Localization of Brain Networks Engaged by the Sustained Attention to Response Task Provides Quantitative Markers of Executive Impairment in Amyotrophic Lateral Sclerosis

Roisin McMackin, Stefan Dukic, Emmet Costello, Marta Pinto-Grau, Antonio Fasano, Teresa Buxo, Mark Heverin, Richard Reilly, Muthuraman Muthuraman, Niall Pender, Orla Hardiman, Bahman Nasseroleslami, Roisin McMackin, Stefan Dukic, Emmet Costello, Marta Pinto-Grau, Antonio Fasano, Teresa Buxo, Mark Heverin, Richard Reilly, Muthuraman Muthuraman, Niall Pender, Orla Hardiman, Bahman Nasseroleslami

Abstract

Objective: To identify cortical regions engaged during the sustained attention to response task (SART) and characterize changes in their activity associated with the neurodegenerative condition amyotrophic lateral sclerosis (ALS).

Methods: High-density electroencephalography (EEG) was recorded from 33 controls and 23 ALS patients during a SART paradigm. Differences in associated event-related potential peaks were measured for Go and NoGo trials. Sources active during these peaks were localized, and ALS-associated differences were quantified.

Results: Go and NoGo N2 and P3 peak sources were localized to the left primary motor cortex, bilateral dorsolateral prefrontal cortex (DLPFC), and lateral posterior parietal cortex (PPC). NoGo trials evoked greater bilateral medial PPC activity during N2 and lesser left insular, PPC and DLPFC activity during P3. Widespread cortical hyperactivity was identified in ALS during P3. Changes in the inferior parietal lobule and insular activity provided very good discrimination (AUROC > 0.75) between patients and controls. Activation of the right precuneus during P3 related to greater executive function in ALS, indicative of a compensatory role.

Interpretation: The SART engages numerous frontal and parietal cortical structures. SART-EEG measures correlate with specific cognitive impairments that can be localized to specific structures, aiding in differential diagnosis.

Keywords: EEG; amyotrophic lateral sclerosis; attention; hyperactivity; source localization.

© The Author(s) 2020. Published by Oxford University Press.

Figures

Figure 1
Figure 1
Mean Go (blue) and NoGo (red) trial ERPs in controls and ALS patients. N2 peaks are visible in the NoGo trial ERP in Fz and Cz in the 220–350-ms window. P3 peaks are present in the 350–550-ms window in both Go and NoGo trial ERPs in all electrodes. Green asterisks represent significantly larger P3 peak amplitudes in NoGo versus Go trials. Red asterisks represent significantly larger (more negative) N2 peak amplitudes in NoGo versus Go trials. Black asterisks represent significant differences in NoGo-Go N2 peak amplitude between ALS patients and controls. **P < 0.01, ****P < 0.0001. CON: controls.
Figure 2
Figure 2
Correlations between NoGo minus Go (NoGo-Go) N2 peak amplitude in Cz and cognitive task performance. (A) Correlation with response time and NoGo trial accuracy in controls demonstrates that those with smaller NoGo versus Go N2 peak differences had significantly faster response times and better NoGo accuracy. (B) Correlation with patient ECAS total and ALS-specific score demonstrates that those with smaller (less negative) N2 peak differences had lower ECAS scores.
Figure 3
Figure 3
Correlations between P3 peak characteristics and SART performance. In controls, (A) later responses correlate with later P3 peaks in Fz during NoGo trials, (B) better NoGo accuracy inversely correlates with Go P3 peak size in Cz, (C) Go accuracy positively correlates with NoGo P3 peak amplitude in Pz, and (D) overall accuracy inversely correlates with NoGo P3 peak amplitude in Fz. In all participants, (E) later responses correlate with longer peak latency and (F) smaller peak amplitude during Go trials in Cz. In patients, (G) greater overall accuracy correlates with longer Go P3 peak latency in Cz.
Figure 4
Figure 4
Primary sources (regions with top 5% power) of N2 during Go trials, NoGo trials, and NoGo trials relative to Go trials (“difference”) in controls (first rows) and patients (second rows).
Figure 5
Figure 5
Primary sources (regions with 5% power) of P3 during Go trials, NoGo trials, and NoGo trials relative to Go trials (“difference”) in controls (first rows) and patients (second rows).
Figure 6
Figure 6
P3 sources with statistically significant differences in activity in ALS compared with controls. Differences between NoGo and Go trial source activity during the P3 peak were compared between ALS patients and controls. All highlighted areas represent significant (FDR = 10%, type II error=0.38 Bayesian Posterior probability=0.87) increases in power with heat map values representing AUROC = –0.5 (i.e., perfect discrimination = 0.5). Orthogonal MRI scans show only those differences with an AUROC >0.75, that is, very good discriminators. AUROC: area under the receivership operating curve.
Figure 7
Figure 7
Greater behavioral inhibition in ALS is associated with increased right precuneus activity during NoGo P3 relative to Go P3. Higher CWIT inhibition score indicates poorer behavioral inhibition.

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