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bioRxiv · 10.1101/2023.05.05.539548

Altered Brain Dynamics in idiopathic REM sleep behavior disorder: Implications for a continuum from prodromal to overt alpha-synucleinopathies

Roascio, M.·Wang, S. H.·Myrov, V.·Siebenhuhner, F.·Tro', R. D.·Mattioli, P.·Fama', F.·Morbelli, S. D.·Pardini, M.·Palva, J. M.·Arnaldi, D.·Arnulfo, G.
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Abstract

Idiopathic/isolated REM sleep behavior disorder (iRBD) is considered a prodromal stage of alpha-synucleinopathies. Cortical and sub-cortical brain modifications begin years before the emergence of overt neurodegenerative symptoms. To better understand the pathophysiological process impacting the brain from the prodromal to the overt stage of alpha-synucleinopathy, it is essential to assess iRBD patients over time. Recent evidence suggests that the human brain operates at an operating point near a critical phase transition between subcritical and supercritical phases in the systems state space to maintain cognitive and physiological performance. In contrast, a deviation from the critical regime leading to altered oscillatory dynamics has been observed in several pathologies. Here, we investigated if the alpha-synucleinopathy produces a deviation of the operating point already evident in the prodromal phase and if this shift correlates with biological and clinical disease severity. We analyzed a dataset of 59 patients with iRBD (age 69.61 {+/-} 6.98, 50 male) undergoing resting-state high-density EEG, presynaptic dopaminergic imaging, and clinical evaluations. Thirty-one patients (age 72.41 {+/-} 7.05, 31 male) also underwent clinical and instrumental follow-up (mean follow-up period 25.85 {+/-} 10.20 months). To localize the individual operating points along the excitation-inhibition (EI) continuum, we assessed both measures of neuronal EI balance and measures of critical brain dynamics such as long-range temporal correlation (LRTCs) and neuronal bistability in spontaneous narrow-band oscillations. Finally, we correlated critical brain dynamics and EI balance metrics with phase synchronization, nigro-striatal dopaminergic functioning, and clinical performances. Compared to 48 healthy subjects (age 70.25 {+/-} 10.15, 23 male), iRBD patients showed higher values of LRTCs and bistability in the 2-7 Hz band at diagnosis. Patients who eventually phenoconverted to overt alpha-synucleinopathy exhibited a more excitation-dominated (fEI > 1) condition than stable iRBD patients in 5-7 Hz. This higher excitation also directly correlated with phase synchronization in 2-7 Hz, further suggesting a shift of the operating point toward a supercritical state with the disease progression. Moreover, excitation-dominated state and low bistability were associated with deterioration of the nigro-striatal dopaminergic function and tended to correlate with stronger clinical symptoms. In conclusion, this study shows for the first time a deviation of the working point from inhibition-to excitation-dominated states along the continuum from prodromal to overt phases of the disease. These cortical brain dynamics modifications are associated with nigro-striatal dopaminergic impairment. These results increase our knowledge of the physiopathological process underlying alpha-synucleinopathies since prodromal stages, possibly providing new clues on disease-modifying strategies.

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Roascio, M., Wang, S. H., Myrov, V., Siebenhuhner, F., Tro', R. D., Mattioli, P., Fama', F., Morbelli, S. D., Pardini, M., Palva, J. M., Arnaldi, D., Arnulfo, G.. 2023-05-08. Altered Brain Dynamics in idiopathic REM sleep behavior disorder: Implications for a continuum from prodromal to overt alpha-synucleinopathies. https://doi.org/10.1101/2023.05.05.539548

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