Flexibility of Fast Brain Dynamics and Disease Severity in Amyotrophic Lateral Sclerosis

Abstract

Background and Objectives:Amyotrophic lateral sclerosis (ALS) is a multisystem disorder, as supported by clinical, molecular and neuroimaging evidence. As a consequence, predicting clinical features requires a description of large-scale neuronal dynamics. Normally, brain activity dynamically reconfigures over time, recruiting different brain areas. Brain pathologies induce stereotyped dynamics which, in turn, are linked to clinical impairment. Hence, based on recent evidence showing that brain functional networks become hyper-connected as ALS progresses, we hypothesized that the loss of flexible dynamics in ALS would predict the symptoms severity.Methods:To test this hypothesis, we quantified flexibility utilizing the “functional repertoire” (i.e. the number of configurations of active brain areas) as measured from source-reconstructed magnetoencephalography (MEG) in ALS patients and healthy controls. The activity of brain areas was reconstructed in the classical frequency bands, and the functional repertoire was estimated to quantify spatio-temporal fluctuations of brain activity. Finally, we built a k-fold cross validated multilinear model to predict the individual clinical impairment from the size of the functional repertoire.Results:Comparing 42 ALS patients and 42 healthy controls, we found a more stereotyped brain dynamics in ALS patients (P < 0.05), as conveyed by the smaller functional repertoire. The relationship between the size of the functional repertoire and the clinical scores in the ALS group showed significant correlations in both the delta and the theta frequency bands. Furthermore, through a k-fold cross validated multilinear regression model, we found that the functional repertoire predicted both clinical staging (P < 0.001 and P < 0.01, in delta and theta bands, respectively) and symptoms severity (P < 0.001, in both delta and theta bands).Discussion:Our work shows that: 1) ALS pathology reduces the flexibility of large-scale brain dynamics; 2) sub-cortical regions play a key role in determining brain dynamics; 3) reduced brain flexibility predicts disease stage as well as symptoms severity. Our approach provides a non-invasive tool to quantify alterations in brain dynamics in ALS (and, possibly, other neurodegenerative diseases), thus opening new opportunities in disease management as well as a framework to test, in the near future, the effects of disease-modifying interventions at the whole-brain level.

Topological changes of fast large-scale brain dynamics in Mild Cognitive Impairment predict the decay of the hippocampal memory

“…Thus, MCI patients displayed a reduction of their brain flexibility which implies less reconfigurations of brain activity and a more stereotyped brain dynamics . This is in line with previous reports that used the same approach in other neurodegenerative diseases such as Parkinson's disease and Amyotrophic Lateral Sclerosis (Polverino et al, 2022), suggesting that the loss of flexibility might be a common dynamical change induced by different neurodegenerative processes.…”

“…In this study, in analogy with previous findings (Polverino et al, 2022; Sorrentino et al, 2021), we hypothesise that MCI would result in a more stereotyped brain dynamics, as measured by a smaller functional repertoire. Then we moved on to an in-depth characterization of the spatio-temporal dynamics of avalanches (Sorrentino et al, 2021).…”

“…Flexible dynamics is maintained in health and, conversely, is disrupted in disease (Muñoz, 2018; Sorrentino et al, 2021). In fact, smaller functional repertoires occur in neurological diseases and are predictive of both clinical disability and disease progression (Polverino et al, 2022; Sorrentino et al, 2021).…”

Altered spreading of neuronal avalanches in temporal lobe epilepsy relates to cognitive performance: A resting‐state hdEEG study

“…These studies highlighted that neuronal avalanches spread preferentially across the white-matter bundles, 11,12 and that they are drastically altered in neurodegenerative diseases. [11][12][13] In the context of epilepsy, the criticality framework has been used to investigate global brain dynamics during ictal and interictal epileptic activity, [14][15][16] showing a deviation of the system from the critical state in both conditions.…”

Altered spreading of neuronal avalanches in temporal lobe epilepsy relates to cognitive performance: a resting-state hdEEG study

“…More recently, avalanche transition matrices have been applied to magneto/electroencephalography (M/EEG) data, in order to encapsulate the spatio-temporal spreading of neuronal avalanches on the large scale. These studies highlighted that neuronal avalanches spread preferentially across the white-matter bundles (Sorrentino et al, 2021), and that they are drastically altered in neurodegenerative diseases (Polverino et al, 2022; Romano et al, 2022, Sorrentino et al, 2021). In the context of epilepsy, the criticality framework has been used to investigate global brain dynamics during ictal and interictal epileptic activity (Osorio et al, 2009, Meisel et al, 2012, Arviv et al, 2016) showing a deviation of the system from the critical state in both conditions.…”