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Understanding the neurobiology of fatigue

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

Professor Trudie Chalder, King's College London, UK

Professor Trudie Chalder, King's College London, UK
Trudie Chalder is Professor of Cognitive Behavioural Psychotherapy at King’s College London. She has worked as a clinician and a researcher in the area of long term conditions and persistent symptoms for over 25 years. More specifically she has focused much of her attention on fatigue and chronic fatigue syndrome. She examines processes that may be causing and/or maintaining symptoms and /or associated disability and develops specific cognitive behavioural treatments based on research findings and theory. Treatments are then evaluated within the context of randomised controlled trials in primary and secondary care. Her research involves investigating not only whether treatment works in the context of gold standard randomised controlled trials but how and for whom it works. Her work spans adolescents and adults.
Trudie has published approximately 200 articles. She was the President of the British Association of Behavioural and Cognitive Psychotherapy and is an Editor of the Journal of Mental Health.
09:45 - 10:20 |
Standing up for fatigue
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. ![]() Professor Julia Newton, Newcastle University, UK
![]() Professor Julia Newton, Newcastle University, UKProfessor Julia Newton is Director of Newcastle Academic Health Partners in Newcastle and is a Clinical Academic whose research focuses upon understanding the pathophysiology of fatigue in chronic disease. She is Director of the Newcastle Fatigue Research Centre and has received grant funding from the MRC and NIHR EME focussed upon understanding cardiac and muscle function in CFS/ME and for a clinical trial of rituximab in the autoimmune liver disease primary biliary cirrhosis. She is patron of ME North East and Medical Advisor to Action for ME and an inaugural member of the UK CFS/ME Research Collaborative. |
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10:20 - 10:55 |
Neuroimaging and fatigue in MS and TBI
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. ![]() Professor John DeLuca, Kessler Foundation and Rutgers New Jersey Medical School, USA
![]() Professor John DeLuca, Kessler Foundation and Rutgers New Jersey Medical School, USAJohn DeLuca, PhD, is the Senior Vice President for Research and Training at Kessler Foundation, a Professor in the Department of Physical Medicine and Rehabilitation, and the Department of Neurology at Rutgers, New Jersey Medical School. He is board certified in Rehabilitation Psychology by the American Board of Professional Psychology. Dr DeLuca is internationally known for his research on disorders of memory and information processing in a variety of clinical populations including: multiple sclerosis, traumatic brain injury, aneurysmal subarachnoid hemorrhage, and Chronic Fatigue Syndrome. Dr DeLuca has published over 300 articles and book chapters in these areas, has edited 5 books in neuropsychology, neuroimaging and rehabilitation, and is a co-editor for the Encyclopedia of Clinical Neuropsychology. He has received over 32 million dollars in grant support for his research. Dr DeLuca's most recent research ventures include the cerebral mapping of human cognitive processes using functional neuroimaging, as well as the development of research-based techniques to improve cognitive impairment. |
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10:55 - 11:15 | Coffee | |
11:15 - 11:50 |
A biopsychosocial model of fatigue and depression following stroke
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 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. ![]() Professor Heidi Kristin Ormstad, University College of Southeast Norway, Norway
![]() Professor Heidi Kristin Ormstad, University College of Southeast Norway, NorwayHeidi Ormstad finished her PhD in immunology in 1998 at the University in Oslo. Her current position is professor of biomedicine at University College of Southeast Norway. Most of the carrier she has performed own research and teaching. For five years, however, she was the research director at a hospital. She has participated in, or led, a number of research projects, and has a broad research expertise in terms of both methodology and disciplines. Methodically she has a wide span; from basic research in experimental animals and cells, electron microscopy and immunological methods and techniques, to more clinical research the last years, both quantitative and qualitative. Her publications concerns several different areas: nutrition medicine, environmental medicine, immunology, allergology, neuro immunology, stroke, fatigue, depression and autism. The last years she has mostly studied pro-inflammation and kynurenine pathway in several diseases, like stroke, depression and autism. She has also some experiences from qualitative research of fatigue. ![]() Dr Grethe Eilertsen, University College of Southeast Norway, Norway
![]() Dr Grethe Eilertsen, University College of Southeast Norway, NorwayGrethe Eilertsen is a nurse and holds a doctorate in nursing science from the University of Oslo. She is a professor of clinical nursing at the University College of Southeast Norway, Faculty of Health and Social Science, Department of Nursing and Health Sciences. Her research areas specifically address the elderly's health, long-term illness and rehabilitation. For many years, she has studied subjective experiences of stroke, with a particular focus on post stroke fatigue. |
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11:50 - 12:25 |
Fatigue symptoms in clinical models of chronic inflammation: pathophysiological correlates and clinical implications
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. ![]() Dr Lucile Capuron, INRA University of Bordeaux, France
![]() Dr Lucile Capuron, INRA University of Bordeaux, FranceDr Lucile Capuron, PhD, (INRA-University of Bordeaux, France) is Research Director at the French National Institute for Agricultural Research (INRA) and leader of the team Nutrition and Psychoneuroimmunology. Her main research activity focuses on understanding the relationships between inflammation and neuropsychiatric symptoms, in particular depression, in clinical/human settings and their modulation by nutritional and metabolic factors. Dr Capuron has worked extensively on the model of cytokine therapy to investigate the mood, cognitive and neurovegetative effects of immune factors in medically ill patients and the pathophysiological mechanisms underlying these effects. Dr Capuron is also an adjunct Assistant Professor of the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine, Atlanta, GA, USA. She has authored more than 75 peer-reviewed publications, book chapters and reviews in the field of psychoneuroimmunology, neuroscience, psychiatry and medicine. |
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12:25 - 12:45 | Panel discussion |
Chair

