Increasing evidence suggests that ALS begins in the cortical regions of the brain, which is referred to as the “dying-forward hypothesis.” Features of cortical hyperexcitability – heralded by reduction in short interval intracortical inhibition – have been detected during the early phases of ALS in transcranial magnetic stimulation studies (Thomsen et al., 2014; Menon et al., 2015). This can precede the clinical onset of bulbar/spinal motor dysfunction by ∼3–6 months (Vucic et al., 2008; Bakulin et al., 2016). The dying forward hypothesis is consistent with Charcot, who first postulated that ALS begins in the cortex (Charcot, 1874). Clinical observations that MNs without monosynaptic connections to cortical MNs, such as the oculomotor, abducens, and Onuf’s nuclei, are spared in ALS, and that pure LMN forms of ALS are rare, also support this hypothesis. Further evidence is provided by the observation that MNs receiving direct, monosynaptic cortical input also predominantly develop TDP-43 pathology, while subcortical MNs do not (Eisen et al., 2017). Similarly, TDP-43 pathology develops in patients only in structures under the control of corticofugal projections (Brettschneider et al., 2013; Menon et al., 2015; Eisen et al., 2017)