New vistas of the disease progression in patients with idiopathic rapid-eye-movement sleep behavior disorder

Multiple empirical and modeling evidence suggests that the brain behaves as a complex system that evolves near a critical point where communication and information processing are optimized. Brain oscillations represent a possible controlling mechanism to regulate shifts in the working regime. Brain disorders alter the optimal balance and lead to a deviation of the operating point to sub- or super-critical regimes. Observing altered brain oscillation patterns and their effects on the working regime could yield novel insights into neurodegenerative diseases. Idiopathic rapid-eye-movement sleep behavior disorder (iRBD) is a prodromal stage of alpha-synucleinopathies with a 70% chance of phenoconversion in 10-15 years. Patients with iRBD have a wide variety of symptoms that differ among individuals making the diagnosis of phenoconversion difficult. An accurate prediction of the progression in iRBD patients opens the possibility of alternative treatments and can be vital for improving patients’ quality of life. Objective. My PhD project aims to predict the progression trajectories of patients with idiopathic RBD using EEG primarily. First, I aim to quantify how much RBD affects large-scale brain network couplings and critical dynamics. Second, I investigate whether these altered brain dynamics are promising biomarkers for predicting disease progression and phenoconversion. Finally, I observe whether these features provide novel insights into disease progression trajectory. Approach. I analyzed two distinct longitudinal cohorts of patients with iRBD who underwent clinical evaluation and hdEEG recording at least the two following visits. For each hdEEG data, I observed the phase synchronization and the amplitude correlation of brain oscillations to characterize the global level of synchrony. I computed the functional excitation/inhibition (EI) ratio, a detrended fluctuation analysis (DFA) scaling exponent, and the bistability index to evaluate the EI balance and critical regime. Using a progression model, I linked clinical scores and EEG features progression to characterize individual disease trajectories of patients with iRBD. Main results. Compared to healthy subjects, a transition toward a more critical state, but still in an inhibition-dominated state, is characteristic of iRBD patients at baseline. Patients with iRBD who will convert to an alpha-synucleinopathy exhibited a higher phase synchronization in the theta band (5-7 Hz) and a mild excitation-dominated state - suggesting a transition toward a super-critical regime. Moreover, EI imbalance at the first visit correlates with a faster disease progression trajectory in the disease progression model. A stronger phase synchrony is significantly associated with a worsening of cognitive symptoms. A mild excitation-dominated state is significantly correlated to nigro-striatal dopaminergic impairment. Altogether these findings suggest that network mild excitation-dominated state and hyper-synchronization contribute to brain dysfunction in people with iRBD who converted into alpha-synucleinopathy over time. Significance. The efficacy and tolerability of treatments depend on the progression trajectory of iRBD patients. Nowadays, there is a great interest in looking for new biomarkers able to identify a suitable population to test in clinical trials. These results suggest that people with iRBD exhibiting higher phase synchrony and mild excitation-dominated state could be eligible for effective early treatments using disease-modifying therapy.