Fig. 1

The dying forward hypothesis in ALS. The dying-forward hypothesis suggests that the dysfunction and death of motor neurons, (especially involving Betz cells), begins in the motor and pre-motor cortices and then progresses downwards to lower motor neuron (LMN) through an anterograde pattern along the cortical-spinal cord projection, leading to motor neuronal death in the brainstem and spinal cord. Excitotoxicity due to the hyperexcitability is an important mediator of upper motor neuron (UMN) dysfunction, but not the only factor