Understanding the neurobiology of fatigue

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.

Professor Masud Husain, University of Oxford, UK

Professor Masud Husain, University of Oxford, UK

Masud is Professor of Neurology and Cognitive Neuroscience at the University of Oxford. He holds a Wellcome Trust Principal Research Fellow and is based at the Nuffield Department of Clinical Neurosciences and Department of Experimental Psychology, where he leads the Cognitive Neuropsychology Centre.

After completing clinical training at Oxford and London he held a Wellcome Trust Senior Fellowship, first at Imperial College and then at University College London. At UCL he was Deputy Director of the Institute of Cognitive Neuroscience and Head of Department Brain Repair and Rehabilitation at the Institute of Neurology.

His current research focuses on understanding mechanisms underlying motivation and short-term memory, in healthy people and in patients with neurological disorders.

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.

Dr Annapoorna Kuppuswamy, UCL, UK

Dr Annapoorna Kuppuswamy, UCL, UK

Anna is a Henry Dale fellow investigating mechanisms of perceptual fatigue in human stroke model at Institute of Neurology, UCL. Anna started her career as a physiotherapist in India whilst she developed an interest in understanding neurological disorders and brain derived mechanisms of neurological symptoms. After having completed her PhD at Imperial College London and a post-doctoral visiting fellowship at the National Institutes of Health, USA, she moved to UCL to investigate mechanisms of fatigue in stroke. She is funded by the Wellcome Trust, Royal Society and Stroke Association.

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.

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

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

Robert Dantzer is Professor and Deputy Chairman in the Department of Symptom Research in the Division of Internal Medicine at The University of Texas MD Anderson Cancer Center, Houston, Texas. He has conducted research for many years on the psychobiology of stress, the influence of neuropeptides on behaviour, and the interactions between the immune system and the brain. His current research aims at understanding the mechanisms of cytokine-induced sickness behaviour and the role of inflammation in the production of symptoms, including depression and fatigue. He has authored or co-authored more than 400 original research papers and 120 book chapters on stress, anxiety, neuropeptides, and psychoneuroimmunology (h-index = 81). He is also the author or the editor of several books on stress, emotions, psychosomatics, and neurobiology of cytokines. He is the Editor-in-Chief of the journal Psychoneuroendocrinology (Elsevier) and the past President of the Psychoneuroimmunology Research Society.

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.

Professor John Salamone, University of Connecticut, USA

Professor John Salamone, University of Connecticut, USA

Dr John Salamone received his bachelor's degree from Rockhurst University in Kansas City, Missouri in 1978. He was a psychology major and biology minor. Dr Salamone then entered the psychobiology program at Emory University in Atlanta, Georgia, and graduated with a PhD in 1982. For postdoctoral training, Dr Salamone received a National Science Foundation grant, and studied at Cambridge University in England. Dr Salamone stayed in England for several more years, working at Merck, Sharpe and Dohme pharmaceutical laboratories. Upon returning to the United States, Dr Salamone joined the Behavioral Neuroscience department at the University of Pittsburgh in 1986, and joined the Psychology Department at the University of Connecticut in the fall of 1988. Dr Salamone is now a Board of Trustees Distinguished Professor; he also is the chair of the Interdisciplinary Program in Neuroscience, and the head of the Behavioral Neuroscience Division of the Psychology Department. Dr Salamone's research is largely in the fields of behavioural neuroscience and psychopharmacology, with an emphasis on studies related to animal models of depression, motivation, effort-related decision making, and drug-induced Parkinsonism. He has published more than 230 articles and book chapters, and has been cited in the scientific literature more than 12,000 times. Dr Salamone has been the research advisor for more than 70 undergraduate honors students at the University of Connecticut, and 20 PhD students. He was inducted as a member of the Connecticut Academy of Arts and Sciences in 2002, and he has received the University of Connecticut Alumni Association Award for Excellence in Teaching. His daughter, Isabella Salamone, is currently a graduate student studying molecular biology at the Northwestern University. Dr Salamone’s hobbies include travel, astronomy, book collecting and cooking.

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.

Professor Konrad Kording, Northwestern University, USA

Professor Konrad Kording, Northwestern University, USA

Kording obtained a diploma degree in Physics from the Federal Institute of Technology (ETH), Zurich (2000) and a PhD in physics from the Institute of Neuroinformatics at the ETH (2003). He was a postdoctoral fellow at UCL London, and a Heisenberg Fellow at the Department of Brain and Cognitive Sciences at the MIT. He is now full Professor of Physical Medicine and Rehabilitation, Physiology, and Applied Mathematics at Northwestern University. He is leading the Bayesian Behavior Laboratory in the Rehabilitation Institute of Chicago.

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.

Professor Florian Waszak,CNRS and Université Paris Descartes, France

Professor Florian Waszak,CNRS and Université Paris Descartes, France

Florian Waszak is a senior researcher at the French CNRS. He currently works in the Laboratoire Psychologie de la Perception in Paris.  He is the head of the team Action, Volition and Consciousness that investigates modality-unspecific higher-order functions of adult perception and performance. It addresses notably three major themes: (1) Human voluntary and stimulus-driven action control, (2) perceptual plasticity and sensation/action reciprocity, and (3) consciousness and attention in experimental and clinical setting.

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.

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

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

Klaas Enno Stephan is Full Professor at the University of Zurich & ETH Zurich and Founding Director of the Translational Neuromodeling Unit (TNU), Zurich. Integrating computational scientists and clinicians under one roof, the mission of the TNU is to develop computational assays for inferring individual disease mechanisms and for predicting individual treatment response. Following doctoral degrees in Medicine and Neuroinformatics, Klaas’ scientific track record includes the construction of the connectivity database CoCoMac, development of various neuroinformatics tools and computational modeling techniques, and numerous studies on psychiatric and neurological conditions. In addition to his work at Zurich, he is Honorary Principal at the Wellcome Trust Centre for Neuroimaging, London, and External Scientific Member at the Max Planck Institute for Metabolism Research, Cologne. His work has been recognized by several awards and honours, including the Wiley Young Investigator Award for Human Brain Mapping and election to the Max Planck Society.

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.

Professor Robert Kurzban, University of Pennsylvania, USA

Professor Robert Kurzban, University of Pennsylvania, USA

Robert Kurzban is a Professor at the University of Pennsylvania in the Psychology Department. He received his PhD at the University of California Santa Barbara at the Center for Evolutionary Psychology in 1998, and received postdoctoral training at Caltech in the Division of Humanities and Social Sciences, UCLA Anthropology, and the University of Arizona’s Economic Science Laboratory with Vernon Smith. In 2003, he founded the Penn Laboratory for Experimental Evolutionary Psychology. He has published on a wide array of topics, including morality, cooperation, friendship, mate choice, supernatural beliefs, modularity, and self-control. He is the Editor-in-Chief of the flagship journal of the Human Behavior and Evolution Society, Evolution and Human Behavior and he is the Director of Undergraduate Studies in the Department of Psychology at the University of Pennsylvania. His most recent book is entitled The Hidden Agenda of the Political Mind.