De neurale correlaten van bimanueel motorisch leren: Neurometabolieten, synaptische densiteit en effectieve premotor–motor connectiviteit

Human movement, and particularly bimanual motor control, which involves coordinating both hands, is fundamental to our everyday lives, for example when getting dressed, driving a car, or playing a musical instrument. Acquiring new motor skills relies heavily on motor learning and neuroplasticity. Hence, understanding the neural mechanisms behind these processes is essential for ultimately optimizing training interventions and rehabilitation strategies. This PhD research aimed to enhance our understanding of the neural correlates underlying bimanual motor learning and neuroplasticity in the human brain. Through various techniques such as magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and dual-site transcranial magnetic stimulation (dsTMS), we explored changes in neurotransmitter levels, synaptic density, and connectivity between key brain regions involved in motor function. The findings have enhanced our understanding of the relationship between motor learning on the one hand, and neurotransmitters and synaptic density on the other hand. Furthermore, a novel dsTMS setup has been validated to study the effective connectivity between the motor-related brain regions with a focus on dorsal premotor cortex (PMd) and primary motor cortex (M1) in the context of motor learning. The results of Chapter 2 showed the importance of both the inhibitory gamma-aminobutyric acid (GABA) and excitatory Glx (a compound measure of glutamate and glutamine) in motor learning. Not only were baseline (resting state) GABA and Glx levels linked to long-term motor learning, but also was the task-related modulation of GABA and Glx in the left PMd of importance for short-term motor learning progress. Lastly, resting state Glx levels in SM1 changed significantly over the course of the four-week motor learning intervention. These neurometabolic correlates of human motor learning were complemented by the findings in Chapter 3, in which the association between motor learning and synaptic density were examined. Specifically, a decreased synaptic vesicle glycoprotein 2A (SV2A) uptake in the left temporal pole was observed after motor learning. Further, associations between motor learning progress and baseline as well as learning-related changes in SV2A uptake in various brain regions were observed. Together, these findings indicated potential synaptic pruning processes. Surprisingly, no overlap was found between regions showing learning-related changes in GM and those showing alterations in SV2A uptake, suggesting that each method measures a distinct feature of the neuroplastic process. In Chapters 4 and 5, a novel dsTMS setup to test intrahemispheric PMd-M1 effective connectivity was introduced. The new setup demonstrated promising feasibility and reliability, and revealed an inhibitory influence of PMd on M1 for shorter inter-stimulus intervals, and a facilitatory influence for longer ones. This setup paves the way for future research on motor task performance and learning. This dsTMS setup has already been used in the bimanual motor learning experiment and results will be described in future reports. Together, these studies enhance our understanding of the neural mechanisms underlying motor training-induced neuroplasticity, with a special emphasis on PMd and M1, and provide valuable tools, insights and fundaments for future research and potential rehabilitation strategies.