Cancer-related fatigue is a prominent and debilitating side effect of cancer and its treatment. It can develop prior to diagnosis, generally peaks during cancer treatment, and can persist long after treatment completion. Its mechanisms are multifactorial, and its expression is highly variable. Unfortunately, treatment options are limited. Our research uses syngeneic murine models of cancer and cisplatin-based chemotherapy to better understand these mechanisms. Our data indicate that both peripherally and centrally processes may contribute to the developmental of fatigue. These processes include metabolic alterations, mitochondrial dysfunction, pre-cachexia, and inflammation. However, our data has revealed that behavioral fatigue can persist even after the toxicity associated with cancer and its treatment recover. For example, running during cancer treatment attenuates kidney toxicity while also delaying recovery from fatigue-like behavior. Additionally, administration of anesthetics known to disrupt memory consolidation at the time treatment can promote recovery, and treatment-related cues can re-instate fatigue after recovery. Cancer-related fatigue can also promote habitual behavioral patterns, as observed using a devaluation task. We interpret this data to suggest that limit metabolic resources during cancer promote the utilization of habit-based behavioral strategies that serve to maintain fatigue behavior into survivorship. This line of work is exciting as it points us toward novel interventional targets for the treatment of persistent cancer-related fatigue.

From a workout at the gym to helping a colleague with their work, everyday we make decisions about whether we are willing to exert effort to obtain some sort of benefit. Increases in how effortful actions and cognitive processes are perceived to be has been linked to clinically severe impairments to motivation, such as apathy and fatigue, across many neurological and psychiatric conditions. However, the vast majority of neuroscience research has focused on understanding the benefits for acting, the rewards, and not on the effort required. As a result, the computational and neural mechanisms underlying how effort is processed are poorly understood. How do we compute how effortful we perceive a task to be? How does this feed into our motivation and decisions of whether to act? How are such computations implemented in the brain? and how do they change in different environments? I will present a series of studies examining these questions using novel behavioural tasks, computational modelling, fMRI, pharmacological manipulations, and testing in a range of different populations. These studies highlight how the brain represents the costs of exerting effort, and the dynamic processes underlying how our sensitivity to effort changes as a function of our goals, traits, and socio-cognitive processes. This work provides new computational frameworks for understanding and examining impaired motivation across psychiatric and neurological conditions, as well as why all of us, sometimes, can’t be bothered.

In many learning and decision scenarios, especially sequential settings like mazes or games, it is easy to state an objective function but difficult to compute it, for instance because this can require enumerating many possible future trajectories. This, in turn, motivates a variety of more tractable approximations which then raise resource-rationality questions about whether and when an efficient agent should invest time or resources in computing decision variables more accurately. Previous work has used a simple all-or-nothing version of this reasoning as a framework to explain many phenomena of automaticity, habits, and compulsion in humans and animals. Here, I present a more finegrained theoretical analysis of deliberation, which attempts to address not just whether to deliberate vs. act, but which of many possible actions and trajectories to consider. Empirically, I first motivate and compare this account to nonlocal representations of spatial trajectories in the rodent place cell system, which are thought to be involved in planning. I also consider its implications, in humans, for variation over time and situations in subjective feelings of mental effort, boredom, and cognitive fatigue. Finally, I present results from a new study using magnetoencephalography in humans to measure subjective consideration of possible trajectories during a sequential learning task, and study its relationship to rational prioritization and to choice behavior.