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.
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.
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.
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.