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.

Caffeine and cortical excitability, as measured with paired-pulse transcranial magnetic stimulation.

INTRODUCTION/AIMS: The transcranial magnetic stimulation tests of short-interval intracortical inhibition (SICI) by both conventional amplitude measurements (A-SICI) and threshold-tracking (T-SICI) are important methods to investigate intracortical inhibitory circuits, and T-SICI has been proposed to aid the diagnosis of amyotrophic lateral sclerosis. Beverages containing caffeine are widely consumed, and caffeine has been reported to affect cortical excitability. The aim of this study was to determine whether these SICI tests are affected by caffeine. METHODS: Twenty-four healthy subjects (13 females, 11 males, aged from 19 to 31, mean: 26.2 ± 2.4 years) were studied in a single fixed-dose randomized double-blind placebo-controlled cross-over trial of 200 mg caffeine or placebo ingested as chewing gum. A-SICI and T-SICI, using parallel tracking (T-SICIp), were performed before and after chewing gum. RESULTS: There was no significant change in SICI parameters after placebo in A-SICI (p > .10) or T-SICIp (p > .30), and no significant effect of caffeine was found on A-SICI (p > .10) or T-SICIp (p > .50) for any of the interstimulus intervals. DISCUSSION: There is no need for caffeine abstention before measurements of SICI by either the T-SICI or A-SICI measurements.

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.

Methodology for eliciting the brainstem trigeminal-hypoglossal reflex in humans under general anesthesia.

OBJECTIVE: Brainstem trigeminal-hypoglossal reflexes (THRs), also known as the jaw-tongue reflexes, coordinate the position of the tongue in the mouth in relation to the jaw movement during oromotor behaviors such as mastication, swallowing, vocalization, and breathing. Their use in brainstem surgery however, has never been assessed in spite of its potential benefit possibly due to the lack of a methodology to elicit these reflexes under general anesthesia. METHODS: We proposed a technique to elicit the THRs during total intravenous anesthesia (TIVA) consisting on a V3 infrazygomatic train stimulation paradigm and recording from the Styloglossus (31 patients) and the Genioglossus (21 patients) muscles to elicit long latency responses. RESULTS: The THR was successfully recorded using the V3 stimulation point in 82.1% of patients, of which 96.9% presented a response on the Styloglossus muscle (Jaw-opening reflex) while 0.06% presented a response on the Genioglossus muscle instead (Jaw-closing reflex). CONCLUSIONS: The THRs can be successfully recorded in surgery under general anaesthesia with the predominant reflex seen being the jaw-opening reflex. SIGNIFICANCE: We provide a novel method to elicit the THRs during general anesthesia, which could be of aid in brainstem surgery.

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.

Short interval intracortical inhibition: Variability of amplitude and threshold-tracking measurements with 6 or 10 stimuli per point.

Reduced short-interval intracortical inhibition (SICI) in motor neuron disease has been demonstrated by amplitude changes (A-SICI) and threshold-tracking (T-SICI) using 10 stimuli per inter-stimulus interval (ISI). To test whether fewer stimuli would suffice, A-SICI and T-SICI were recorded twice from 30 healthy subjects using 6 and 10 stimuli per ISI. Using fewer stimuli increased mean A-SICI variances by 23.8% but the 7.3% increase in T-SICI variance was not significant. We conclude that our new parallel threshold-tracking SICI protocol, with 6 stimuli per ISI, can reduce time and stimulus numbers by 40% without appreciable loss of accuracy.

Test-Retest Reliability of Short-Interval Intracortical Inhibition Assessed by Threshold-Tracking and Automated Conventional Techniques.

