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Understanding the neurobiology of fatigue

Scientific meeting


Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ


Theo Murphy scientific meeting organised by Professor Raymond Dolan FRS, Dr Annapoorna Kuppuswamy and Professor John Rothwell.

Credit: DigitalStorm

Fatigue is poorly understood, yet it is a common problem. Recent developments uncovering mechanistic underpinnings of pathological fatigue suggest a complex psychological and neural aetiology. This inter-disciplinary meeting brings together views from different disciplines: sensorimotor processing, decision-making, emotion, meta-cognition, energy economics and neuro-immunology to examine the pathogenesis of fatigue that will be informative to both basic neuroscientists and clinicians interested in fatigue.

Speaker biographies and abstracts are available below. Recorded audio of the presentations is also available below.

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Schedule of talks

18 September


Session 1

5 talks Show detail Hide detail


Professor Trudie Chalder, King's College London, UK

09:45-10:20 Standing up for fatigue

Professor Julia Newton, Newcastle University, UK


Fatigue is a common symptom that arises in association with a range of chronic diseases and when it occurs with a recognised constellation of symptoms is Chronic Fatigue Syndrome or Myalgic Encephalomyelitis. Fatigue impacts significantly upon quality of life and recent research has confirmed is frequently associated with autonomic nervous system dysfunction. The talk will focus upon research exploring the role of autonomic dysfunction in the manifestation of the symptom of fatigue. This will include both subjective and objective assessment of autonomic dysfunction and describe novel MR methodologies to explore the association of muscle, cardiac and liver dysfunction in those with chronic fatigue syndrome and fatigue associated conditions. The importance of autonomic dysfunction as a recognised phenomenon in fatigue highlights the opportunities that there may be for targeted therapeutic intervention for autonomic phenotypes in those with CFS/ME and fatigue in chronic disease.

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10:20-10:55 Neuroimaging and fatigue in MS and TBI

Professor John DeLuca, Kessler Foundation and Rutgers New Jersey Medical School, USA


Fatigue has been an enigma for over 100 years. While definitions abound, there have been recent efforts to differentiate primary fatigue (that due to systemic causes such as neurological damage) from secondary fatigue (factors that exacerbate primary fatigue (eg, depression, medication, deconditioning, etc).  The current presentation examines the neural mechanism of primary fatigue using functional MRI techniques in MS and TBI. Cognitive fatigue is induced by having patients conduct a complex cognitive task in the MRI scanner over prolonged durations. Changes in brain networks based on the work of Chaudhuri and Behan are examined and compared to objective cognitive performance and on-task subjective fatigue (fatigue related before and after each cognitive challenge). These results show that the caudate is a major driver of a ‘fatigue network’ in the brain that is related to subjective fatigue. Implications of these results on theories and mechanisms of central fatigue will be discussed.

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10:55-11:15 Coffee

11:15-11:50 A biopsychosocial model of fatigue and depression following stroke

Professor Heidi Kristin Ormstad, University College of Southeast Norway, Norway
Dr Grethe Eilertsen, University College of Southeast Norway, Norway


Poststroke fatigue (PSF) and poststroke depression (PSD) are both common and difficult sequelae following acute ischemic stroke (AIS). Two main perspectives to explain these sequelae are the biomedical perspective and the psychosocial perspective. Research has shown that PSF and PSD are undoubtedly
associated with each other, although each can occur in the absence of the other. However, the nature of the relationship is unclear. For example, do stroke patients become fatigued because of being depressed, or do they become depressed because they are fatigued? Alternatively, is there a bidirectional relationship between these two sequelae, with each influencing the other? Professor Ormstad and Dr Eilertsen propose a biopsychosocial model of PSF and PSD, indicating that from a biological perspective, the immune response and IDO activation following AIS can predict fatigue but not (directly) depression.

However, stroke survivors may also develop depression over time. The importance of acknowledging PSF should not be overlooked, since this can facilitate the ability to cope with the symptoms of fatigue, and thus possibly reduce the risk of developing depression over time. Providing stroke survivors with acknowledgment – which is a key to coping with the symptoms of PSF – will make it easier for them find the correct balance between rest and activity, which in our opinion is essential to avoiding depression.

