Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a heterogeneity of underlying pathogenic mechanisms. Corticomotoneuronal dysfunction is increasingly postulated as the harbinger of clinical disease, and neurophysiological exploration of the motor cortex in vivo using transcranial magnetic stimulation (TMS) has suggested that motor cortical hyperexcitability may be a critical pathogenic factor linked to clinical features and survival. Region-specific selective vulnerability at the level of the motor cortex may drive the observed differences of clinical presentation across the ALS motor phenotypes, and thus, further understanding of phenotypic variability in relation to cortical dysfunction may serve as an important guide to underlying disease mechanisms. This review article analyses the cortical excitability profiles across the clinical motor phenotypes, as assessed using TMS, and explores this relationship to clinical patterns and survival. This understanding will remain essential to unravelling central disease pathophysiology and for the development of specific treatment targets across the ALS clinical motor phenotypes.
Highlights
The clinical manifestations of amyotrophic lateral sclerosis (ALS) largely result from progressive degeneration of the human motor system, there is marked phenotypic heterogeneity between cases and a wide range of unexplained clinical severity [1,2,3].While phenotypic complexity is increased by the presence of non-motor symptoms such as frontotemporal dementia, the selectivity for the motor system remains the clinical hallmark of the disease
The clinical motor phenotypes reflect the in vivo anatomy of underlying neuropathology; their differences are attributable to motor degeneration occurring with strikingly dissimilar onset, severity, and rate across upper motor neuron (UMN) and lower motor neuron (LMN) levels [1]
A reduction of short interval intracortical inhibition (SICI), which is a marker of GABAA ergic inhibitory interneuronal function, accompanied by an increase in intracortical facilitation (ICF) in some studies, likely reflecting excitatory motor cortical circuits, are the main paired-pulse transcranial magnetic stimulation (TMS) biomarkers that have supported the early presence of relative motor cortical hyperexcitability in ALS [12,17,40,41,42]
Summary
The clinical manifestations of amyotrophic lateral sclerosis (ALS) largely result from progressive degeneration of the human motor system, there is marked phenotypic heterogeneity between cases and a wide range of unexplained clinical severity [1,2,3]. Has suggested the early presence of cortical hyperexcitability, Evidence of regional differences in cortical excitability across the ALS motorwhich cortex appears linked to clinical site of onsetcortical [12,13,14].abnormalities This technique axonal and synaptic have recently questioned whether aremeasures relevant to all clinical excitability through and non-invasive electromagnetic interrogation of the corticomotoneumotor phenotypes whether this is an important driver of the variable clinical outronal system [15], and findings in ALSthe patients are likely to be a result of several comes [13,18,19]. ALS, bulbar-onset (classical blue; respiratory-onset (classical withpurple; permission from Chio et al [4].ALS), Copyright
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