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Review
Mechanisms of poststroke fatigue
  1. William De Doncker1,
  2. Robert Dantzer2,
  3. Heidi Ormstad3,
  4. Annapoorna Kuppuswamy1
  1. 1 Institute of Neurology, University College London, London, UK
  2. 2 Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  3. 3 Faculty of Health and Social Sciences, University of South West Norway, Oslo, Norway
  1. Correspondence to Dr Annapoorna Kuppuswamy, University College London Institute of Neurology, London WC1N 3BG, UK; a.kuppuswamy{at}ucl.ac.uk

Footnotes

  • Contributors AK conceptualised the review. All authors contributed equally to the writing of the review.

  • Funding Wellcome Trust (202346/Z/16/Z).

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

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Introduction

Stroke is a leading cause of disability,1 with increasing incidence2 and higher survival rates,3 set to make management of long-term consequences of stroke, one of the biggest challenges of the future. Of the many sequelae of stroke, the least understood, most difficult to manage and that which has significant impact on daily life are chronic affective symptoms such as fatigue, pain and mood disturbances.4–6 There is an urgent need to understand the underlying biological mechanisms of chronic affective symptoms to develop evidence-based management strategies and possibly even treatments. In this review, we focus on poststroke fatigue (PSF), a common debilitating symptom that has significant implications for morbidity, disability, quality of life and mortality.4–6 Management of fatigue has been identified by stroke survivors as their top unmet need7–9 and is a top priority for further research.10 Fatigue affects a significant percentage of stroke survivors, ranging from 25% to 85%, the large variability is a result of the definition and the scale used to measure fatigue,11–13 including those with mild strokes and little disability.14 Here, we review recent developments in our understanding of potential triggers for fatigue after stroke, mechanisms that might perpetuate and maintain fatigue in the long term and theoretical models of PSF that might usefully inform future research into PSF.

How do we define and measure fatigue?

Fatigue is a term that is instantly recognisable and understood by all; however, defining fatigue for purposes of quantification and comparison across individuals is notoriously difficult. The difficulty is partly a result of inability to distinguish between the phenomenon of fatigue and its impact. Despite difficulty in defining fatigue, one of the key differences between physiological and pathological fatigue is its resistance to rest and the report of PSF being a distinctly different experience from prestroke ‘normal’ fatigue.15 Beyond these distinctions, there is little consensus on a definition for PSF. Several attempts have been made to capture the felt experience of fatigue16–18: ‘Fatigue is a multidimensional motor-perceptive, emotional and cognitive experience’16; ‘Fatigue is a feeling of lack of energy, weariness, and aversion to effort’17; and ‘decrease or loss of abilities associated with a heightened sensation of physical or mental strain, even without conspicuous effort, an overwhelming feeling of exhaustion, which leads to inability or difficulty to sustain even routine activities and which is commonly expressed verbally as a loss of drive’.18 While definitions based on felt experience define fatigue from a stroke survivors’ perspective, others have attempted to define fatigue from a mechanistic perspective.19 20 ‘Pathological fatigue is, thus, best understood as an amplified sense of normal (physiological) fatigue that can be induced by changes in one or more variables regulating work output. Fatigue could develop during a disease because of dissociation between the level of internal input (motivational and limbic) and that of perceived exertion from applied effort’.19 ‘A plausible mechanism of post-stroke fatigue wherein inflammation, the commonest cause of fatigue in neurological conditions, sets in motion a series of changes that include alterations in sensorimotor processing such as sensory prediction associated with effort mechanisms leading to chronic fatigue in stroke survivors’.20 Little has been done to understand the neurobiological basis of chronic PSF beyond attempting to define it mechanistically, and the only validated tools available to measure fatigue are in the form of questionnaires. The most commonly used scale is the Fatigue Severity Scale (FSS)4 5 11 13 21–25 with Neurological Fatigue Index,26 Fatigue Assessment Scale27 28 and Multidimensional Fatigue Inventory29–32 also used in several studies. These questionnaires capture both the multidimensional nature of fatigue and its impact on daily life. The information captured by the questionnaires and the above definitions allow us to develop plausible mechanistic hypothesis for chronic PSF. The repeated references to ‘effort’ in the definitions, and effort-related statements in the questionnaires, suggest that PSF may be a disorder of effort. We elaborate on evidence that might support this hypothesis in later sections of this review.

