The Cortical “Upper Motoneuron” in Health and Disease

Abstract

Upper motoneurons (UMNs) in motor areas of the cerebral cortex influence spinal and cranial motor mechanisms through the corticospinal tract (CST) and through projections to brainstem motor pathways. The primate corticospinal system has a diverse cortical origin and a wide spectrum of fibre diameters, including large diameter fibres which are unique to humans and other large primates. Direct cortico-motoneuronal (CM) projections from the motor cortex to arm and hand motoneurons are a late evolutionary feature only present in dexterous primates and best developed in humans. CM projections are derived from a more restricted cortical territory (‘new’ M1, area 3a) and arise not only from corticospinal neurons with large, fast axons but also from those with relatively slow-conducting axons. During movement, corticospinal neurons are organised and recruited quite differently from ‘lower’ motoneurons. Accumulating evidence strongly implicates the corticospinal system in the early stages of ALS, with particular involvement of CM projections to distal limb muscles, but also to other muscle groups influenced by the CM system. There are important species differences in the organisation and function of the corticospinal system, and appropriate animal models are needed to understand disorders involving the human corticospinal system.

The strength of corticomotoneuronal drive underlies ALS split phenotypes and reflects early upper motor neuron dysfunction

“…As we have stressed, dominant muscle atrophy in the thenar as compared to the hypothenar complex is supportive evidence favoring a primary cortical degeneration in ALS (Eisen, 2021;Lemon, 2021).…”

Neurophysiological differentiation of upper motor neuron damage in neurodegenerative disorders

“…Alternatively the difference in CMCT could reflect different pathologies of the pyramidal tract in ALS and MSA. Large myelinated fibres comprising the direct cortico-motoneuron system are considered the main target of degeneration in ALS ( Lemon, 2021 , Smith, 1960 , Sobue et al, 1987 ), whereas selective loss of the small-diameter myelinated fibres of pyramidal tract were noticed in MSA ( Sobue et al, 1987 ). Because CMCT is believed to be more representative of large-diameter than small-diameter fibres with fast conduction velocity in the pyramidal tract ( Tang et al, 2020 , Udupa and Chen, 2013 ), such pathological difference would be a plausible reason for different CMCT between the two despite similar clinical features.…”

SBT-272 improves TDP-43 pathology in the ALS motor cortex by modulating mitochondrial integrity, motility, and function

“…Upper motor neurons (UMNs) are one of the key components of motor neuron circuitry, as they have a unique ability to collect synaptic input from many different types of cortical neurons and to relay the integrated information to spinal cord targets with very high specificity (Eisen, 2021; Lemon, 2008; Lemon, 2021). Their degeneration is a hallmark of many motor neuron diseases, including amyotrophic lateral sclerosis (ALS) (Brown and Robberecht, 2001; Brunet et al, 2020; Charcot and Marie, 1885; Fink, 2013; Gunes et al, 2020).…”