Recent evidence suggests that ALS is initiated in the motor cortex, impacting in particular layer V pyramidal neurons, and subsequently affects spinal motor neurons [62]; cortical hyperexcitability has been detected in sporadic ALS patients prior to spinal motor neuron dysfunction and in carriers of a SOD1 mutation conferring familial ALS, as well as in models of ALS [8, 53, 63]. The gene discussed is SOD1; the disease is amyotrophic lateral sclerosis.