Incidence, overlap and impact of PSF

Fatigue after stroke is highly debilitating, with a significant impact on return to work and a major effect on economy.33 Several studies have documented the rates at which fatigue is reported in stroke survivor populations, which ranges from 25% to 85%.13 There could be several contributing factors for the reported differences in incidence. Use of different fatigue scales that measure different aspects of fatigue, combined with a lack of consensus on a ‘cut-off’ point that differentiates the low from high fatigue are limiting factors. Nevertheless, examining the incidence and overlap of fatigue with other affective symptoms could potentially inform our knowledge about origins of fatigue and possibly even the mechanisms of long-term fatigue. Reports of fatigue 6 months poststroke ranges from 40% to 70%4 12 23 34–36 of which anywhere between 29% and 87% suffer from poststroke depression (PSD).4 9 11 25 37 A further 33%–62% also report sleep problems,4 12while 50%–60% suffer from symptoms of pain.4 38 Poststroke anxiety was also correlated with fatigue, but after controlling for depression, the association was non-significant.39 The picture is one of a complex incidence with significant overlap with other affective symptoms. This has previously led to mistaken belief that PSF may be secondary to other primary disorders; however, recent work has highlighted the primary occurrence of fatigue after stroke,40 for example, almost everyone with depression report fatigue, but not all with fatigue have depression.41 This complex picture of incidence is perhaps suggestive of common origins or partial overlap of pathways that mediate affective disturbances alongside independent mediators of fatigue.

Investigations have also studied the influence of characteristics such as the type of stroke, age and gender on incidence of fatigue, which might provide some clues for origins of fatigue. There is no reported difference in incidence of fatigue between haemorrhagic and ischaemic stroke.12 Some studies show a positive correlation between degree of fatigue and age, others show no correlation, while some others report a higher incidence in younger stroke survivors.6 12 13 24 42–45 The lack of a consistent report of age positively correlating with fatigue is suggestive of PSF being a direct result of stroke as opposed to a general decline in energy levels with advancing age. A pragmatic approach to age and fatigue is that younger stroke survivors have higher expectations of returning to work that may result in higher reports of fatigue.46 47 Several investigations report higher incidence of fatigue in female stroke survivors6 12 24 25 30 45 48; however, this association has not been consistently reported in the stroke population.9 11 41 49 It is unclear why there might be a difference in fatigue prevalence between the two genders. Interpretation of the difference is further complicated by higher prevalence of fatigue in females in the general population.50

Time line

Further insight into potential mechanisms can be gained by examining the time course of fatigue after stroke. As previously mentioned, cross-study comparison is limited by differences in inclusion criteria, methods of assessing fatigue and assessment at different time points after the stroke. Longitudinal studies report a consistency in fatigue levels over time4 13 30 34 50 with some studies reporting an increase in fatigue prevalence with time12 35 and others reporting a decrease in fatigue prevalence from acute stages (1–3 months poststroke) to 3 months and thereafter remaining stable.30 34 PSF can therefore be divided into early and late fatigue, with most studies defining early as up to 2–3 months poststroke (acute stage) and late as being anything over 3 months poststroke.40 51 Some stroke survivors suffering from early fatigue continue to suffer high levels of fatigue in the chronic phase, while some stroke survivors only report fatigue in the late phase.40 52 53 However, a common pattern among the majority of stroke survivors is that early fatigue is a strong predictor of late fatigue.52 A differentiation between early and late fatigue might be indicative of more than a single trigger and possibly several mediating factors that persist beyond the acute stage of recovery following a stroke.

