Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease with no precise biomarkers that makes early diagnosis challenging. The current diagnostic criteria, such as the El-Escorial and Gold Coast criteria, have limited sensitivity, often delaying neuroprotective treatments and clinical trial recruitment. Transcranial Magnetic Stimulation (TMS) has emerged as a valuable tool to assess corticospinal pathway integrity, offering a potential alternative in detecting early cortical hyperexcitability. Despite promising findings, inconsistencies in methodology and protocol standardization remain inconclusive.

This study aims to evaluate the effectiveness of Single-Pulse TMS in ALS diagnosis, addressing key gaps and challenges in existing research.

In this scoping review, we searched for articles on Single-Pulse TMS using parameters like Resting Motor Threshold (RMT), Central Motor Conduction Time (CMCT), Motor Evoked Potential (MEP), and Silent Period (SP). The PICO strategy guided the research question, ensuring relevant evidence retrieval. Only cross-sectional studies were included, selected from Scopus, PubMed, Embase, and Web of Science (May 2021–Feb 2025). Inclusion criteria required ALS diagnosis using Single-Pulse TMS, while exclusions involved non-relevant techniques, ALS treatment, or language restrictions. Data extraction included patient demographics and disease characteristics. Methodological quality was assessed using JBI checklists for cross-sectional studies, addressing potential biases.

A total of 1,222 articles were identified across four databases, with 19 totally meeting inclusion criteria. The JBI appraisal identified 11 studies as high quality and eight as moderate quality, based on criteria assessing bias, methodological rigor, and validity in cross-sectional research. The studies included 730 ALS patients and 526 controls. Findings in the majority showed reduced SP, lower MEP amplitude, prolonged CMCT, and shorter RMT. Five studies had ambiguous cortical hyperexcitability results.

The lack of standardized protocols and inconsistent methodology limit conclusions on ALS diagnosis using TMS. Furthermore, it becomes difficult to relate the impact of factors such as the onset of symptoms, affected hemisphere, and time of diagnosis with the presence/absence of hyperexcitability. Future research should focus on refining diagnostic criteria based on the standardization of corticospinal activity measurement.

The study highlights the potential of Single-Pulse TMS for early ALS diagnosis but faces limitations such as methodological heterogeneity, lack of standardized protocols, and inconsistent parameter definitions. These challenges impact result reproducibility and clinical applicability. In clinical approach, improved TMS standardization could enhance early ALS detection, optimizing patient referral for neuroprotective therapies and clinical trials. In physiotherapy, better diagnostic accuracy may guide personalized interventions, delaying functional decline.