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11:50-12:25 Fatigue symptoms in clinical models of chronic inflammation: pathophysiological correlates and clinical implications

Dr Lucile Capuron, INRA University of Bordeaux, France


Increasing amounts of data point to chronic inflammation as a major contributor of fatigue symptoms in clinical settings. Inflammatory mediators released by chronically activated immune cells are able to reach the brain where they activate potent neuroinflammatory processes and alter the activity of key neurobiological systems, including the neuroendocrine and neurotransmitter systems. These alterations are believed to play a pivotal role in the pathophysiology of fatigue. 

To further elucidate the mechanisms involved in inflammation-related fatigue, our group and others have used clinical models of chronic inflammation, either induced exogenously (ie, cytokine immunotherapy) or endogenously (chronic medical conditions such as the metabolic syndrome and obesity). Findings have shown that inflammation-induced alterations in monoamine metabolism together with changes in fronto-striatal brain circuitry represent key processes in the development and expression of fatigue symptoms. They also contributed to indentify reliable biomarkers of these effects. 

Altogether, these data provide important information regarding the role of inflammatory processes in the pathophysiology of fatigue symptoms and highlight potential new treatment targets. 

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12:25-12:45 Panel discussion




Session 2

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Professor Simon Gandevia, University of New South Wales, Australia

14:00-14:35 Corticospinal responses to sustained locomotor exercise

Associate Professor Timothy Carroll, The University of Queensland, Australia


Physical exercise leads to a reduced capacity to produce skeletal muscle force that typically outlasts the exercise bout. This exercise-induced fatigue can be due both to impaired muscle function, termed ‘peripheral fatigue’, and a reduction in the capacity of the central nervous system to activate muscles, termed ‘central fatigue’. In this talk, Professor Carroll will describe changes in the responsiveness of neurons within the corticospinal tract that occur as a consequence of fatiguing exercise. He will focus evidence provided by artificially-evoked forces and compound muscle action potentials measured in intact humans, with specific emphasis on recent work from my laboratory involving cycling exercise. The data suggest that sustained cycling exercise modulates the responsiveness of the neurons within the human motor cortex in ways that differ somewhat from exercise that is isolated to a single joint. The differences in central nervous system responses to everyday exercises like running and cycling, and those to isolated muscle contractions that have been studied most thoroughly in the past, may be due to the relative proportion of muscle masses involved, and the consequent challenges to systemic homeostasis. For example, running and cycling can increase brain temperature and challenge substrate availability. However, some corticospinal responses are similar for locomotor versus single joint exercise, and these effects are likely to be driven by process common to fatiguing exercise of any format; such as local accumulation of fatigue metabolites.

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14:35-15:10 Psychobiology of perception of effort during physical tasks

Professor Samuele Marcora, University of Kent, UK


Perception of effort is the conscious sensation of how hard, heavy and strenuous a physical task is. An increase in perception of effort is one of the main features of fatigue in both athletes and patients. Furthermore, the perception of effort is considered an important barrier to physical activity in the general population. With regards to its proximate cause, Professor Marcora will discuss whether the perception of effort is generated by brain processing of multiple afferent sensory signals about the physiological condition of the body, or corollary discharges from premotor and motor areas of the cortex. With regards to its ultimate cause, Professor Marcora will present an alternative to the current proposal that perception of effort is part of a complex system aimed at preventing a catastrophic failure of homoeostasis (eg myocardial ischaemia, rigor mortis in the active muscles, or even death) during excessively intense and/or prolonged physical tasks. Instead, Professor Marcora proposes that perception of effort is part of a complex system aimed at maintaining a relatively high level of body fat which, in turns, has several fitness functions. Finally, he will discuss the translation of this psychobiological research into practical interventions to treat fatigue, improve human performance, and reduce physical inactivity in the general population.

