Multimodal Analysis for Brain Network Fingerprints in Parkinson's Disease Patients

Abstract

Parkinson's disease is a neurodegenerative disorder that causes structural and functional abnormalities in the central nervous system. The disease leads to the development of cardinal motor symptoms, including bradykinesia, tremor, and rigidity. Other motor symptoms, such as postural instability, gait impairments (including freezing of gait and falls), micrographia, and speech impairments, are also prevalent. In this doctoral thesis, we investigated various aspects of parkinsonian motor dysfunction in both upper and lower limbs. Given the complexity of brain communication within the motor cortex, we used a multimodal approach to assess the interplay within the motor cortex in healthy humans and investigate specific questions regarding the associated alterations in functional characteristics of the brain among people with Parkinson's disease from a network perspective.

In this context, the aims of the thesis were: i) to quantify the neural dynamics within the motor cortex during upper limb motor activities and delineate associated electrophysiological neural modulations as well as the prominent motor region (study one), ii) to identify the distinct neural networks and their neural oscillatory profiles associated with tremor phenotypes (study two), and iii) to characterise the underlying mechanism of improvements following treadmill training as a commonly applied physical therapy (study three). In the first study, we explored neural modulations within the motor cortex during different voluntary upper limb movements. Our findings emphasise the pivotal role of the premotor cortex in upper limb movements within the motor cortex based on its bilateral modulation with primary motor cortex and supplementary motor area that is sensitive across various upper limb voluntary movements. The correlation between motor evoked potential and ipsilateral connectivity in right-M1 -> right-SMA highlighted the engagement of ipsilateral motor activity and the potential modulatory effect of this neural pathway on the degree of ipsilateral primary motor activation. The second study highlighted that the primary sensorimotor cortex may act as an intermediary, modulating cortical-subcortical communication in tremor phenotypes. We demonstrated that re-emergent tremors may increasingly depend on the cerebello-thalamo-cortical pathway and reduce reliance on the basal ganglia circuit. Additionally, tremor-related neuronal oscillations within cortical-subcortical network influenced by pathological beta and prokinetic gamma oscillations. The third study corroborated that treadmill training may lead to the recruitment of compensatory processes recruited from other brain regions to the motor cortex. The cerebellum and its intrinsic connectivity with the brainstem and subcortical region constructed the main skeleton of the cortical-subcortical network pattern underlying walking performance. Prefrontal-directed connectivity (from brainstem and subcortical region) may reflect brain reorganisation in the alleviated prefrontal activity following treadmill training.

In conclusion, this doctoral work utilises biomechanical analyses, neuroimaging techniques, and electrophysiological measurements to establish a link between specific and general motor impairments and structural and functional alterations within the motor network. The study highlights the importance of investigating new tools to quantify motor impairments. On a broader scale, this research should enhance our understanding of Parkinson's disease and ultimately promote the advancement of current therapeutic approaches and the development of future ones.