Two novel short-interval intracortical inhibition (SICI) protocols, assessing SICI across a range of interstimulus intervals (ISIs) using either parallel threshold-tracking transcranial magnetic stimulation (TT-TMS) or automated conventional TMS (cTMS), were recently introduced. However, the test-retest reliability of these protocols has not been investigated, which is important if they are to be introduced in the clinic. SICI was recorded in 18 healthy subjects using TT-TMS (T-SICI) and cTMS (A-SICI). All subjects were examined at four identical sessions, i.e., morning and afternoon sessions on 2 d, 5-7 d apart. Both SICI protocols were performed twice at each session by the same observer. In one of the sessions, another observer performed additional examinations. Neither intraobserver nor interobserver measures of SICI differed significantly between examinations, except for T-SICI at ISI 3 ms (p = 0.00035) and A-SICI at ISI 2.5 ms (p = 0.0103). Intraday reliability was poor-to-good for A-SICI and moderate-to-good for T-SICI. Interday and interobserver reliabilities of T-SICI and A-SICI were moderate-to-good. Although between-subject variation constituted most of the total variation, SICI repeatability in an individual subject was poor. The two SICI protocols showed no considerable systematic bias across sessions and had a comparable test-retest reliability profile. Findings from the present study suggest that both SICI protocols may be reliably and reproducibly employed in research studies, but should be used with caution for individual decision-making in clinical settings. Studies exploring reliability in patient cohorts are warranted to investigate the clinical utility of these two SICI protocols.

Conventional and Threshold-Tracking Transcranial Magnetic Stimulation Tests for Single-handed Operation.

Most single-pulse transcranial magnetic stimulation (TMS) parameters (e.g., motor threshold, stimulus-response function, cortical silent period) are used to examine corticospinal excitability. Paired-pulse TMS paradigms (e.g., short- and long-interval intracortical inhibition (SICI/LICI), short-interval intracortical facilitation (SICF), and short- and long-latency afferent inhibition (SAI/LAI)) provide information about intracortical inhibitory and facilitatory networks. This has long been done by the conventional TMS method of measuring changes in the size of the motor-evoked potentials (MEPs) in response to stimuli of constant intensity. An alternative threshold-tracking approach has recently been introduced whereby the stimulus intensity for a target amplitude is tracked. The diagnostic utility of threshold-tracking SICI in amyotrophic lateral sclerosis (ALS) has been shown in previous studies. However, threshold-tracking TMS has only been used in a few centers, in part due to the lack of readily available software but also perhaps due to uncertainty over its relationship to conventional single- and paired-pulse TMS measurements. A menu-driven suite of semi-automatic programs has been developed to facilitate the broader use of threshold-tracking TMS techniques and to enable direct comparisons with conventional amplitude measurements. These have been designed to control three types of magnetic stimulators and allow recording by a single operator of the common single- and paired-pulse TMS protocols. This paper shows how to record a number of single- and paired-pulse TMS protocols on healthy subjects and analyze the recordings. These TMS protocols are fast and easy to perform and can provide useful biomarkers in different neurological disorders, particularly neurodegenerative diseases such as ALS.

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

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.

Comparison of figure-of-8 and circular coils for threshold tracking transcranial magnetic stimulation measurements.

OBJECTIVES: The transcranial magnetic stimulation (TMS) technique of threshold-tracking short-interval intracortical inhibition (T-SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS). Most of these studies have used a circular coil, whereas a figure-of-8 coil is usually recommended for paired-pulse TMS measurements. The aim of this study was to compare figure-of-8 and circular coils for T-SICI in the upper limb, with special attention to reproducibility, and the pain or discomfort experienced by the subjects. METHODS: Twenty healthy subjects (aged: 45.5 ±â€¯6.7, mean ±â€¯SD, 9 females, 11 males) underwent two examinations with each coil, in morning and afternoon sessions on the same day, with T-SICI measured at interstimulus intervals (ISIs) from 1-7 ms. After each examination the subjects rated degree of pain/discomfort from 0 to 10 using a numerical rating scale (NRS). RESULTS: Mean T-SICI was higher for the figure-of-8 than for the circular coil at ISI of 2 ms (p < 0.05) but did not differ at other ISIs. Intra-subject variability did not differ between coils, but mean inhibition from 1-3.5 ms was less variable between subjects with the figure-of-8 coil (SD 7.2% vs. 11.2% RMT, p < 0.05), and no such recordings were without inhibition (vs. 6 with the circular coil). The subjects experienced less pain/discomfort with the figure-of-8 coil (mean NRS: 1.9 ±â€¯1.28 vs 2.8 ±â€¯1.60, p < 0.005). DISCUSSION: The figure-of-8 coil may have better applicability in patients, due to the lower incidence of lack of inhibition in healthy subjects, and the lower experience of pain or discomfort.

