The pattern of neurodegeneration in ALS/FTD is not random; it targets specific large-scale distributed networks in the brain and spinal cord. Motor manifestations begin in one region of the body in ∼98% of patients (Ravits et al., 2007) accompanied by unilateral, focal damage to MNs in the motor cortex or spinal cord, that innervate the corresponding peripheral body regions. It has been previously suggested that ALS targets specific evolutionarily linked, interdependent functions, and as the disease progresses these deficits combine into failure of specific networks (Eisen et al., 2014). More recently, several clinical studies have revealed that neurodegeneration and TDP-43 pathology spread to continuous anatomical regions during disease course (Ravits et al., 2007; Brettschneider et al., 2013; Walhout et al., 2018), and symptoms arise in the contralateral regions following a unilateral limb onset (Walhout et al., 2018). This also implies that neuronal circuitry might drive disease progression to specific MN populations in ALS/FTD. The spread of misfolded proteins from cell-to-cell, particularly TDP-43, provides a molecular explanation for the specific network and anatomical vulnerability observed in ALS. However, it must be noted that whilst contiguous spread is observed for most patients, this is not the case for all (Ravits and La Spada, 2009).