Professor Simon Gandevia, University of New South Wales, Australia

Professor Simon Gandevia, University of New South Wales, Australia
Simon Gandevia (PhD, MD, DSc) is Deputy Director of Neuroscience Research Australia in Sydney and an NHMRC Senior Principal Research Fellow. He studied medicine at the University of New South Wales and subsequently conducted research in clinical neurophysiology at the Prince Henry Hospital. In 1992, he established the Prince of Wales Medical Research Institute (now Neuroscience Research Australia). His research on volunteers and patients focuses on four areas: proprioceptive mechanisms, human motor control and muscle fatigue, neural control of breathing, and the passive behaviour of muscles. He has published more than a hundred papers in the Journal of Physiology.
He has had longstanding editorial roles with the Journal of Physiology and Journal of Applied Physiology and currently heads an NHMRC program in ‘Motor Impairment’. He was elected a Fellow of the Australian Academy of Science in 1998.
14:00 - 14:35 |
Corticospinal responses to sustained locomotor exercise
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. ![]() Associate Professor Timothy Carroll, The University of Queensland, Australia
![]() Associate Professor Timothy Carroll, The University of Queensland, AustraliaTim Carroll is an Associate Professor in sensorimotor control. He received his doctorate in Neuroscience at the University of Queensland in 2001, and took an Isaac Walton Killam Memorial Postdoctoral Fellow at the University of Alberta before holding academic positions at the University of New South Wales. He is currently based at the University of Queensland, where he is the Director of the Research Centre for Sensorimotor Performance. He has broad interests in how exercise affects the Central Nervous System, and particular interests in the use of non-invasive nerve and brain stimulation to assess acute and chronic exercise effects on corticospinal tract function. |
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14:35 - 15:10 |
Psychobiology of perception of effort during physical tasks
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. ![]() Professor Samuele Marcora, University of Kent, UK
![]() Professor Samuele Marcora, University of Kent, UKProfessor Samuele Marcora is Professor of Exercise Physiology and Director of Research at the School of Sport and Exercise Sciences at the University of Kent. After a sabbatical in the School of Psychology at Bangor University in 2006, he has adopted an interdisciplinary approach to fatigue research. Specifically, Professor Marcora integrates his expertise in exercise physiology with motivation psychology and cognitive neuroscience to investigate the psychobiology of perceived effort in relation to performance in endurance athletes, physical inactivity in the general population, and fatigue in chronic diseases. He has produced innovative and influential research on the relationship between physical and mental fatigue. |
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15:10 - 15:30 | Tea | |
15:30 - 16:05 |
Dissociating physical effort from fatigue in decision making
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. ![]() Dr Miriam Klein-Flügge, University of Oxford, UK
![]() Dr Miriam Klein-Flügge, University of Oxford, UKMiriam Klein-Flügge is a neuroscientist interested in understanding the brain processes underlying complex decision behaviours. She obtained her PhD at UCL and is currently a Sir Henry Wellcome Postdoctoral Fellow with Professor Matthew Rushworth at the University of Oxford. Her current work focuses on subcortico-cortical interactions supporting complex real-life decisions in the healthy human brain with an interest in extending this work to mental health conditions where abnormal decision making is observed. Miriam’s work uses a combination of computational modelling, brain imaging (fMRI, MEG) and brain stimulation (TMS) techniques. One of her main contributions to date has been on how motor costs (or anticipated fatigue) influence reward-guided decision making both behaviourally and at the level of the brain. |
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16:05 - 16:40 |
Fatigue and Functional Neurological Disorder – making a pathophysiological link
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. ![]() Professor Mark Edwards, St George's University of London, UK
![]() Professor Mark Edwards, St George's University of London, UKMark Edwards is Professor of Neurology at St George’s University of London and St Georges Hospital. He has a specialist clinical and research interest in movement disorders and in neurophysiological and psychophysical methods for exploring their pathophysiology. He did his PhD at the UCL Institute of Neurology and was then a Senior Lecturer and Honorary Consultant Neurologist at UCL and the National Hospital for Neurology. Here he built up a specific interest in functional neurological symptoms and developed an NIHR funded research program and specialist clinical diagnostic and treatment service for patients with functional movement disorders. At St George’s he is developing an integrated diagnostic and treatment service for functional neurological disorder while continuing research work in the pathophysiology and treatment of movement disorders in general. |
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16:40 - 17:00 | Panel discussion |
Chair