Mechanisms of PSF

The reported experience of a distinctly different type of fatigue poststroke and the development of fatigue in later stages in some but not other stroke survivors indicates that PSF may not be a non-specific reaction to an insult to the brain but a direct result of the stroke. Here, it is worth reiterating that the majority of stroke survivors report fatigue in the first few weeks after stroke, which is thought to be a general non-specific reaction to a major disruptive event, hospitalisation and readjustment to life after stroke. However, the more debilitating symptom is fatigue that fails to resolve (or manifests) several weeks after stroke, which is thought to be a stroke-related sequela. To identify potential stroke resultant factors that might lead to fatigue, one needs to consider both the direct tissue damage and biochemical imbalances caused by stroke.

Lesion location

The relationship between lesion location and PSF remains controversial.9 18 48 51–53 53–55 The consensus is that lesion location is not determinant of development of fatigue9 11 30 41 49 56; however, some studies suggest there may be a higher incidence of fatigue in subcortical strokes when compared with cortical strokes.18 Subcortical strokes may be further broadly classified as basal ganglia and cerebellar strokes, with basal ganglia strokes more likely to give rise to fatigue possibly due to disturbances in the limbic–motor integration networks.48 57 There is not enough information available about detailed distribution of cortical lesions and the incidence of fatigue; however, any lesion to attention networks could result in fatigue, as poor attention may be a key element of high effort, a feature of fatigue, as described later in the review.58 Posterior cerebral artery strokes resulting in thalamic and brainstem lesions have previously been associated with high levels of fatigue. High fatigue in posterior artery strokes may be a result of poor attention mediated by lesions in attentional networks including the ascending reticular activating system and the lenticular, hypothalamic and thalamic nuclei.18 50 Some authors investigated the difference in incidence of fatigue based on type of lesion. Patients with large vessel stroke experienced greater fatigue than small vessel involvement,59 while other studies report an association with cerebral microbleeds.60 Those with stroke reported greater fatigue than transient ischaemic attack (TIA) despite minimal impairment.14 An association was seen between fatigue and white matter lesion.61 These findings suggest that the presence of a brain lesion rather than poststroke disability or vascular risk factors might be important in the aetiology of PSF. Furthermore, small vessel disease and development of PSF remains controversial. Whether lesion location significantly influences the development of PSF is still an open question, and future studies will benefit from a systematic anatomical correlation of lesion location with fatigue incidence and severity.

Proinflammatory response in the acute phase and subsequent fatigue

In a systematic review published in 2012 and based on examination of the literature until the last trimester of 2010, Kutlubaev and colleagues51 conclude that biological factors probably play a major role in PSF. The mechanisms remain uncertain when looking at possible involvement of stroke-induced alterations in hypothalamic–pitutary–adrenal axis and in neurotransmitter systems. In a more recent systematic review, Ponchel et al 62 propose that inflammatory factors appear to play a role, although it still needs to be confirmed. Inflammation is well known to be associated with fatigue. Several mechanisms have been proposed for this association (64). Inflammation is mediated by the production and release of proinflammatory cytokines that take place in the brain during stroke because of the peripheral blood mononuclear cells and is amplified by resident macrophages, known as microglia.63 In addition, inflammation can propagate from the brain to the periphery and vice versa by various communication mechanisms.64 Brain proinflammatory cytokines can act on neurotransmitters such as serotonin and dopamine by several mechanisms including alterations in synthesis, packaging in microvesicles, release and reuptake. These mechanisms have been mainly studied in the context of inflammation-induced depression.65 Inflammation can also induce oxidative stress which, if anti-inflammatory and antioxidant processes are deficient, can lead to neurodegeneration that affects primarily dopaminergic neurons in the mesostriatal and mesolimbic pathways.66 Inflammation can also activate the kynurenine (KYN) pathway that, in the context of activated microglia and ongoing neuroinflammation, favours the formation of neurotoxic KYN metabolites to the detriment of neuroprotective KYN metabolites and therefore enhances further the risk for neurodegeneration. In this section we will examine the evidence supporting the involvement of each of these mechanisms in stroke-associated fatigue.

