Dysfunction of attention switching networks in amyotrophic lateral sclerosis

Abstract

Objective: To localise and characterise changes in cognitive networks in Amyotrophic Lateral Sclerosis (ALS) using source analysis of mismatch negativity (MMN) waveforms.

Rationale: The MMN waveform has an increased average delay in ALS. MMN has been attributed to change detection and involuntary attention switching. This therefore indicates pathological impairment of the neural network components which generate these functions. Source localisation can mitigate the poor spatial resolution of sensor-level EEG analysis by associating the sensor-level signals to the contributing brain sources. The functional activity in each generating source can therefore be individually measured and investigated as a quantitative biomarker of impairment in ALS or its sub-phenotypes.

Methods: MMN responses from 128-channel electroencephalography (EEG) recordings in 58 ALS patients and 39 healthy controls were localised to source by three separate localisation methods, including beamforming, dipole fitting and exact low resolution brain electromagnetic tomography.

Results: Compared with controls, ALS patients showed significant increase in power of the left posterior parietal, central and dorsolateral prefrontal cortices (false discovery rate = 0.1). This change correlated with impaired cognitive flexibility (rho = 0.45, 0.45, 0.47, p = .042, .055, .031 respectively). ALS patients also exhibited a decrease in the power of dipoles representing activity in the inferior frontal (left: p = 5.16 × 10^-6, right: p = 1.07 × 10^-5) and left superior temporal gyri (p = 9.30 × 10^-6). These patterns were detected across three source localisation methods. Decrease in right inferior frontal gyrus activity was a good discriminator of ALS patients from controls (AUROC = 0.77) and an excellent discriminator of C9ORF72 expansion-positive patients from controls (AUROC = 0.95).

Interpretation: Source localization of evoked potentials can reliably discriminate patterns of functional network impairment in ALS and ALS subgroups during involuntary attention switching. The discriminative ability of the detected cognitive changes in specific brain regions are comparable to those of functional magnetic resonance imaging (fMRI). Source analysis of high-density EEG patterns has excellent potential to provide non-invasive, data-driven quantitative biomarkers of network disruption that could be harnessed as novel neurophysiology-based outcome measures in clinical trials.

Keywords: Amyotrophic lateral sclerosis; Cognition; EEG; Mismatch negativity; Network; Source localisation.

Fig. 1

Location of dipoles modelled by dipole fitting. Centroids of the left (blue) and right (orange) superior temporal gyri and left (red) and right (green) inferior frontal pars triangularis were used to seed dipoles for dipole fitting. Axial MRI view is from above (L-Left, R-Right).

Fig. 2

ALS patients show decreased power in both inferior frontal gyri and the left superior temporal gyrus. Boxes illustrate the interquartile range with whiskers illustrating the maximum and minimum power (A-m) within twice the interquartile range for ALS patients (P) and controls (C), determined by dipole fitting. Outliers are illustrated in black. Dashed line caps up to two outliers beyond this value. L – Left, R – Right, IFG – Inferior frontal gyrus, STG – Superior Temporal Gyrus.

Fig. 3

ELORETA identified a pattern of decreased activity in the left superior temporal and inferior frontal sources, and an increase in activity in posterior areas. Location of MMN sources with (a) top 50% of power (10*log₁₀(Deviant power / Standard power)) in healthy controls and (b) power differences >25% of maximum between ALS patients and healthy controls as determined by eLORETA. Red denotes increase in power, blue denotes decrease in power. Axial MRI views are from above (L-Left, R-Right).

Fig. 4

LCMV identified a pattern of decreased activity in bilateral superior temporal and inferior frontal sources, and an increase in activity in the left hemisphere. Location of MMN sources with (a) top 25% of power (10*log₁₀(Deviant power / Standard power)) in healthy controls and (b) power differences >25% of maximum between ALS patients and healthy controls as determined by LCMV beamforming. Red denotes increase in power, blue denotes decrease in power. Axial MRI views are from above (L-Left, R-Right).

Fig. 5

Increased activity in the left posterior parietal, central and dorsolateral prefrontal cortex in ALS is statistically significant. Statistically significant (false discovery rate = 10%) differences in power between ALS patients and healthy controls as determined by LCMV. Heat map values are AUROC-0.5. Red denotes AUROC>0.5, blue denotes decrease in AUROC<0.5. Axial MRI views are from above (L-Left, R-Right).

Fig. 6

Increased activity in the posterior parietal and dorsolateral prefrontal cortex correlates to poorer performance in cognitive switching tasks. Correlation of inhibition/switching score (in seconds) for 27 patients with mean power in the left primary motor cortex (red), posterior parietal cortex (PPC, green), and middle and superior frontal gyri (M/SFG, blue) illustrated by scatterplot with line of best fit.