Understanding and improving human motivational capacities: A focus on glutathione in the ventral striatum

Motivation -the process that facilitates overcoming the cost of effortful actions to attain desired outcomes- is key to achievement and well-being. Importantly, there are major individual differences in motivational levels.

Low motivation can reflect states of fatigue or depression not only in patients, but also in the general population, and there is currently no effective treatment to ameliorate this condition.

Understanding the brain mechanisms linked to variation in motivated behavior will be of utmost importance to advancing treatments.

Brain metabolism in the ventral striatum -a brain’s motivation hub- is emerging as a strong regulator of motivated behaviors.

Strong pilot data from the host lab has underscored a striking correspondence between glutathione (GSH) - the most prominent antioxidant – levels in the ventral striatum and motivate on the prediction of effort-based motivated behavior. However, solid evidence is still lacking.

The goal of this proposal is to determine whether GSH levels in the ventral striatum relate to widespread levels of effortful performance in healthy human subjects.

To this end, I will use a combination of high-field (7T) 1H-Magnetic Resonance Spectroscopy (1H-MRS; to quantify GSH levels in the ventral striatum, and in the occipital cortex as control region), functional Magnetic Resonance Imaging (fMRI; focusing on BOLD activity in the ventral striatum), behavioral testing for physical and cognitive effort-based motivation, and computational modeling (allowing to dissect specific motivational components).

In addition, a 7-days nutritional intervention (N-acetyl-cysteine or placebo) to manipulate the GSH system will be tested for its effectiveness to 1) increase striatal GSH levels; and 2) improve specific aspects of motivated behavior (e.g., incentive valuation, effortful performance) in the physical and/or cognitive effort tasks.

Therefore, LGCMOT outcomes will greatly advance knowledge in the emerging field of neurometabolism.