Inflammation and fatigue

There is cumulative evidence for an inflammatory reaction in acute ischaemic stroke (AIS), indicating important interactions between the nervous and immune systems.67 68 Cytokines are upregulated in the brain after stroke and are expressed in invading immune cells and in glial cells and neurons.69 Brain inflammation caused by the stroke episode does not remain local. As mentioned in the previous paragraph, it propagates to the periphery. Peripheral inflammation preceding and following a stroke episode has potent modulatory effects on the pathology of stroke. As inflammation measured by peripheral concentrations of C reactive protein and cytokines in serum plasma depends on both pre-existing inflammatory clinical status related to, for example, atherosclerosis and cardiovascular disease and propagation of brain inflammation to the periphery, the results of clinical studies on the relationship between the inflammatory response following AIS and infarct volume70–78 and stroke subtype73 are likely to be very variable. The role of the cytokines involved thus remain unclear, and whether postischaemic inflammatory responses are deleterious or beneficial to brain recovery is still a matter of discussion.79 80 A study, in which the serum levels of 13 cytokines were evaluated in blood samples taken from 45 acute stroke patients (within 72 hours of stroke onset) and 40 healthy controls,81 showed for instance significantly higher levels of interleukin (IL)-1ra, IL-6, IL-8, IL-9, IL-10, IL-12, IL-18 and CXCL-1 in stroke patients. The authors concluded that this evidence suggested an early proinflammatory response and an early activation of endogenous immunosuppressive mechanism following stroke.

Considering fatigue as a dependent variable in the relationship between stroke and inflammation still adds to the complexity. Despite these difficulties, Ormstad and colleagues investigated the association between PSF, PSD, stroke type, infarct volume, laterality and the levels of various cytokines.82 83 PSF and PSD were measured using the FSS and Beck Depression Inventory, respectively, at 6, 12 and 18 months after stroke onset. The results indicated a role for the poststroke proinflammatory response in the appearance of PSF. The finding that IL-1β seems to be a predictor of PSF82 suggests fatigue after stroke could be part of what has been described as inflammation-induced sickness behaviour.84 Animal models of stroke support this possibility. For instance, Kunze et al 85 showed that experimental stroke in Lewis rats resulted in behaviour consistent with depression, while Wistar and Sprague-Dawley rats exhibited sickness-like behaviour including fatigue-like behaviour. The role of genetic factors has also been taken into consideration in clinical studies. For instance, Becker and colleagues86 showed that single neucleotide polymorphisms in the gene coding for the IL-1 receptor antagonist and the gene coding for Toll Like Receptor 4 (TLR4) were associated with high and low fatigue, respectively. However, the small size of the sample (n=39) precludes any definitive conclusion.

A possible neurochemical mechanism for cytokine-mediated fatigue, as discussed earlier, could be due to reduced capability for 5-hydroxytryptamine (5-HT) synthesis. However, the ineffectiveness of serotonin reuptake inhibitors on PSF87 may rule out serotonergic pathways as a source of fatigue. Hypodopaminergic activity induced by inflammatory cytokines could potentially be the source of cytokine-induced fatigue.88 89 An association between serum cytokines and PSD was not found, despite numerous reports of an association between PSD and PSF.83 Recent hypotheses suggest that glutamate might be the source of affective symptoms related to depression90 91 but may not mediate fatigue unrelated to depression.

