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

Project Information

LGCMOT

Grant agreement ID: 101032219

DOI

10.3030/101032219

Project closed

EC signature date 16 April 2021

Start date 1 May 2021

End date 30 April 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 191 149,44

EU contribution

€ 191 149,44

Coordinated by

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Switzerland

Periodic Reporting for period 1 - LGCMOT (Understanding and improving human motivational capacities: A focus on glutathione in the ventral striatum)

Reporting period: 2021-05-01 to 2023-04-30

Summary of the context and overall objectives of the project

There are important individual differences in motivation, and these differences are key to individuals’ well-being. Motivational alterations are at the core of several pathologies, including neurodegenerative diseases such as Parkinson’s disease or Alzheimer’s Disease and psychopathologies such as major depressive disorder and schizophrenia. Moreover, lack of motivation and increased effort sensitivity relates to a more sedentary lifestyle which is associated with higher risks for cardiovascular disease, diabetes, and cancer. Motivation can be defined as a series of value-based decisions which drive behavior based on a cost-benefit tradeoff between the costs and the expected benefits of an action. Despite considerable advances in the last decades in the neural correlates of value-based decision-making, the biological underpinnings that determine individual differences in effort-based decision-making remain unclear. Increasing evidence is providing strong support to implicate brain metabolism in different motivational components. Effort perception, perseverance, and mental fatigue have been related to specific metabolites, such as glutamine, glutathione, and glutamate in different brain areas related to motivated behavior, such as the ventral striatum and the dorsolateral prefrontal cortex. However, the contribution of specific metabolites, in brain regions crucially involved in decision-making, to brain function and behavior in human subjects is still rather unexplored. Understanding the neuromolecular underpinnings of effort-based decision-making in humans offers great potential for developing treatments and interventions for altered motivation in a wide range of pathologies and in healthy human individuals. In the current project, we assessed how the baseline levels of glutathione, the main antioxidant in the body, of 75 participants (N=40 females) in two different structures of the brain related to motivated behavior, relate to effort-based decision-making. These insights can pave the way for the development of new approaches -e.g. antioxidant treatments- to ameliorate motivational dysfunctions.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

To answer our main questions, we have measured the baseline level of metabolites of 75 subjects (N= 40 females) in a 7 Tesla scanner using proton magnetic resonance spectroscopy (1H-MRS) in two cortical brain areas related to motivated behavior. After this measurement, subjects were extensively trained to perform physical and mental efforts in the scanner. Afterward, they went back in the MRI scanner to perform two binary choice tasks that parametrically varied either cognitive or physical effort. During fMRI, participants indicated their preferences between two options associated to different levels of monetary incentive and different levels of effort. We could observe that the neurometabolic state of the brain was predictive of inter-individual differences in motivated behavior.

The results of this study will soon be published in research articles. They will also be accompanied by official press releases by the EPFL communication office, available on the EPFL website.

Based on the results of this study, the researcher has also entered in contact with psychiatrists from the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, in order to re-analyze pre-existing data from early psychosis patients whose symptoms include motivational alterations and see whether the results of the current study were, or not, confirmed in this population where motivation is altered. If this is confirmed, the results of the current study could open the way for new treatments for helping patients suffering from motivational deficits across a wide range of pathologies.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The LGCMOT project allowed us to confirm the predominant role of some cortical structures in both physical and mental effort-based motivated behavior. Moreover, we discovered that glutathione, the main antioxidant in the body, in these brain areas correlated with the level of motivation of each individual in our experiment, mediated by the level of activity of these brain areas.

Our discoveries establish the neurometabolic state of the brain, in particular regarding its glutathione content, as a good biomarker for effort-based motivated behavior in both the physical and cognitive domains. This discovery paves the way for future studies in patients with impaired motivation including neurodegenerative disease patients such as Parkinson’s Disease, Alzheimer’s Disease, or Huntington’s Disease patients, but also psychiatric patients such as major depressive disorder or schizophrenia patients. Future research could look at the levels of glutathione in different parts of the brain of those patients to see whether they are altered and how this could eventually relate to their motivational impairment. The researcher has already contacted psychiatrists from the Centre Hospitalier Universitaire Vaudois (CHUV) to see whether this is the case in pre-existing data. Our study also suggests that nutritional interventions with glutathione precursors, such as N-acetyl-cysteine, could form relevant targets for future studies on these pathologies. Finally, the LGCMOT project also opens the way for more research on nutritional deficits in both healthy individuals and in patients, where solving nutritional deficits could help individuals to gain energy in their daily lives.

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