Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.

Upper motor neuron (UMN) dysfunction is an important feature of amyotrophic lateral sclerosis (ALS) for the diagnosis and understanding of pathogenesis. The identification of UMN signs forms the basis of ALS diagnosis, although may be difficult to discern, especially in the setting of severe muscle weakness. Transcranial magnetic stimulation (TMS) techniques have yielded objective physiological biomarkers of UMN dysfunction in ALS, enabling the interrogation of cortical and subcortical neuronal networks with diagnostic, pathophysiological, and prognostic implications. Transcranial magnetic stimulation techniques have provided pertinent pathogenic insights and yielded novel diagnostic and prognostic biomarkers. Cortical hyperexcitability, as heralded by a reduction in short interval intracortical inhibition (SICI) and an increase in short interval intracortical facilitation (SICF), has been associated with lower motor neuron degeneration, patterns of disease evolution, as well as the development of specific ALS clinical features including the split hand phenomenon. Reduction in SICI has also emerged as a potential diagnostic aid in ALS. More recently, physiological distinct inhibitory and facilitatory cortical interneuronal circuits have been identified, which have been shown to contribute to ALS pathogenesis. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction. Resting-state EEG is a novel neurophysiological technique developed for directly interrogating cortical neuronal networks in ALS, that have yielded potentially useful physiological biomarkers of UMN dysfunction. The present review discusses physiological biomarkers of UMN dysfunction in ALS, encompassing conventional and novel TMS techniques developed to interrogate the functional integrity of the corticomotoneuronal system, focusing on pathogenic, diagnostic, and prognostic utility.

Utility of the split hand index (SI) in amyotrophic lateral sclerosis (ALS) has been reported when using the compound muscle action potential (CMAP) amplitude method (SI_{CMAP amp}). A motor unit number index (MUNIX) based SI method (SI_MUNIX) was purported to exhibit higher sensitivity. The present study assessed the clinical utility of SI, derived by CMAP amplitude, MUNIX and MScan-MUNE (SI_{MScanFit-MUNE}) methods, in ALS. Sixty-two consecutive patients with neuromuscular symptoms (36 ALS and 26 ALS-mimics) were prospectively recruited. The SI was derived by dividing the product of the CMAP amplitude, MUNIX and MScan-MUNE values recorded over first dorsal interosseous and abductor pollicis brevis by values recorded over abductor digit minimi. SI_{CMAP amp}, SI_MUNIX and SI_{MScanFit-MUNE} were significantly reduced in ALS, with SI_{CMAP amp} (area under curve (AUC) = 0.801) and SI_{MScanFit-MUNE} (AUC = 0.805) exhibiting greater diagnostic utility than SI_MUNIX (AUC = 0.713). SI_{CMAP amp} and SI_{MScanFit-MUNE} exhibited significant correlations with clinical measures of functional disability and weakness of intrinsic hand muscles. SI differentiated ALS from mimic disorders, with SI_{CMAP amp} and SI_{MScanFit-MUNE} exhibiting greater utility. The split hand index represents could serve as a potential diagnostic biomarker in ALS.