Chairs
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
Professor Masud Husain, University of Oxford, UK
Abstract
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.
Show speakers
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.
10:05-10:40
Post-stroke fatigue: a disorder of poor sensory attenuation?
Dr Annapoorna Kuppuswamy, UCL, UK
Abstract
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.
Show speakers
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.
11:00-11:35
Motivational aspects of inflammation-associated fatigue
Professor Robert Dantzer, The University of Texas MD Anderson Cancer Center, USA
Abstract
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.
Show speakers
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.
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
Abstract
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.
Show speakers
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.
12:10-12:30
Panel discussion