Why do we get physically tired from mental effort? Why are we mentally spent after a day of physical exertion? We propose to work with scientists from Chicago, UK, France, Switzerland and the Netherlands to investigate the neurobiological basis of fatigue. Our first step is to host a meeting on Neural Mechanisms of Fatigue to be held at the Paris Center. The goals of this meeting are to identify the core questions to answer, methodologies to use, and populations to study in forthcoming experiments. We will fix upon a common protocol to be run at the Paris Center (for roughly one quarter’s time, by PM), in Chicago, and in the Netherlands. Experiments are designed to test whether both physical and cognitive fatigue arise from cognitive effort. To determine if physical fatigue scales with cognitive supervision, we will compare fatigue after gestures (cognitively undemanding movements) and after reaches to differently sized targets, actions that can be highly demanding. We will then compare the fatigue produced by mental rotation tests of hands, feet and 3-D puzzle pieces. Finally, we will examine a potential brain mechanism underlying both cognitive and physical fatigue. After completing our experiments, the results will be submitted for publication.