The Corticospinal System and Amyotrophic Lateral Sclerosis: IFCN handbook chapter.

Corticospinal neurons located in motor areas of the cerebral neocortex project corticospinal axons which synapse with the spinal network; a parallel corticobulbar system projects to the cranial motor network and to brainstem motor pathways. The primate corticospinal system has a widespread cortical origin and an extensive range of different fibre diameters, including thick, fast-conducting axons. Direct cortico-motoneuronal (CM) projections from the motor cortex to arm and hand alpha motoneurons are a recent evolutionary feature, that is well developed in dexterous primates and particularly in humans. Many of these projections originate from the caudal subdivision of area 4 ('new' M1: primary motor cortex). They arise from corticospinal neurons of varied soma size, including those with fast- and relatively slow-conducting axons. This CM system has been shown to be involved in the control of skilled movements, carried out with fractionation of the distal extremities and at low force levels. During movement, corticospinal neurons are activated quite differently from 'lower' motoneurons, and there is no simple or fixed functional relationship between a so-called 'upper' motoneuron and its target lower motoneuron. There are key differences in the organisation and function of the corticospinal and CM system in primates versus non-primates, such as rodents. These differences need to be recognized when making the choice of animal model for understanding disorders such as amyotrophic lateral sclerosis (ALS). In this neurodegenerative brain disease there is a selective loss of fast-conducting corticospinal axons, and their synaptic connections, and this is reflected in responses to non-invasive cortical stimuli and measures of cortico-muscular coherence. The loss of CM connections influencing distal limb muscles results in a differential loss of muscle strength or 'split-hand' phenotype. Importantly, there is also a unique impairment in the coordination of skilled hand tasks that require fractionation of digit movement. Scores on validated tests of skilled hand function could be used to assess disease progression.