Inflammation-mediated activation of the KYN pathway and fatigue

Inflammation can induce neurotoxicity by upregulating the indoleamine 2,3-dioxygenase (IDO) enzyme (which catalyses the rate-limiting step in the synthesis of KYN from tryptophan (TRP)) in multiple central and peripheral cell types.92 93 Activation of IDO can be measured by increased plasma/serum KYN over TRP ratio. KYN by itself acts as a ligand of the aryl hydrocarbon receptor, which generates regulatory T cells. The evidence in favour of such a mechanism in PSF is still weak. One study in particular reported reduced percentage of circulating regulatory T cells combined with increased systemic Th17 and proinflammatory cytokines and reduced anti-inflammatory cytokines.94 In addition, interferon-gamma, the cytokine primarily responsible for upregulating IDO, was not higher in stroke81 when compared with healthy controls. KYN produced in the brain in response to injury or transported from the periphery is further metabolised into the neuroprotective KYN metabolite kynurenic acid (KA) by KYN aminotransferase and the neurotoxic KYN metabolites 3-hydroxykynurenine and quinolinic acid by KYN monooxygenase. Activation of microglia, the main cellular source of proinflammatory cytokines in the brain during neuroinflammation, favours the neurotoxic pathway at the same time as it results in the extracellular release of glutamate. Whether microglial activation and the formation of neurotoxic KYN metabolites is involved in PSF is not clear. A few studies based on variations in plasma levels of KYN metabolites indicate activation of the KYN pathway could play a role in poststroke sequelae.95–98 Darlington et al 96 showed increased TRP catabolism after stroke and suggest that oxidative TRP metabolism contributes to oxidative stress and brain damage. Brouns et al 95 showed a correlation between KYN/TRP ratio and stroke severity and long-term stroke outcome that did not correlate with KA/3-hydroxyanthranillic acid ratio. Mo et al 98 showed an upregulation of IDO activation in ischaemic stroke. Ormstad et al 97 indicated an increase in TRP oxidation and reduced capability for 5-HT synthesis in the brain following AIS.

Ormstad et al 99, also investigated the mechanisms involved in PSD and PSF by studying the relationship between KYN pathway activity in the acute ischaemic phase and subsequent PSF and PSD in the stroke sample referred in their previous publication. Compared with the other neutral amino acids that compete with TRP for entry into the brain, plasma levels of TRP index were significantly lower in patients with an FSS score of ≥4 than in those with an FSS score of <4 at 12 months. However, in contradiction with the neurotoxic hypothesis, the serum levels of KA were significantly higher in patients with an FSS of score ≥4 than in those with an FSS score of <4 at 18 months. This indicates stroke patients with PSF might have a lower bioavailability of TRP in the acute stroke phase. In contrast to PSF, no predictors of PSD were found. These findings suggest that the immune response and IDO activation that follows AIS can predict PSF but not PSD. Interestingly, the TRP index did not correlate with fatigue at earlier time points (6 months) and similarly another study100 also showed no correlation between KYN/TRP ratio and fatigue in the very early stages poststroke (1 month). Emerging evidence appears to suggest that early activation of the KYN pathway does not manifest immediately as fatigue and depression but may have long-term consequences that has led to the proposal of a biopsychosocial model for PSF and depression.101

Neurophysiological and behavioural perturbations in chronic PSF

A particularly challenging aspect of investigating persistent fatigue is the difficulty in differentiating the causes from the effects of fatigue. Persistent symptoms such as fatigue result in significant behavioural and neurophysiological changes, which in turn may cause further fatigue resulting in a vicious cycle.101 Thus, identifying the mechanism that first establishes persistent fatigue is not straightforward. To date, investigations addressing behavioural and neurophysiological underpinnings of PSF have all been correlational studies, which for reasons stated below, do provide minimal insights into the direction of causality between behaviour, fatigue and physiology. However, causality remains to be confirmed by interventional studies aimed at alleviating fatigue.

Physical deconditioning is a common sequela after stroke and is believed to trigger PSF. Physical deconditioning results in fatigue and, subsequently, avoidance of physical activity. This further deteriorates deconditioning and can lead to more fatigue.102 A recent systematic review however failed to find an association between fatigue and any measures of physical activity or fitness.103 Both motor and cognitive deficits are seen in PSF. In the first year after stroke, in the absence of any obvious motor deficit, PSF was associated with poor attention and executive function as measured using phasic attention test and modified Stroop task.104 While fatigue correlated with attentional and executive function, neither correlated with lesion location. Another independent investigation105 confirmed poor executive and memory functions in high PSF in the first 6 months after stroke. They also showed that side and size of lesion did not correlate with presence of PSF. Despite subtle differences between the two investigations in terms of PSF definition and tests used to measure cognitive function, both investigations suggest that at 6 months poststroke, cognitive impairment correlates with fatigue with no obvious link to the lesion itself.