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15:10-15:30 Tea

15:30-16:05 Dissociating physical effort from fatigue in decision making

Dr Miriam Klein-Flügge, University of Oxford, UK


Understanding the neural mechanisms underlying fatigue requires knowledge of the brain systems that evaluate potential causes of fatigue. In other words, the network of brain regions that helps decide whether it is worth investing effort to obtain a reward. Integrating costs and benefits is crucial for optimal decision-making. Yet, while costs such as delay and risk are relatively well understood, how the brain incorporates motor costs has received little attention. In this work, healthy volunteers made decisions between choice options which varied in their associated monetary reward and grip force. First, the group developed a behavioural model to capture individual effort discounting preferences, ie how much effort an individual is willing to invest given the incentive. They then used functional magnetic resonance imaging (fMRI) to identify regions that signal the trade-off between the two choice options. Importantly, this design allowed them to identify the evaluation of effort independent of muscle fatigue. The group demonstrates that a region in midcingulate cortex fulfils the criteria for implementing this trade-off, and signalled how precisely the overall cost-benefit value determined participants’ choices. By contrast, separate signals in supplementary motor area and ventromedial prefrontal cortex correlated with participants’ tendency to avoid effort and seek reward, respectively. These findings suggest that distinct frontal circuits drive behaviour towards reward-maximization and effort-minimization, and thus provide new insights into the neural pathways that might mediate fatigue. This behavioural model may also prove useful for characterizing the propensity to motivate effortful behaviours in patient populations.

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16:05-16:40 Fatigue and Functional Neurological Disorder – making a pathophysiological link

Professor Mark Edwards, St George's University of London, UK


Functional neurological disorder (conversion disorder/psychogenic disorder) is one of the commonest diagnoses made in neurology clinics. People present with genuine neurological symptoms, but such symptoms ‘break rules’ regarding basic anatomy and physiology. Patients with functional neurological disorder have traditionally fallen down the crack between the dualistic divide of neurology and psychiatry, and tend to have a poor prognosis. Recent developments in pathophysiological thinking in this disorder has provided a neurobiological account of functional symptoms to go alongside psychodynamic accounts. This account uses models of brain function based on active inference to explain functional symptoms. This lecture will consider if there is an extension of this work to help us understand the pathophysiology of fatigue, and how this might also enhance treatment.

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16:40-17:00 Panel discussion

19 September


Session 3

5 talks Show detail Hide detail


Professor John Rothwell FMedSci, UCL, UK

09:30-10:05 When the spark goes out: the role of motivation and apathy in fatigue 

Professor Masud Husain, University of Oxford, UK


Fatigue is a very common symptom in neurological disorders but we understand very little about its underlying mechanisms in patients. Here we ask whether loss of motivation to act – apathy – might be contributory factor, focusing on Parkinson’s disease (PD) as a model disease. In PD, apathy and fatigue often co-exist, with questionnaire measures suggesting that some elements of these syndromes might be closely related. To examine the cognitive mechanisms associated with these symptoms we have adopted the framework of cost-benefit evaluation in decision-making. 

Several lines of evidence suggest that when we make decisions about how much effort we put into actions, we weigh up the costs involved for the potential benefits to be obtained. This evaluation is altered in PD patients with apathy who show blunted sensitivity to rewards and less inclination to invest effort for low rewards than healthy individuals. Both these factors can be improved by dopaminergic medication. Functional imaging in healthy people reveals both medial frontal and ventral striatal involvement when people make such decisions, with levels of motivation related to medial frontal activity. 

Previous work has suggested that fatigue might have two components. The first is a resource that is depleted by effortful exertion but restored by rest; while the second is a non-recoverable resource that continues to decrease with time-on-task throughout effortful exertion. The group examined people’s willingness to put in effort as a function of these ‘recoverable’ and ‘unrecoverable’ factors. Intriguingly, dopamine depletion in PD was linked to a reduction in how easily motivation to exert effort could be recovered by rests. These findings are discussed in the context of how motivation might affect fatigue and how dopamine might be an important modulator of both.

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10:05-10:40 Post-stroke fatigue: a disorder of poor sensory attenuation?

Dr Annapoorna Kuppuswamy, UCL, UK


Stroke survivors suffer from fatigue, sometimes months and even years after stroke and in many survivors fatigue is the only residual problem. Here Dr Kuppuswamy presents neurophysiological data from chronic stroke survivors that associate fatigue with reduced motor cortex excitability, slowed ballistic movement speeds and perceived limb heaviness, despite no overt sensorimotor motor functional deficits. She then discusses a possible mechanism based on sensory attenuation that might explain fatigue and is in line with the above-mentioned findings. A defining feature of fatigue is high perceived effort when performing simple activities of daily living. Previous work suggests that perceived effort arises from expected sensory input and modulated by the actual sensory input. It is also known that the brain suppresses some of the expected sensory input, a phenomenon known as sensory attenuation. Here Dr Kuppuswamy suggests that in post-stroke fatigue, high perceived effort may be a result of poor sensory attenuation where the brain in unable to suppress expected sensory input which is interpreted as high perceived effort. Persistent feeling of high effort due to poor sensory attenuation can lead to a baseline perceptual state of fatigue. She will also present some preliminary data from a force-matching task, designed to measure sensory attenuation in stroke survivors with and without fatigue.

