Tracking Developmental Change in the Dopamine System Using Neuromelanin-Sensitive MRI in Children and Adults

Abstract

The study of the dopaminergic system in humans has been predominantly obstructed by the lack of practical and advanced imaging techniques. Neuromelanin-sensitive MRI (NM-MRI) leverages the properties of NM, a byproduct of dopamine metabolism, to measure its accumulation in the Substantia Nigra (SN), and its impact on the function and integrity of the dopaminergic system, opening the potential for its use as a neuroimaging biomarker. In this thesis we explore NM-MRI to gain more insights into the function and dynamics of the dopaminergic system across the lifespan. The first aim of this thesis is to identify the normative range of NM-MRI values in cognitively normal older individuals (53-86 years old), a key initial step towards its use as a clinical biomarker. Our results did not show any significant age-related change in NM metrics in this age range. The stable normative metrics in older individuals play an essential part in helping differentiate between normal aging processes and those marking the potential onset of neurodegenerative conditions. The second aim explores the change in NM dynamics across the lifespan in the human brain. Two types of NM-MRI sequences are used to study these dynamics, Magnetization Transfer (MT) and Turbo Spin Echo (TSE). We found that throughout the SN, different clusters of voxels behave differently with age, highlighting the importance of voxelwise analysis when interpreting the patterns of NM accumulation within the SN, in parallel with looking at the SN as a whole structure. The third aim looks for a potential correlation between NM signal within the SN and cognitive performance in young individuals. Our results show a strong positive link between NM signal accumulation in the SN and working memory performance, specifically localized in specific subregions of the SN. These results highlight the dynamic nature of the dopaminergic system in early life. The fourth and last aim of this thesis compares the NM-MRI signal in a group of children and adolescents with Attention-Deficit-Hyperactivity-Disorder (ADHD) to age-matched healthy controls. A significant decrease in NM-MRI signal was observed in ADHD patients compared to their healthy peers, suggesting that lower dopamine levels in the SN could have an underlying role in the disorder. This makes NM a promising biomarker for diagnosis and treatment monitoring in ADHD. Overall, this work reveals valuable insights into the differential development of NM patterns during life, reaffirming the growing utility of NM-MRI for future research and its clinical role for early identification of neurodegenerative and neurodevelopmental disorders.