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 muscle responses cannot disentangle the 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 a patient with ALS 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 from the patient were compared with those recorded in 10 conscious control subjects. Compared with 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 noninvasive TMS studies, the findings from this single-case study may provide valuable insights into the pathophysiological mechanisms of the disease.NEW & NOTEWORTHY The response evoked by direct activation of corticospinal neurons is reduced in human amyotrophic lateral sclerosis (ALS). In contrast, the response evoked by trans-synaptic activation of these cells is enhanced. The activity of inhibitory inputs to corticospinal neurons is reduced. These abnormalities related to abnormal excitatory and inhibitory input processing by corticospinal neurons may trigger neurodegeneration.