Functional alterations in large-scale resting-state networks of amyotrophic lateral sclerosis: A multi-site study across Canada and the United States

Abstract

Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder characterized by progressive degeneration of upper motor neurons and lower motor neurons, and frontotemporal regions resulting in impaired bulbar, limb, and cognitive function. Magnetic resonance imaging studies have reported cortical and subcortical brain involvement in the pathophysiology of ALS. The present study investigates the functional integrity of resting-state networks (RSNs) and their importance in ALS. Intra- and inter-network resting-state functional connectivity (Rs-FC) was examined using an independent component analysis approach in a large multi-center cohort. A total of 235 subjects (120 ALS patients; 115 healthy controls (HC) were recruited across North America through the Canadian ALS Neuroimaging Consortium (CALSNIC). Intra-network and inter-network Rs-FC was evaluated by the FSL-MELODIC and FSLNets software packages. As compared to HC, ALS patients displayed higher intra-network Rs-FC in the sensorimotor, default mode, right and left fronto-parietal, and orbitofrontal RSNs, and in previously undescribed networks including auditory, dorsal attention, basal ganglia, medial temporal, ventral streams, and cerebellum which negatively correlated with disease severity. Furthermore, ALS patients displayed higher inter-network Rs-FC between the orbitofrontal and basal ganglia RSNs which negatively correlated with cognitive impairment. In summary, in ALS there is an increase in intra- and inter-network functional connectivity of RSNs underpinning both motor and cognitive impairment. Moreover, the large multi-center CALSNIC dataset permitted the exploration of RSNs in unprecedented detail, revealing previously undescribed network involvement in ALS.

Hippocampal Metabolic Alterations in Amyotrophic Lateral Sclerosis: A Magnetic Resonance Spectroscopy Study

“…Similar to our study, MRS metrics have consistently captured the substrate of clinical disability, medication effects, and progressive clinical decline [ 19 , 22 , 82 ], suggesting that it is a worthy addition to both academic and clinical protocols in ALS. Pharmacological trials of ALS continue to primarily rely on clinical metrics and wet biomarkers [ 95 , 111 ], and the few multi-site imaging initiatives [ 112 , 113 , 114 ] rely on structural, functional, and DTI data alone. There is now ample evidence that MRS is both sensitive to detect focal changes and exhibit good correlations with relevant clinical metrics and therefore should be incorporated in both future single-centre and multi-centre studies.…”

Basal ganglia alterations in amyotrophic lateral sclerosis

“…Functional MRI, in particular resting-state functional connectivity (RS-FC) analysis, has provided important insights into the brain functional reorganization in ALS. The presence of altered functional connectivity and activation of BG in ALS patients has been demonstrated by several studies ( Konrad et al, 2006 ; Tessitore et al, 2006 ; Mohammadi et al, 2015 ; Ma et al, 2016 ; Abidi et al, 2020 , 2022 ; Temp et al, 2021 ; Bharti et al, 2022 ; Castelnovo et al, 2022 ).…”

“…A multicentric study which investigated intra-network and inter-network RS-FC in a large sample of ALS patients (not classified in terms of cognitive status) reported higher intra-network RS-FC in several RS circuits, including BG network, in ALS patients compared to controls ( Bharti et al, 2022 ). These findings were associated with a worse performance at ECAS, worse finger and foot tapping scores, and greater disease severity ( Bharti et al, 2022 ). In addition, ALS patients compared to controls showed a higher inter-network RS-FC between the BG and orbitofrontal networks, which were related to lower ECAS ALS-specific score ( Bharti et al, 2022 ).…”

“…These findings were associated with a worse performance at ECAS, worse finger and foot tapping scores, and greater disease severity ( Bharti et al, 2022 ). In addition, ALS patients compared to controls showed a higher inter-network RS-FC between the BG and orbitofrontal networks, which were related to lower ECAS ALS-specific score ( Bharti et al, 2022 ). A seed-based FC analysis which investigated the RS-FC of the globus pallidus in ALScn patients showed an increased RS-FC between bilateral globus pallidus and postcentral, supramarginal, and superior temporal gyri, and reduced RS-FC between the left globus pallidus and left middle and inferior temporal gyri and bilateral caudate, with these latter alterations related to worse disgust recognition in patients and controls ( Castelnovo et al, 2022 ).…”

“…As such, given BG involvement in voluntary movement and high-order aspects of motor control ( Groenewegen, 2003 ), structural and functional changes in BG were often associated with greater disease severity ( Sharma et al, 2013 ; Menke et al, 2018 ; Abidi et al, 2020 ; Bharti et al, 2022 ; Li et al, 2022 ), worsening of clinical symptoms, including greater disability and motor decline ( Sharma et al, 2013 ; Bharti et al, 2022 ), as well as faster disease progression ( Basaia et al, 2020 ; Tae et al, 2020 ), and shorter survival ( Westeneng et al, 2015 ; Zhang J. Q. et al, 2017 ).…”