Several studies show that PSF is not correlated with motor deficits. However, a closer look at these investigations show that tests used to identify motor deficits are normally questionnaire-based scores of activities of daily living such as Barthel index, Rankin scale and National Institutes of Health Stroke Scale.25 28 34 46 56 86 104 105 Some studies use laboratory-based tasks to measure motor function such as action research arm test, nine-hole peg test (NHPT), grip strength106 and scales such as Fugl-Meyer.107 These measures, although useful to identify gross motor limitations relevant to daily life, are not accurate measures of motor impairment. A recent investigation showed that in evenly matched, minimal motor functional deficit high and low PSF groups, there was a significant reduction in ballistic movement speeds in the affected limb of the high fatigue group,108 while no difference in simple reaction times, attention and information processing speed was observed. The significantly slower ballistic speeds did not reflect on laboratory test scores, such as the NHPT times, possibly because tasks such as NHPT capture movement velocity and other features such as dexterity. Does this mean that, after all, PSF is related to motor impairment? The above investigation did not determine if those with slower movement speeds were capable of achieving higher speeds. It could be that in the task, one chose to move slower than their maximum speed. Those with slower movement speeds also reported heaviness of the affected limb,109 possibly a central sensory processing problem, which in turn may have led to choosing slower movement speeds. Those with slower movement speeds also exhibited low motor cortex excitability.106 It is unclear if these two findings have a direct relationship as it has previously been shown that motor cortex excitability does not encode movement speeds,110however, motor cortex excitability seems to be crucial in motor learning involving movement speeds.111 Low motor cortex excitability was also significantly correlated with high levels of PSF, but interestingly, voluntary activation, a measure of excitability of structures upstream of motor cortex such as secondary motor areas, was not significantly related to fatigue. Thus, PSF appears to be associated with behavioural108 and perceptual109 sensorimotor deficits with some underlying neurophysiological106 perturbations in the sensorimotor pathway.

Do any of the above findings suggest a causal role for motor and cognitive, behavioural and neurophysiological deficits in development of PSF? The attention and executive impairments seen in PSF are global. Structural and physiological changes remote to the site of lesion resulting in global attentional and executive impairment is a well-documented phenomenon after stroke. However, without further investigations, the correlations between fatigue and attention/executive impairment cannot be interpreted as being causal to fatigue; fatigue-related sensorimotor behavioural, physiological and perceptual findings are confined to the affected hemisphere. Should they be a consequence of fatigue, one would expect a more global effect on behaviour, hence there may be a causal role for sensorimotor alterations in development of fatigue. A small pilot interventional study reported significant benefits to using cognitive behavioural therapy and graded exercise112 for PSF. However, the effect size was not great enough to suggest that the intervention had targeted the underlying causal neural perturbations, but rather may have succeeded in compensating for some of the fatigue resultant behavioural changes. Moreover, the length of follow-up was not sufficient to determine fully the long-term effects of the intervention.

