BACKGROUND: Diagnosis of amyotrophic lateral sclerosis (ALS) remains 
problematic, with substantial diagnostic delays. We assessed the sensitivity and 
specificity of a threshold tracking transcranial magnetic stimulation (TMS) 
technique, which might allow early detection of upper motor neuron dysfunction, 
for the diagnosis of the disorder.
METHODS: We did a prospective study of patients referred to three neuromuscular 
centres in Sydney, Australia, in accordance with the Standards for Reporting of 
Diagnostic Accuracy. Participants had definite, probable, or possible ALS, as 
defined by the Awaji criteria; or pure motor disorder with clinical features of 
upper and lower motor neuron dysfunction in at least one body region, 
progressing over a 6 month follow-up period; or muscle wasting and weakness for 
at least 6 months. All patients underwent threshold tracking TMS at recruitment 
(index test), with application of the reference standard, the Awaji criteria, to 
differentiate patients with ALS from those with non-ALS disorders. The 
investigators who did the index test were masked to the results of the reference 
test and all other investigations. The primary outcome measures were the 
sensitivity and specificity of TMS in differentiating ALS from non-ALS 
disorders; these measures were derived from receiver operator curve analysis.
FINDINGS: Between Jan 1, 2010, and March 1, 2014, we screened 333 patients; 281 
met our inclusion criteria. We eventually diagnosed 209 patients with ALS and 68 
with non-ALS disorders; the diagnosis of four patients was inconclusive. The 
threshold tracking TMS technique differentiated ALS from non-ALS disorders with 
a sensitivity of 73·21% (95% CI 66·66-79·08) and specificity of 80·88% 
(69·53-89·40) at an early stage in the disease. All patients tolerated the study 
well, and we did not record any adverse events from performance of the index 
test.
INTERPRETATION: The threshold tracking TMS technique reliably distinguishes ALS 
from non-ALS disorders and, if these findings are replicated in larger studies, 
could represent a useful diagnostic investigation when combined with the Awaji 
criteria to prove upper motor neuron dysfunction at early stages of ALS.
FUNDING: Motor Neuron Disease Research Institute of Australia, National Health 
and Medical Research Council of Australia, and Pfizer.