Cortical Hyperexcitability in the Driver’s Seat in ALS

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by the degeneration of cortical and spinal motor neurons. With no effective treatment available to date, patients face progressive paralysis and eventually succumb to the disease due to respiratory failure within only a few years. Recent research has revealed the multifaceted nature of the mechanisms and cell types involved in motor neuron degeneration, thereby opening up new therapeutic avenues. Intriguingly, two key features present in both ALS patients and rodent models of the disease are cortical hyperexcitability and hyperconnectivity, the mechanisms of which are still not fully understood. We here recapitulate current findings arguing for cell autonomous and non-cell autonomous mechanisms causing cortical excitation and inhibition imbalance, which is involved in the degeneration of motor neurons in ALS. Moreover, we will highlight recent evidence that strongly indicates a cardinal role for the motor cortex as a main driver and source of the disease, thus arguing for a corticofugal trajectory of the pathology.