Active inference-based theoretical model of PSF20 113–115

Poor attention, slower processing speed, diminished memory, reduced movement speed and perceived limb heaviness: how might the above deficits give rise to fatigue, when no seemingly direct cause for fatigue such as sustained exertion exist? To answer this, we must first understand how sustained exertion might give rise to fatigue. With sustained activity, performance in the task drops and, importantly, subjects report fatigue, or more precisely, the need for higher effort to maintain task performance and at task failure, the inability to exert required effort to perform the task.116 It is also well established that task performance and report of fatigue are not correlated.117 Hence, the notion of higher effort is inextricably linked to fatigue, while drop in task performance itself may be seen as behavioural consequence of fatigue. A dissociation between task performance and fatigue, with a closer link between effort or ‘estimated action cost’ and fatigue, is indicative of a possible causal link between estimated action cost and fatigue. A recent review discussed how the low motor cortex excitability, reduced movement speed and perceived limb heaviness could underpin aberrant ‘estimated action cost’ or effort. Aberrant effort results in higher than normally required effort for everyday tasks.20 Persistent high effort for simple tasks gives rise to fatigue. This fits well with the clinical symptoms of PSF, such as fatigue without prior activity, fatigue that does not respond to rest and fatigue that limits everyday activities.

Effort is a perceptual inference that has its origins in intention (efferent information) and is modulated by feedback (afferent information). The active inference theory of sensorimotor control integrates efferent and afferent inputs to explain movement initiation and motor control113 and provides a framework within which effort, as defined above, may arise.118 The active inference theory of sensorimotor control postulates that the (efferent) output from corticomotor system is in the form of sensory (proprioceptive) predictions and (afferent) input from the somatosensory systems is in the form of sensory (prediction) errors. For a movement to be initiated, that is, sensory predictions to be fulfilled, ascending sensory errors must not be attended to, and to maintain status quo, sensory errors must be attended to. This property of altering precision of sensory errors is known as ‘sensory attenuation’. It has been postulated118 that in PSF, inference of high effort could be the result of poor sensory attenuation. In the context of muscle contractions, the inability to suppress ascending prediction errors is inferred by the brain as needing more than the estimated effort to perform the contraction. The motor cortex encodes prediction errors as shown by a suppression of sensory attenuation when motor cortex excitability is artificially reduced using non-invasive brain stimulation.119 The observed reduction in motor cortex excitability in stroke survivors with high fatigue106 further suggests poor sensory attenuation may be the mechanism by which fatigue arises. Evidence from other pathological conditions implicating dopaminergic systems in poor sensory attenuation115 combined with PSF-related molecular disturbances and preclinical work in muscle metabolism poststroke120 121 lend support to both central and peripheral mechanisms playing a role in poor sensory attenuation.

Conclusion

PSF is highly prevalent and has a significant impact on lives of stroke survivors. Here we summarise our current knowledge about possible causes of PSF. Preliminary evidence supports the idea of stroke triggered early biochemical imbalance resulting in altered homeostasis, leading to beliefs about estimated action cost that manifest as behavioural changes that fail to reverse in the long term presenting as chronic PSF. Understanding mechanisms of PSF is a relatively new field of study and several outstanding questions need to be addressed by future investigations.

Early changes in the biochemical environment after stroke has been implicated in development of a whole host of affective symptoms including fatigue, some of which have been discussed here. It is as yet unclear if there are biochemical imbalances in the chronic phase that might account for fatigue. Further work is also required to identify what biochemical signatures distinguish fatigue from depression. A limitation of current investigations is that all studies rely on biochemical markers in the plasma, which is not necessarily a reflection of the biochemical environment in the brain. Cerebrospinal fluid markers of fatigue will help establish more accurately fatigue-specific triggers.

The main behavioural consequence of fatigue is a significant reduction in self-initiated voluntary behaviour, possibly driven by altered effort calibration as discussed previously. Identifying specific motor and non-motor behaviours that are affected by effort miscalibration might be helpful in developing interventions for managing fatigue. However, it is imperative that we first establish that the identified behavioural alterations are mediators of fatigue and not merely a result of fatigue. Future work must also concentrate on developing and validating frameworks within which one can explain fatigue, such as the one proposed here, the active inference-based framework of fatigue.

In summary, fatigue is a complicated phenomenon with several contributing factors, most of which are poorly understood. Here, we have attempted to bring together several lines of enquiry and proposed a potential unified framework of fatigue.

References

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Footnotes

  • Contributors AK conceptualised the review. All authors contributed equally to the writing of the review.

  • Funding Wellcome Trust (202346/Z/16/Z).

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

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