation or compensation) post-TBI may be helpful in alleviating
fatigue [17]. Schnieders et al. [16] reported that poor sleep,
vitamin D deficiency and anxiety explained 59% of the
variance in the patients’ subjective fatigue scores. Vitamin D
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deficiency, a well-known cause of muscle aches and weakness
in humans [108], was attributed to a reduction of sun exposure
secondary to injury-related lifestyle changes (e.g. sedentary)
in their sample of patients with TBI [16]. Hence, bright light
therapy was suggested as having potential effectiveness in
reducing symptoms of fatigue in patients with TBI [4, 16].
In their randomized, blinded, placebo controlled study, Jha
et al. [11] did not demonstrate evidence for the effectiveness
of modafinil (wakefulness-promoting agent) in treating
fatigue in patients with TBI.
Growth hormone replacement therapy may have strong
potential for improving fatigue, particularly in patients with
TBI. The rationale behind treating TBI-related fatigue with
GH replacement therapy is based upon data that has
demonstrated that 15–20% of individuals with a history of
TBI exhibit evidence of GHD (see discussion above; [16, 81,
86, 88, 109]). While TBI-related GHD has been shown to be
related to central fatigue [81, 86, 88, 109], previous work has
not demonstrated a consistent relationship [17, 110]. Notably,
no studies of the efficacy of GH replacement therapy for the
reduction of central fatigue in patients with TBI and GHD or
GH insufficiency have been published to date, although prior
work using patients with moderate-to-severe TBI with GHD
revealed improvements over time on tests of neuropsycho-
logical functioning that assess speed of information process-
ing, learning and memory and executive functions [111].
It has been previously recommended that patients with
TBI be screened for pituitary hormonal deficiencies
because appropriate pharmaceutical supplementation early
on in the rehabilitation process may result in improved
quality-of-life of TBI survivors [111–114]. Given the rela-
tively high occurrence of GHD in TBI, early screening and
assessment of pituitary hormone deficiencies seems clinically
warranted.
In addition or as a complement to strategies targeting
a specific TBI-related impairment (such as GHD), other
therapeutic agents could potentially reduce fatigue in TBI
patients by reducing ‘baseline’ fatigue (i.e. non-TBI-related
fatigue). Phosphodiesterase (PDE5) inhibitors are a potential
therapeutic agent for fatigue post-TBI that may target both
TBI-related and non-TBI related fatigue, although they have
not been investigated for this purpose to date. Sildenafil is
a potent and selective type 5 phosphodiesterase (PDE5)
inhibitor and PDE5 is expressed in skeletal muscle as well as
blood vessels. Sildenafil acts by augmenting NO-mediated
signalling via reduced degradation of the downstream medi-
ator cGMP. In situ and in vivo studies suggest that higher
skeletal muscle NO levels may be associated with reduced
skeletal muscle and central fatigue through neural and
haemodynamic mechanisms [49, 115–118]. Chronic NO
exposure also leads to mitochondrial biogenesis [119–125]
by increasing concentrations of cGMP [124, 125] and
induction of peroxisome proliferator activated receptor
gamma coactivator 1 alpha (PGC1-), a regulator of mito-
chondrial biogenesis and function [124]. Mitochondrial
biogenesis is a hallmark adaptation to endurance training
[126–131] and is associated with resistance to skeletal muscle
fatigue [129, 130]. Sheffield-Moore et al. [132] recently
reported that sildenafil improves skeletal muscle function
by increasing resistance to muscle fatigue while stimulating
skeletal muscle protein synthesis. Thus, pharmacological
agents such as sildenafil that may influence several potential
aetiologic mediators (e.g. mitochondrial or haemodynamic
dysfunction) may represent a viable therapeutic strategy for
combating TBI-related fatigue in those patients not found
to be GHD.
Conclusions
Several studies have investigated the potential neuropsycho-
logical and physiological correlates of fatigue post-TBI,
including cognitive impairment, mood disorder, endocrine
dysfunction, skeletal muscle changes and cardiorespiratory
insufficiency. However, the relationship between TBI physio-
logical and neuropsychological sequelae and fatigue is
complex and not entirely understood.
Prior work has demonstrated a consistent, albeit not
necessarily causative relationship between psychological
sequelae and fatigue post-TBI. Fatigue symptoms can vary
with changes (improvements or declines) of other factors
including pain severity, sleep quality, lifestyle changes and/or
level of independence. TBI-related cognitive impairment can
lead to an increase in subjective fatigue, as patients may lack
the level of mental effort or capacity necessary to perform
previously manageable tasks (i.e. coping hypothesis).
Growth hormone deficiency, secondary to post-traumatic
hypopituitarism, is believed to be one of the major causes of
impairment and disability post-TBI and may directly and/or
indirectly impact skeletal muscle mitochondrial function
(i.e. enzyme activity and ATP synthesis) and cardiorespira-
tory capacity. Inflammation and oxidative stress in the post-
traumatic period results in a decline in skeletal muscle
activity, which activates neural feedback that ultimately
results in heightened perception (i.e. subjective appraisal) of
fatigue in the individual. Reduced NO-cGMP signalling
reduces exercise capacity and may further contribute to
fatigue. Prolonged physical inactivity (i.e. debility and/or
sedentary lifestyle) post-TBI may also depress skeletal muscle
mitochondria function, which results in reduced oxygen
extraction.
The most effective strategies for the treatment of fatigue in
patients with TBI are not yet established; however, the need to
address this phenomenon is paramount as it can potentially
facilitate participation in brain injury rehabilitation services
with an increase in the rate of recovery of functional gains.
Increased physical activity, adequate sleep and improved
blood flow may be the most appropriate and beneficial
solutions to alleviate fatigue, especially in the acute phase
post-TBI. The existence of such deficits and their potential
contribution to the fatigue experienced by individuals with
TBI, as well as potential therapeutic strategies or pharmaco-
logical agents, will remain conjectural until well-controlled
clinical trials are performed in this patient population.
Declaration of interest
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of the paper. This
work was partially funded by the generous support of the
Moody Endowment, a grant from the National Cancer
Institute (5R01CA127971, to M.S.M.) and a pilot grant
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(to W.J.D.) from the Claude D. Pepper Older Americans
Independence Center (5P30-AG024832, to E. Volpi).
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DOI: 10.3109/02699052.2014.884242 Fatigue and traumatic brain injury 397
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