Abstract
BackgroundSplit 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.MethodsWe 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).ConclusionsWe 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.
Highlights
Upper motor neuron deficits in amyotrophic lateral sclerosis (ALS) can be elusive and difficult to identify (Swash, 2012), but they are important for early diagnosis and admission into therapeutic drug trials (Hannaford et al, 2021)
There is a larger corticomotoneuronal drive projecting to the tibialis anterior (TA) and extensor digitorum brevis (EDB) motoneurons compared with the soleus and the gastrocnemius motoneurons (Advani & Ashby, 1990; Brouwer & Ashby, 1992; Brouwer & Qiao, 1995; Brouwer et al, 1992)
Split phenotypes in ALS are rationally considered to reflect upper motor neuron disease and, in particular, compromise of corticomotoneuronal drive to those motor units innervating the weakened and/or wasted muscles. The distribution of these phenotypes is shared by those muscles which are weakest in ALS, which are muscles controlled through the strongest corticomotoneuronal drive
Summary
Upper motor neuron deficits in amyotrophic lateral sclerosis (ALS) can be elusive and difficult to identify (Swash, 2012), but they are important for early diagnosis and admission into therapeutic drug trials (Hannaford et al, 2021). In ALS, defective motor paradigms are largely subserved by the motor units and their respective muscles having the strongest CM drive, as alluded to the above (Ludolph et al, 2020) We postulate that this is likely true of the involved (weaker) muscle in the dissociated pair of split phenotypes of ALS, but this remains to be proven. With this in mind, we discuss possible methodologies to investigate ALS split phenotypes from an upper motor neuron perspective, with the intention that this can be used as early clinical upper motor neuron marker of ALS. Several studies have proposed that 1. split phenotypes are not specific to ALS and 2. that they are primarily, or based upon peripheral nerve/muscle dysfunction, we briefly consider these contradictions to failed CM drive as the primary cause of ALS split phenotypes
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