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10:40-11:00 Coffee

11:00-11:35 Motivational aspects of inflammation-associated fatigue

Professor Robert Dantzer, The University of Texas MD Anderson Cancer Center, USA


The exact nature and pathophysiology of fatigue remain largely elusive despite its high prevalence in the general population. A role for inflammation in the pathophysiology of fatigue has been proposed based on the clinical association between elevated levels of serum or plasma biomarkers of inflammation and symptoms of fatigue. The pivotal role of inflammation in fatigue has been confirmed by experiments showing that systemic inflammation induces behavioural signs of fatigue in laboratory rodents. Inflammation-induced fatigue has a strong motivational component as inflammatory stimuli that reduce spontaneous activity and voluntary wheel running have also potent effects on incentive motivation. This is not due to a decrease in the positive valence of motivational stimuli as inflamed mice increase their high effort-high reward mode of responding compared to their low effort-low reward mode of responding in an effort-based decision making task. These effects are mediated by a reduction in dopaminergic neurotransmission induced by proinflammatory cytokines produced in the brain by microglia. A role for inflammation has also been proposed for cancer-related fatigue. Cancer survivors show the same pattern of responding in a decision making task as inflamed subjects. However, a systematic study of behavioural signs of fatigue in a mouse model of human papilloma virus-related head and neck cancer shows that behavioural fatigue lacks motivational components and is mainly driven by tumour-driven metabolic alterations. These findings refute inflammation as a final common pathway for fatigue and point to the diversity of mechanisms responsible for this symptom.

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11:35-12:10 Fatigue, anergia and effort-related aspects of motivational dysfunction in animal models: the role of mesolimbic dopamine and related circuitry

Professor John Salamone, University of Connecticut, USA


Motivational symptoms such as anergia, fatigue, or apathy are observed in patients with psychiatric and neurological disorders. Humans with these disorders can show reduced selection of high-effort activities, and effort-based choice procedures have been developed as animal models of motivational symptoms. In rodents, effort-based choice tasks allow animals to select between a more valued reinforcer that is obtained by high effort actions versus a low effort/low reward option. Dopamine (DA) antagonism and mesolimbic DA depletions shift choice behaviour, decreasing selection of the high effort option and increasing choice of the low effort alternative. A low-effort bias is induced by conditions associated with depression and Parkinsonism, including injections of tetrabenazine (TBZ), which blocks monoamine storage, and pro-inflammatory cytokines (IL-1, IL-6). Several drugs can reverse the effort-related effects of TBZ or cytokines, including the DA uptake blockers bupropion, GBR12909, methylphenidate, modafinil, PRX-14040, and lisdexamfetamine. The norepinephrine (NE) uptake blocker desipramine does not reverse the effects of TBZ, nor do the serotonin uptake blockers (SSRIs) fluoxetine or S-citalopram.  The lack of effect of SSRIs is consistent with clinical reports showing that SSRIs are relatively ineffective for treating fatigue and anergia. Furthermore, injections of DA uptake blockers increased progressive ratio work output, while fluoxetine, desipramine, and atomoxetine did not. Bupropion and GBR12909 at behaviorally active doses elevated extracellular DA in accumbens as measured by microdialysis, while fluoxetine, desipramine and atomoxetine did not. These results demonstrate that effort-related motivational symptoms can be modelled in rodents, and demonstrate a role for DA in regulating these symptoms.

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12:10-12:30 Panel discussion




Session 4

6 talks Show detail Hide detail


Professor Patrick Haggard, UCL, UK

13:30-14:05 Statistically overcoming fatigue

Professor Konrad Kording, Northwestern University, USA


Fatigue is ubiquitous. Our muscles fatigue, our minds fatigue, and, arguably, our neurons fatigue as well. This produces an obvious but simple problem - the maximal strength, performance, or response gets reduced. However, it also produces a less obvious problem, a control problem. If our muscles are weaker and we do not know about it, then our commands will be wrong, leading to bad performances. Similarly, if neurons transfer function decreases we may go from a critical state where information is processed to what may amount to a quiescent state without much information processing. To overcome such problems, any controlling system needs to implicitly model the process of fatigue. In this presentation, Professor Kording will review how control systems can undo the effect of fatigue. He will highlight how synapses and motor control could constantly undo fatigue. He will speculate how similar phenomena are necessarily relevant across biology.

