Apathy is a core symptom in patients with behavioral variant frontotemporal dementia (bvFTD). It is defined by the observable reduction in goal-directed behavior, but the underlying mechanisms are poorly understood. According to decision theory, engagement in goal-directed behavior depends on a cost-benefit optimization trading off the estimated effort (related to the behavior) against the expected reward (related to the goal). In this framework, apathy would thus result from either a decreased appetence for reward, or from an increased aversion to effort. Here, we phenotyped the motivational state of 21 bvFTD patients and 40 matched healthy controls, using computational analyses of behavioral responses in a comprehensive series of behavioral tasks, involving both expression of preference (comparing reward value and effort cost) and optimization of performance (adjusting effort production to the reward at stake). The primary finding was an elevated aversion to effort, consistent across preference and performance tasks, in bvFTD patients compared to controls. Within the bvFTD group, effort avoidance was correlated to cortical atrophy in the dorsal anterior cingulate cortex and to apathy score measured on a clinical scale. Thus, our results highlight elevated effort aversion (not reduced reward appetence) as a core dysfunction that might generate apathy in bvFTD patients. More broadly, they provide novel behavioral tests and computational tools to identify the dysfunctional mechanisms producing motivation deficits in patients with brain damage.

The trade-off between effort and reward is one of the main determinants of behavior, and its alteration is at the heart of major disorders such as depression or Parkinson's disease. Monoaminergic neuromodulators are thought to play a key role in this trade-off, but their relative contribution remains unclear. Rhesus monkeys (Macaca mulatta) performed a choice task requiring a trade-off between the volume of fluid reward and the amount of force to be exerted on a grip. In line with a causal role of noradrenaline in effort, decreasing noradrenaline levels with systemic clonidine injections (0.01 mg/kg) decreased exerted force and enhanced the weight of upcoming force on choices, without any effect on reward sensitivity. Using computational modeling, we showed that a single variable ("effort") could capture the amount of resources necessary for action and control both choices (as a variable for decision) and force production (as a driving force). Critically, the multiple effects of noradrenaline manipulation on behavior could be captured by a specific modulation of this single variable. Thus, our data strongly support noradrenaline's implication in effort processing.