Direct evidence of upper motor neuron excitability changes in a patient with ALS

A key feature of amyotrophic lateral sclerosis (ALS) pathophysiology is motor neuron hyperexcitability. However, the mechanisms of hyperexcitability are not well understood. Prior studies have used transcranial magnetic stimulation (TMS) to demonstrate increased motor cortex excitability and reduced intracortical inhibition in human ALS. Yet interpretation of these findings is limited because measurement of muscles responses cannot disentangle specific contribution of upper and lower motor neurons and of cortical interneurons to excitability changes. We had the rare opportunity to record directly the corticospinal output evoked by TMS upstream of the spinal circuitry in an ALS patient who had undergone epidural electrode implantation for intractable pain. Single pulse stimulation was performed both with a coil orientation inducing a current that activates corticospinal neurons directly, and with a coil orientation inducing a current that activates corticospinal neurons trans-synaptically. Short interval intracortical inhibition (SICI) was also studied using paired pulse stimulation. Data obtained in the patient were compared with those recorded in 10 conscious control subjects. Compared to control subjects, patient showed a reduced amplitude in response to direct corticospinal neuron activation, yet an enhanced amplitude of corticospinal output after trans-synaptic corticospinal neuron activation together with a SICI reduction. Present findings provide direct evidence of hyperexcitability of monosynaptic glutamatergic inputs to corticospinal neurons that, in association with reduced intracortical inhibition, can trigger neurodegeneration. Taken together with the extensive body of evidence generated by non-invasive TMS studies, the findings from this single-case study may provide valuable insights into the pathophysiological mechanisms of the disease.