Threshold tracking transcranial magnetic stimulation and neurofilament light chain as diagnostic aids in ALS.

OBJECTIVE: There is a need for sensitive biomarkers in amyotrophic lateral sclerosis (ALS), to enable earlier diagnosis and to help assess potential treatments. The main objective of this study was to compare two potential biomarkers, threshold-tracking short-interval cortical inhibition (T-SICI), which has shown promise as a diagnostic aid, and neurofilament light chains (NfL). METHODS: Ninety-seven patients with ALS (mean age 67.1 ± 11.5 years) and 53 ALS mimics (aged 62.4 ± 12.9) were included. Mean disease duration was 14 months ±14.1. Patients were evaluated with revised ALS functional rating score (ALSFRS-R), Penn upper motor neuron score (UMNS), muscle strength using the Medical Research Council (MRC) score and examined with T-SICI, quantitative electromyography (EMG), and NfL measured in spinal fluid. RESULTS: NfL increased with increasing UMNS (rho = 0.45, p = 8.2 × 10-6) whereas T-SICI at 2.5 ms paradoxically increased toward normal values (rho = 0.53, p = 1.9 × 10-7). However, these two measures were uncorrelated. Discrimination between ALS patients and mimics was best for NfL (area under ROC curve 0.842, sensitivity 84.9%, specificity 83.5%), compared with T-SICI (0.675, 39.6%, 91.8%). For the patients with no UMN signs, NfL also discriminated best (0.884, 89.3%, 82.6%), compared with T-SICI (0.811, 71.4%, 82.6%). However, when combining NfL and T-SICI, higher AUCs of 0.854 and 0.922 and specificities of 93.8 and 100 were found when considering all patients and patients with no UMN signs, respectively. INTERPRETATION: Both T-SICI and NfL correlated with UMN involvement and combined, they provided a strong discrimination between ALS patients and ALS mimics.

Systematic review and co-ordinate based meta-analysis to summarize the utilization of functional brain imaging in conjunction with human models of peripheral and central sensitization.

BACKGROUND AND OBJECTIVE: Functional magnetic resonance imaging, in conjunction with models of peripheral and/or central sensitization, has been used to assess analgesic efficacy in healthy humans. This review aims to summarize the use of these techniques to characterize brain mechanisms of hyperalgesia/allodynia and to evaluate the efficacy of analgesics. DATABASES AND DATA TREATMENT: Searches were performed (PubMed-Medline, Cochrane, Web of Science and Clinicaltrials.gov) to identify and review studies. A co-ordinate based meta-analysis (CBMA) was conducted to quantify neural activity that was reported across multiple independent studies in the hyperalgesic condition compared to control, using GingerALE software. RESULTS: Of 217 publications, 30 studies met the inclusion criteria. They studied nine different models of hyperalgesia/allodynia assessed in the primary (14) or secondary hyperalgesia zone (16). Twenty-three studies focused on neural correlates of hyperalgesic conditions and showed consistent changes in the somatosensory cortex, prefrontal cortices, insular cortex, anterior cingulate cortex, thalamus and brainstem. The CBMA on 12 studies that reported activation coordinates for a contrast comparing the hyperalgesic state to control produced six activation clusters (significant at false discovery rate of 0.05) with more peaks for secondary (17.7) than primary zones (7.3). Seven studies showed modulation of brain activity by analgesics in five of the clusters but also in four additional regions. CONCLUSIONS: This meta-analysis revealed substantial but incomplete overlap between brain areas related to neural mechanisms of hyperalgesia and those reflecting the efficacy of analgesic drugs. Studies testing in the secondary zone were more sensitive to evaluate analgesic efficacy on central sensitization at brainstem or thalamocortical levels. SIGNIFICANCE: Experimental pain models that provide a surrogate for features of pathological pain conditions in healthy humans and functional imaging techniques are both highly valuable research tools. This review shows that when used together, they provide a wealth of information about brain activity during pain states and analgesia. These tools are promising candidates to help bridge the gap between animal and human studies, to improve translatability and provide opportunities for identification of new targets for back-translation to animal studies.

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.

The test-retest reliability of large and small fiber nerve excitability testing with threshold tracking.

Objective: Standard nerve excitability testing (NET) predominantly assesses Aα- and Aß-fiber function, but a method examining small afferents would be of great interest in pain studies. Here, we examined the properties of a novel perception threshold tracking (PTT) method that preferentially activates Aδ-fibers using weak currents delivered by a novel multipin electrode and compared its reliability with NET. Methods: Eighteen healthy subjects (mean age:34.06 ±â€¯2.0) were examined three times with motor and sensory NET and PTT in morning and afternoon sessions on the same day (intra-day reliability) and after a week (inter-day reliability). NET was performed on the median nerve, while PTT stimuli were delivered through a multipin electrode located on the forearm. During PTT, subjects indicated stimulus perception via a button press and the intensity of the current was automatically increased or decreased accordingly by Qtrac software. This allowed changes in the perception threshold to be tracked during strength-duration time constant (SDTC) and threshold electrotonus protocols. Results: The coefficient of variation (CoV) and interclass coefficient of variation (ICC) showed good-excellent reliability for most NET parameters. PTT showed poor reliability for both SDTC and threshold electrotonus parameters. There was a significant correlation between large (sensory NET) and small (PTT) fiber SDTC when all sessions were pooled (r = 0.29, p = 0.03). Conclusions: Threshold tracking technique can be applied directly to small fibers via a psychophysical readout, but with the current technique, the reliability is poor. Significance: Further studies are needed to examine whether Aß-fiber SDTC may be a surrogate biomarker for peripheral nociceptive signalling.

IMI2-PainCare-BioPain-RCT1: study protocol for a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by peripheral nerve excitability testing (NET).

BACKGROUND: Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system. METHODS: This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses. DISCUSSION: Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. TRIAL REGISTRATION: This trial was registered 25/06/2019 in EudraCT ( 2019-000942-36 ).