Modulation of motivation in neurological disease

All human success depends on motivation: to pursue, achieve and complete our goals. Success requires not only motivation to initiate actions, but also to persist with them until completion. Many people start projects but fail to persevere. The ability to maintain motivation on a task is sometimes termed grit1, especially in the face of a challenge or setback. Grit is a key ingredient to success in life2, but despite this, motivation to persist in response to perturbations such as setbacks have rarely been directly measured in controlled human experiments. Consequently little is known about its neural underpinnings in humans3. This lack of knowledge has come into sharp focus with the appreciation that clinical apathy—a pathological loss of motivation—is an extremely common and disabling syndrome across neurological and psychiatric conditions, with no established treatment4. Understanding the mechanisms that lead to loss of motivation is important because apathy significantly impairs quality of life in many conditions5, predicts dementia onset6 and death7, and carries major social and economic costs8. We hypothesise that deficits in grit may critically lead patients with apathy to abort plans early, lose sight of goals, or give up easily in the face of a challenge. Yet, these possibilities have not been systematically investigated in patients. To persist with goals, the brain must represent how much more work needs to be done to succeed (i.e. our distance to a goal). Persistence then involves resilience to pursue the goal in the face of adversities—‘setbacks’. No drug treatments are approved for treating apathy, but neuromodulation could offer new avenues. The circuits underlying motivation include the striatum and medial frontal cortex. Because they lie deep in the brain, these regions have previously been inaccessible to neuromodulation, but a new method using focused ultrasound (FUS) holds promise for targeting these areas in humans. For this project, we have developed a new way to quantify how people persist with motivated actions, in the face of setbacks. Patients repeatedly press a button to reach a goal. We then impose precisely timed setbacks that put them further from their goal, and we measure dynamic adjustments in movement speed. Our first study will build on pilot data that suggests that low dopamine results in an inverted response to setbacks. Our quantitative dynamic model predicts that failure to persist after a setback is due to localised dopamine deficits in ventral striatum (VS), controlled by ventromedial prefrontal cortex (vmPFC). We will also relate persistence to clinical apathy and grit. Second, we will study patients with focal damage to vmPFC. Oxford has a rare cohort of these patients, who also show deficits in other aspects of motivation. Third, we will use FUS to modulate activity in VS and vmPFC in patients with PD. FUS is the only non-invasive method to selectively modulate deep brain areas. It therefore offers unprecedented opportunities for precision therapeutics in PD. We will use brief low doses which have a short-lived effect (30min), and probe persistence in our behavioural task. If the work is successful, we will develop modulation protocols to extend duration of FUS effects, and explore pairing of FUS with learning to achieve longer term benefits. Ultimately, this experimental medicine work will pave the way for longer-lasting therapeutic modulation of deep nuclei for a disorder that currently has no medical treatments.