Abstract
Objective To identify structural and neurochemical properties that underlie functional connectivity impairments of the primary motor cortex (PMC) and how these relate to clinical findings in amyotrophic lateral sclerosis (ALS).
Methods 52 patients with ALS and 52 healthy controls, matched for age and sex, were enrolled from 5 centres across Canada for the Canadian ALS Neuroimaging Consortium study. Resting-state functional MRI, diffusion tensor imaging and magnetic resonance spectroscopy data were acquired. Functional connectivity maps, diffusion metrics and neurometabolite ratios were obtained from the analyses of the acquired multimodal data. A clinical assessment of foot tapping (frequency) was performed to examine upper motor neuron function in all participants.
Results Compared with healthy controls, the primary motor cortex in ALS showed reduced functional connectivity with sensory (T=5.21), frontal (T=3.70), temporal (T=3.80), putaminal (T=4.03) and adjacent motor (T=4.60) regions. In the primary motor cortex, N-acetyl aspartate (NAA, a neuronal marker) ratios and diffusion metrics (mean, axial and radial diffusivity, fractional anisotropy (FA)) were altered. Within the ALS cohort, foot tapping frequency correlated with NAA (r=0.347) and white matter FA (r=0.537). NAA levels showed associations with disturbed functional connectivity of the motor cortex.
Conclusion In vivo neurochemistry may represent an effective imaging marker of impaired motor cortex functional connectivity in ALS.
Introduction
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder. ALS manifests with an impaired ability to perform motor tasks (eg, walking, eating or breathing) due to the degeneration of upper motor neurons (UMNs) in the primary motor cortex (PMC) and lower motor neurons in the brainstem and spinal cord. Clinical signs of ALS include muscular atrophy, fasciculations, hyperreflexia, weakness and spasticity.1 Of these, hyperreflexia, weakness and spasticity are signs of UMN impairment. Task and resting-state functional MRI (fMRI)2–6 studies have shown impairments in synchronous activity (ie, functional connectivity (FC)) occurring within and between motor and extramotor brain regions. Studies using diffusion tensor imaging (DTI) and voxel-based morphometry have respectively shown evidence of altered microstructure of the corticospinal tract7 and atrophy in the precentral gyrus.8 Magnetic resonance spectroscopy (MRS) studies have shown alterations in neurochemical levels in the PMC in patients with ALS when compared with healthy controls.9 These independent observations of UMN impairment, assessed in conjunction, could potentially provide deeper insights into ALS pathophysiology. Previous analyses of multiple MRI techniques have revealed associations between impaired cortical structure and function.10–14 However, there is no adequate understanding of the association between the functional and anatomical (structure and neurochemistry) properties of affected UMNs inherent to the PMC in ALS.
To address this gap in the literature, a multimodal approach was employed. fMRI, MRS and DTI data were analysed to assess FC, neurochemical and microstructural properties of the PMC. It was hypothesised that in ALS (1) there is altered FC of the PMC with the rest of the brain, (2) these FC alterations relate to underlying structural and/or neurochemical deficits and (3) these FC alterations are associated with clinical measures of UMN impairment. An extensive investigational approach was thus applied to evaluate FC of the PMC across different brain regions and to evaluate the relationship between FC and altered structural, neurochemical and clinical measures.
Methods
Study design and participants
A prospective, multicentre MRI study was conducted at academic hospitals affiliated with universities at five centres located in Edmonton (University of Alberta), Calgary (University of Calgary), Montreal (McGill University), Toronto (University of Toronto) and Vancouver (University of British Columbia), as part of the Canadian ALS Neuroimaging Consortium (CALSNIC).15
Participant demographics and clinical characteristics are shown in table 1 (and detailed in the Results section). Fifty-two patients with ALS were recruited from multidisciplinary ALS clinics at all centres. All patients met diagnostic criteria for clinically possible, probable-lab supported, probable or definite ALS according to El Escorial criteria.16 Patients were not included in the study if they had a symptom duration more than 5 years, did not complete imaging acquisition for either of the MRI sequences in this study, or presented with comorbid frontotemporal dementia (FTD) or other neurological conditions. Fifty-two healthy controls matched for age, sex and number of years of education, without a history of neurological or psychiatric conditions were also recruited into the study. See online supplemental file 1 for a breakdown of participant numbers by site. Foot tapping frequencies (number of taps per 10 s) were recorded for all participants bilaterally and averaged. This clinical variable was selected based on the midline localisation of the MRS region of interest, encompassing the foot region of the motor homunculus bilaterally. Therefore, the right/left foot tapping frequencies were averaged to obtain a single representative measure of UMN function.
