Early diagnosis of amyotrophic lateral sclerosis by threshold tracking and conventional transcranial magnetic stimulation

© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Background and purpose: Short-interval intracortical inhibition by threshold tracking (T-SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS) but has not been compared directly with conventional amplitude measurements (A-SICI). This study compared A-SICI and T-SICI for sensitivity and clinical usefulness as biomarkers for ALS. Methods: In all, 104 consecutive patients referred with suspicion of ALS were prospectively included and were subsequently divided into 62 patients with motor neuron disease (MND) and 42 patient controls (ALS mimics) by clinical follow-up. T-SICI and A-SICI recorded in the first dorsal interosseus muscle (index test) were compared with recordings from 53 age-matched healthy controls. The reference standard was the Awaji criteria. Clinical scorings, conventional nerve conduction studies and electromyography were also performed on the patients. Results: Motor neuron disease patients had significantly reduced T-SICI and A-SICI compared with the healthy and patient control groups, which were similar. Sensitivity and specificity for discriminating MND patients from patient controls were high (areas under the receiver operating characteristic curves 0.762 and 0.810 for T-SICI and A-SICI respectively at 1-3.5 ms). Paradoxically, T-SICI was most reduced in MND patients with the fewest upper motor neuron (UMN) signs (Spearman ρ = 0.565, p = 4.3 × 10-6 ). Conclusions: Amplitude-based measure of cortical inhibition and T-SICI are both sensitive measures for the detection of cortical involvement in MND patients and may help early diagnosis of ALS, with T-SICI most abnormal before UMN signs have developed. The gradation in T-SICI from pathological facilitation in patients with minimal UMN signs to inhibition in those with the most UMN signs may be due to progressive degeneration of the subset of UMNs experiencing facilitation.info:eu-repo/semantics/publishedVersio

Exploring threshold-tracking transcranial magnetic stimulation for cortical inhibition as a novel biomarker for γ-aminobutyric acid A α2,3 receptor signalling in humans

Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological method used to investigate the human motor system. Variability of TMS measures remains one of the main concerns in the research field and a major limitation for their clinical application. Conventional TMS paradigms are largely based on the measurement of the motor evoked potential (MEP) size and are confounded by its large trial-to-trial variability. An alternative approach is to measure threshold, i.e. the stimulus intensity required to obtain a MEP of or above a certain size, and threshold-tracking TMS is emerging as a useful diagnostic test. However, little is known about its reliability and comparability with conventional methods. In this thesis, threshold-tracking was for the first time directly compared with conventional TMS approaches in healthy volunteers. Estimation of resting motor threshold by threshold-tracking was validated against common probabilistic methods. The extent of changes in corticospinal excitability observed in individual recordings during a standard TMS session suggested that threshold-tracking may improve the reliability of paired-pulse TMS paradigms as it allows continuous monitoring and adjustment for these fluctuations. This hypothesis was tested with one of the most widely-used paradigms – short-interval intracortical inhibition (SICI). Mean group SICI obtained at an interstimulus interval of 2.5 ms and a range of conditioning stimulus intensities by both conventional ‘amplitude’ method and threshold-tracking showed a close relationship suggesting that they reflect similar inhibitory mechanisms, while threshold-tracking had a potential for improved reproducibility and acquisition speed. Availability of a safe selective positive allosteric γ-aminobutyric acid A α2,3 receptor modulator AZD7325 allowed for the first time to test the hypothesis that SICI is mediated by this pathway and to directly compare the biomarker sensitivity of the two techniques in a randomised double-blind placebo-controlled cross-over study. This trial showed no modulatory effect of the drug on SICI at the exposure level used

Three different short-interval intracortical inhibition methods in early diagnosis of amyotrophic lateral sclerosis

Objectives: To compare the utility of conventional amplitude measurements of short-interval intracortical inhibition (A-SICI) with two threshold-tracking (T-SICI) methods, as aids to early diagnosis of amyotrophic lateral sclerosis (ALS). The new parallel threshold-tracking method (T-SICIp) was compared with the previously used serial tracking method (T-SICIs). / Methods: 112 consecutive patients referred with the suspicion of ALS and 40 healthy controls were prospectively included. Based on clinical follow-up, patients were divided into 67 patients with motor neuron disease (MND) comprising progressive muscular atrophy (PMA) as well as ALS, and 45 patient controls. SICI was recorded from first dorsal interosseus muscle using the three different protocols. / Results: MND patients had significantly reduced T-SICIp, T-SICIs and A-SICI, compared with healthy controls and patient controls, while healthy and patient controls were similar. Paradoxically, T-SICIp was least affected in MND patients with the most upper motor neuron (UMN) signs (Spearman ρ = 0.537, P < 0.0001) whereas there was no correlation for T-SICIs or A-SICI. T-SICIp also provided the best discrimination between patient controls and MND as determined by the receiver operating characteristic (ROC) curves. For patients with no UMN signs, area under ROC curve for 2-3ms inter-stimulus intervals was 0.931 for T-SICIp, 0.771 for T-SICIs and 0.786 for A-SICI. / Conclusions: SICI is a sensitive measure for detection of cortical involvement in ALS patients. T-SICIp has higher sensitivity and specificity than T-SICIs and A-SICI, particularly in patients without any upper motor neuron signs

Short latency afferent inhibition: comparison between threshold-tracking and conventional amplitude recording methods

Short-latency afferent inhibition (SAI), which is conventionally measured as a reduction in motor evoked potential amplitude (A-SAI), is of clinical interest as a potential biomarker for cognitive impairment. Since threshold-tracking has some advantages for clinical studies of short-interval cortical inhibition, we have compared A-SAI with a threshold-tracking alternative method (T-SAI). In the T-SAI method, inhibition was calculated by tracking the required TMS intensity for the targeted MEP amplitude (200 uV) both for the test (TMS only) and paired (TMS and peripheral stimulation) stimuli. A-SAI and T-SAI were recorded from 31 healthy subjects using ten stimuli at each of 12 inter-stimulus intervals, once in the morning and again in the afternoon. There were no differences between morning and afternoon recordings. When A-SAI was normalized by log conversion it was closely related to T-SAI. Between subjects, variability was similar for the two techniques, but within-subject variability was significantly smaller for normalized A-SAI. Conventional amplitude measurements appear more sensitive for detecting changes within-subjects, such as in interventional studies, but threshold-tracking may be as sensitive as detecting abnormal SAI in a patient