Professor John Rothwell FMedSci, UCL, UK

Professor John Rothwell FMedSci, UCL, UK
John Rothwell is currently Professor of Human Neurophysiology at UCL Institute of Neurology and an Honorary Professor at the University of Adelaide. His main interests are in the pathophysiology of human Movement Disorders and in basic mechanisms of restoration of function after brain injury, particularly stroke. Current research projects include using neurophysiological techniques to study the mechanisms of neural plasticity that underpin motor learning, and using this knowledge to devise new therapeutic interventions for rehabilitation after stroke.
He is an elected Fellow of the Academy of Medical Sciences and Editor of the journal Experimental Brain Research. He received the Adrian Award of the International Clinical Neurophysiology Society, the Sherrington Medal of the Royal Society of Medicine, the Gloor Award from the American Clinical Neurophysiology Society and the Caruso Award of the Italian Society for Clinical Neurophysiology.
09:30 - 10:05 |
When the spark goes out: the role of motivation and apathy in 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, UKMasud 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. |
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10:05 - 10:40 |
Post-stroke fatigue: a disorder of poor sensory attenuation?
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, UKAnna 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. |
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10:40 - 11:00 | Coffee | |
11:00 - 11:35 |
Motivational aspects of inflammation-associated fatigue
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, USARobert 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. |
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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
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, USADr 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. |
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12:10 - 12:30 | Panel discussion |
Chair

Professor Patrick Haggard, UCL, UK

Professor Patrick Haggard, UCL, UK
Patrick Haggard leads the 'Action and Body' research group at UCL's Institute of Cognitive Neuroscience. His research interests include voluntary action, self-control, consciousness and somatosensory processes. He has written extensively on the neuroscience of volition and inhibition, and recently contributed an article on volition to the Oxford Handbook of Neuroethics.
13:30 - 14:05 |
Statistically overcoming fatigue
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, USAKording 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. |
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14:05 - 14:40 |
Functional and neurophysiological underpinnings of action control
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, FranceFlorian 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. |
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14:40 - 15:00 | Tea | |
15:00 - 15:35 |
Allostatic self-efficacy: a metacognitive theory of fatigue
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, SwitzerlandKlaas 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. |
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15:35 - 16:10 |
An opportunity cost model of self-control
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, USARobert 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. |
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16:10 - 17:00 | Panel discussion and future directions | |
17:00 - 17:15 |
Closing remarks
![]() Professor Ray Dolan FMedSci FRS
![]() Professor Ray Dolan FMedSci FRSRay Dolan is Mary Kinross Professor of Neuropsychiatry at UCL and Director of the UCL-Max Planck Centre for Computational Psychiatry and Ageing. His research is concerned with the neural basis of decision making and its breakdown in the context of psychopathology. He is a Fellow of the Royal Society (FRS) and an External Member of the Max Planck Society (MPS). He is the recipient of numerous international awards, including the Brain Prize (2017) and Ferrier Medal and Lecture (2019) from the Royal Society. |