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14:05-14:40 Functional and neurophysiological underpinnings of action control

Professor Florian Waszak,CNRS and Université Paris Descartes, France


Humans either carry out actions to accommodate to environmental demands, or to produce effects in the environment meant to meet the agent’s goals. The first type of action may be referred to as stimulus-based or reactive, the latter kind may be referred to as intention-based or voluntary. Voluntary actions are an important component of our interaction with the environment and our social lives. Yet, research on human action only relatively recently began to try to understand the control of voluntary actions as opposed to the ‘traditional’ type of action that is performed in response to some stimulus information in the environment. Professor Waszak will present several experiments, using psychophysical, EEG and fMRI techniques, meant to elucidate the functional and neurophysiological underpinnings of voluntary actions, especially with respect to the anticipation of the sensory consequences of action control. Professor Waszak will propose a cortical mechanism of action effect anticipation that is able to explain many perceptual phenomena related to voluntary action, such as sensory attenuation and intentional binding.

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14:40-15:00 Tea

15:00-15:35 Allostatic self-efficacy: a metacognitive theory of fatigue

Professor Klaas Enno Stephan, University of Zurich and ETH Zurich, Switzerland


This presentation outlines a hierarchical Bayesian framework that connects fatigue and depression to the experience of chronic dyshomeostasis. Specifically, viewing interoception as the inversion of a generative model of viscerosensory inputs allows for a formal definition of dyshomeostasis (as persistent surprise about viscerosensations, or, equivalently, low evidence for the brain’s model of bodily states) and allostasis (as a change in prior beliefs about desirable bodily states that define setpoints for homeostatic reflex arcs). Critically, Professor Stephan proposes that the performance of interoceptive-allostatic circuitry is monitored by a metacognitive layer that updates beliefs about the brain’s capacity to successfully regulate bodily states (allostatic self-efficacy). In this framework, fatigue and depression can be understood as sequential responses to the interoceptive experience of dyshomeostasis and the ensuing metacognitive diagnosis of low allostatic self-efficacy. While fatigue might represent an early response with adaptive value (cf sickness behaviour), the experience of chronic dyshomeostasis may trigger a generalised belief of low self-efficacy and lack of control (cf learned helplessness), resulting in depression. Professor Stephan illustrates how this theory can be tested by experimental and clinical studies and discuss how this framework could help inform the differential diagnosis of fatigue in the future.

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15:35-16:10 An opportunity cost model of self-control

Professor Robert Kurzban, University of Pennsylvania, USA


Exerting ‘effort’ or ‘self-control’ is experienced as aversive. From an evolutionary point of view, this is something of a mystery insofar as aversive phenomenology is usually associated with fitness costs or threats, whereas exerting self control seems to be associated with positive outcomes. A leading explanation among psychologists is the postulate that there is a resource in your brain – the fuel for willpower – that is depleted over time. As this resource is consumed, it becomes phenomenologically harder and harder to resist temptation. However, a growing body of evidence suggests that, as compelling as this explanation might be, there are very good reasons to doubt it. Instead, Professor Kurzban has suggested that the phenomenology of effort and the associated sensation of fatigue are more productively thought of in the context of motivation. Specifically, the proposal is that the reason that it is difficult to persist on effortful tasks is that our brains are continuously entertaining the possibility of switching to another task that is likely to be psychologically rewarding. That is, engaging in effortful tasks carries the opportunity cost of not engaging in a more pleasurable task. These costs, Professor Kurzban will suggest, lead to the aversive experiences of effort and fatigue.

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16:10-17:00 Panel discussion and future directions

17:00-17:15 Closing remarks

Professor Raymond Dolan FMedSci FRS, UCL, UK

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Understanding the neurobiology of fatigue Kavli Royal Society Centre, Chicheley Hall Newport Pagnell Buckinghamshire MK16 9JJ