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.

Somatosensory evoked potentials (SSEPs) are electrical potentials that measure various parts of the ascending somatosensory pathways. They are elicited through stimulating mixed nerves, with subsequent orthodromic stimulation of sensory nerves. Despite advances in imaging, SSEPs complement both the clinical examination and peripheral neurophysiological studies when assessing the functional integrity of the sensory pathways, being especially helpful when imaging is inconclusive. We describe the technique of performing SSEPs and the anatomical substrates of their waveforms, and we highlight important clinical applications both in central and peripheral nervous system disorders.

Background: Cortical hyperexcitability is an early feature of amyotrophic lateral sclerosis (ALS), linked to dysfunction in inhibitory and facilitatory cortical circuits, measurable using paired‐pulse transcranial magnetic stimulation (TMS). Short‐interval intracortical inhibition (SICI) is a robust biomarker of inhibitory function and an ALS diagnostic marker. Short interval intracortical facilitation (SICF) serves as a biomarker of facilitatory function, while the index of excitation assesses the contribution of these circuits to hyperexcitability. This study aimed to evaluate the diagnostic effectiveness of SICF and the index of excitation in distinguishing ALS from non‐ALS mimic disorders.Methods: This cross‐sectional study assessed cortical excitability in participants with suspected ALS from two Sydney centres, classified using the Gold Coast criteria. Threshold tracking TMS measured SICI, SICF, and the index of excitation. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis, with sensitivity, specificity, and optimal cut‐off values determined.Results: Of 154 participants, 95 were diagnosed with ALS and 48 with non‐ALS mimics. SICI demonstrated a marginally higher diagnostic accuracy (AUC 0.84, 95% CI:0.77–0.89) compared to SICF (AUC 0.77, 95% CI:0.68–0.84, p = 0.028). The index of excitation showed comparable accuracy to SICI (AUC 0.82, 95% CI: 0.75–0.88, p = 0.328). The optimal SICF cut‐off (≤ −13.6%) provided 70.5% sensitivity and 70.8% specificity, while the index of excitation cut‐off (≥ 64.5%) yielded 71.6% sensitivity and 70.8% specificity.Conclusions: The present study established modest diagnostic potential of increased SICF and index of excitation in differential ALS from mimic disorders, thereby enhancing understanding of the role of inhibitory and facilitatory cortical circuits in ALS diagnosis.

Cerebral venous sinus thrombosis is an uncommon sequela of low intracranial pressure, which may result from a lumbar puncture (LP). We describe a case of a patient in their 40s presenting with 48 hours of persistent headache following intrathecal administration of nusinersen for spinal muscular atrophy (SMA) type 3. There were no focal neurological signs or symptoms apart from baseline symmetrical proximal limb weakness attributed to SMA. Initial investigations revealed radiological evidence of an acute cerebral venous sinus thrombus (CVST). The patient was promptly started on anticoagulation. Partial recanalisation was seen as soon as 48 hours after commencement of anticoagulation, with almost full resolution of the thrombus at follow-up in 2 months. Awareness of CVST as a potential complication of intrathecal therapies and diagnostic LP allows for early identification, management and prevention of serious neurological consequences.

Introduction/Aims: Far field potentials (FFP) have been proposed as a reliable neurophysiological prognostic biomarker in amyotrophic lateral sclerosis (ALS). This study evaluated the utility of ulnar nerve FFP as a robust research biomarker of lower motor neuron degeneration in spinal muscular atrophy (SMA). Methods: Peripheral neurophysiological assessments were performed in 13 participants with SMA, 19 with amyotrophic lateral sclerosis (ALS), and 19 healthy controls. The ulnar nerve was stimulated at the wrist, and motor responses were recorded over the abductor digiti minimi (ADM) muscle. Recorded measures included compound muscle action potential (CMAP), FFP and near‐field potential (NFP) amplitudes, and motor unit number index (MUNIX). Results: The FFP amplitude was significantly lower in SMA participants compared to healthy volunteers ( p < 0.001), but comparable to ALS ( p = 0.11). The FFP amplitude showed strong correlations with the Revised Upper Limb Module (RULM) ( ρ = 0.92), ALS Functional Rating Score‐Revised ( ρ = 0.85), upper limb MRC score ( ρ = 0.89), CMAP amplitude ( ρ = 0.97), NFP amplitude ( ρ = 0.88), and MUNIX values ( ρ = 0.84), all of which were highly statistically significant. Multiple linear regression indicated that FFP amplitude was an independent predictor of RULM ( p < 0.001). Discussion: FFP amplitude appears to be a promising neurophysiological biomarker for SMA, with potential utility for monitoring disease progression, particularly in a clinical trial setting.