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

• Published in: Brain and behavior Vol. 11; no. 12; pp. e2403 - n/a
• Main Authors: Eisen, Andrew, Bede, Peter
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.12.2021; Wiley Open Access; John Wiley and Sons Inc; Wiley
• Subjects: Amyotrophic Lateral Sclerosis; corticomotoneuronal; corticomuscular coherence; Diffusion models; excitatory post‐synaptic potential; Human health and pathology; Humans; Life Sciences; Motor Neurons - physiology; Neuroimaging; Neurons; Pathology; Phenotype; Review; Reviews; Spinal cord; split phenotypes; Transcranial magnetic stimulation; Transcranial Magnetic Stimulation - methods; split phenotypes; excitatory post-synaptic potential; corticomotoneuronal; corticomuscular coherence; amyotrophic lateral sclerosis; neuroimaging; Funding information Spastic Paraplegia Foundation; excitatory postsynaptic potential; Inc. (SPF) amyotrophic lateral sclerosis
• ISSN: 2162-3279; 2162-3279
• DOI: 10.1002/brb3.2403

Background Split phenotypes, (split hand, elbow, leg, and foot), are probably unique to ALS, and are characterized by having a shared peripheral input of both affected and unaffected muscles. This implies an anatomical origin rostral to the spinal cord, primarily within the cerebral cortex. Therefore, split phenotypes are a potential marker of ALS upper motor neuron pathology. However, to date, reports documenting upper motor neuron dysfunction in split phenotypes have been limited to using transcranial magnetic stimulation and cortical threshold tracking techniques. Here, we consider several other potential methodologies that could confirm a primary upper motor neuron pathology in split phenotypes. Methods We review the potential of: 1. measuring the compound excitatory post‐synaptic potential recorded from a single activated motor unit, 2. cortical‐muscular coherence, and 3. new advanced modalities of neuroimaging (high‐resolution imaging protocols, ultra‐high field MRI platforms [7T], and novel Non‐Gaussian diffusion models). Conclusions We propose that muscles involved in split phenotypes are those functionally involved in the human motor repertoire used particularly in complex activities. Their anterior horn cells receive the strongest corticomotoneuronal input. This is also true of the weakest muscles that are the earliest to be affected in ALS. Descriptions of split hand in non‐ALS cases and proposals that peripheral nerve or muscle dysfunction may be causative are contentious. Only a few carefully controlled cases of each form of split phenotype, using upper motor neuron directed methodologies, are necessary to prove our postulate. Muscles involved in ALS split phenotypes are those with the strongest corticomotoneuronal connectivity used in complex movements developed because of evolutionary pressures.