Abnormal Functional Connectivity Density in Amyotrophic Lateral Sclerosis

Purpose: Amyotrophic lateral sclerosis (ALS) is a motor neuro-degenerative disorder that also damages extra-motor neural pathways. A significant proportion of existing evidence describe alterations in the strengths of functional connectivity, whereas the changes in the density of these functional connections have not been explored. Therefore, our study seeks to identify ALS-induced alternations in the resting-state functional connectivity density (FCD). Methods: Two groups comprising of 38 ALS patients and 35 healthy participants (age and gender matched) were subjected to the resting-state functional magnetic resonance imaging (MRI) scanning. An ultra-fast graph theory method known as FCD mapping was utilized to calculate the voxel-wise short- and long-range FCD values of the brain for each participant. FCD values of patients and controls were compared based on voxels in order to discern cerebral regions that possessed significant FCD alterations. For areas demonstrating a group effect of atypical FCD in ALS, seed-based functional connectivity analysis was then investigated. Partial correlation analyses were carried out between aberrant FCDs and several clinical variables, controlling for age, gender, and total intracranial volume. Results: Patients with ALS were found to have decreased short-range FCD in the primary motor cortex and increased long-range FCD in the premotor cortex. Extra-motor areas that also displayed extensive FCD alterations encompassed the temporal cortex, insula, cingulate gyrus, occipital cortex, and inferior parietal lobule. Seed-based correlation analysis further demonstrated that these regions also possessed disrupted functional connectivity. However, no significant correlations were identified between aberrant FCDs and clinical variables. Conclusion: FCD changes in the regions identified represent communication deficits and impaired functional brain dynamics, which might underlie the motor, motor control, language, visuoperceptual and high-order cognitive deficits in ALS. These findings support the fact that ALS is a disorder affecting multiple systems. We gain a deeper insight of the neural mechanisms underlying ALS.