The spectral slope as a marker of excitation/inhibition ratio and cognitive functioning in multiple sclerosis

Abstract

Background: Multiple sclerosis (MS) is a neurodegenerative disease characterized by neuronal and synaptic loss, resulting in an imbalance of excitatory and inhibitory synaptic transmission and potentially cognitive impairment. Current methods for measuring the excitation/inhibition (E/I) ratio are mostly invasive, but recent research combining neurocomputational modeling with measurements of local field potentials has indicated that the slope with which the power spectrum of neuronal activity captured by electro- and/or magnetoencephalography rolls off, is a non-invasive biomarker of the excitation/inhibition (E/I) ratio. A steeper roll-off is associated with a stronger inhibition. This novel method can be applied to assess the E/I ratio in people with multiple sclerosis (pwMS), detect the effect of medication such as benzodiazepines, and explore its utility as a biomarker. Methods: We recruited 44 healthy control subjects and 95 people with multiple sclerosis (pwMS) who underwent resting-state magnetoencephalographic recordings. The 1/f spectral slope of the neural power spectra was calculated for each subject and for each brain region. Results: As expected, the spectral slope was significantly steeper in pwMS treated with benzodiazepines compared to pwMS not receiving this medication (p = 0.01). In the sub-cohort of pwMS not treated with benzodiazepines, we observed a steeper slope in cognitively impaired pwMS compared to cognitively preserved pwMS (p = 0.01) and healthy subjects (p = 0.02). Furthermore, we observed a significant correlation between 1/f slope and verbal and spatial working memory functioning in the brain regions located in the prefrontal and parietal cortex. Conclusions: In this study, we highlighted the value of the spectral slope, a novel non-invasive biomarker of the E/I ratio, in MS by quantifying the inhibitory effect of benzodiazepines and by putting it forward as a potential biomarker of cognitive deficits in pwMS.

Stimulus-related modulation in the 1/f spectral slope suggests an impaired inhibition during a working memory task in people with multiple sclerosis

“…The slope, representing the steepness of the 1/f power-law component, has been associated with the excitation/inhibition ratio, 7 where a steeper slope indicates a higher level of inhibition. [7][8][9] The value of this novel biomarker in MS is still poorly investigated, but our recent results support this interpretation in pwMS. 8 Working memory is the capacity to actively and temporarily retain and manipulate a limited amount of information for a brief period of time.…”

“…[7][8][9] The value of this novel biomarker in MS is still poorly investigated, but our recent results support this interpretation in pwMS. 8 Working memory is the capacity to actively and temporarily retain and manipulate a limited amount of information for a brief period of time. 10 Maintaining the appropriate balance between excitatory and inhibitory signals has been computationally shown to be essential for efficient information processing and working memory maintenance.…”

“…7–9 The value of this novel biomarker in MS is still poorly investigated, but our recent results support this interpretation in pwMS. 8…”

“…We hypothesize that an impaired excitation/inhibition balance—as suggested in pwMS 2 —will lead to reduced inhibition during distractor trials. Since we have previously demonstrated the potential value of the 1/f slope as a proxy of excitation/inhibition balance in pwMS, 8 we expect a flatter 1/f slope in pwMS compared to healthy controls (HCs). We also hypothesize a correlation between a flatter 1/f slope and longer reaction times (RTs), similar to Kałamała et al 17 where individuals with a flatter 1/f slope have a higher inverse efficiency score (i.e.…”

“…MEG data were acquired in 117 subjects during the n-back task: 38 HCs and 79 pwMS. Since we previously observed that benzodiazepines affect the 1/f spectral slope, 8 we divided the group of pwMS into two separate groups based on their treatment: 19 pwMS treated with benzodiazepines (pwMS(BZDp)) and 60 pwMS not treated with benzodiazepines (pwMS(BZDn)). All pwMS were recruited at the National MS Center Melsbroek and were required to meet the diagnostic criteria for MS according to McDonald's revised criteria 20 while having an Expanded Disability Status Scale (EDSS) score 21 less than or equal to 6 in order to participate in the MEG sessions independently.…”