Short-interval intracortical inhibition as a function of inter-stimulus interval: Three methods compared.

BACKGROUND: Short-interval intracortical inhibition (SICI), as measured by threshold-tracking as a function of inter-stimulus interval (ISI), has been proposed as a useful biomarker for amyotrophic lateral sclerosis (ALS), but its relationship to conventional amplitude measurements has not been established. METHODS: Serial tracking of SICI at increasing ISIs from 1 to 7 ms (T-SICIs) was compared in 50 healthy control subjects with the same ISIs tracked in parallel (T-SICIp), and with conventional amplitude measurements (A-SICI). For T-SICIp and A-SICI, pairs of conditioning and test stimuli with different ISIs were pseudo-randomised and interspersed with test-alone stimuli given at regular intervals. Thresholds were estimated by regression of log peak-to-peak amplitude on stimulus. RESULTS: T-SICIp and A-SICI were closely related: a ten-fold reduction in amplitude corresponding to an approximately 18% increase in threshold. Threshold increases were greater for T-SICIs than for T-SICIp at 3.5-5 ms (P < 0.001). This divergence depended on the initial settings and whether ISIs were progressively increased or decreased, and was attributed to the limitations of the serial tracking protocol. SICI variability between subjects was greatest for T-SICIs estimates and least for A-SICI, and only A-SICI estimates revealed a significant decline in inhibition with age. CONCLUSIONS: The serial tracking protocol did not accurately show the dependence of inhibition on ISI. Randomising ISIs gives corresponding SICI measures, whether tracking thresholds or measuring amplitude measurements. SICI variability suggested that A-SICI measurements may be the most sensitive to loss of inhibition.

Short-interval intracortical inhibition: Comparison between conventional and threshold-tracking techniques.

BACKGROUND: Short-interval intracortical inhibition (SICI) is conventionally measured as the relative amplitude reduction of motor evoked potentials (MEPs) by subthreshold conditioning stimuli. In threshold-tracking SICI (T-SICI), stimulus intensity is instead adjusted repeatedly to maintain a constant MEP and inhibition is measured as the relative threshold increase. T-SICI is emerging as a useful diagnostic test, but its relationship to conventional amplitude SICI (A-SICI) is unclear. OBJECTIVE: To compare T-SICI and its reliability with conventional A-SICI measurements. METHODS: In twelve healthy volunteers (6 men, median age 30 years), conventional and T-SICI were recorded at conditioning stimuli (CS) of 50-80% resting motor threshold (RMT) and interstimulus interval of 2.5 ms. Measurements were repeated on the same day and at least a week later by a single operator. RESULTS: Across the CS range, mean group T-SICI showed a strong linear relationship to the mean group values measured by conventional technique (y = 29.7-0.3x, R2 = 0.99), but there was considerable interindividual variability. At CS 60-80% RMT, T-SICI had excellent intraday (intraclass correlation coefficient, ICC, 0.81-0.92) and adequate-to-excellent interday (ICC 0.61-0.88) reproducibility. Conventional SICI took longer to complete (median of 5.8 vs 3.8 min, p < 0.001) and tended to have poorer reproducibility (ICC 0.17-0.42 intraday, 0.37-0.51 interday). With T-SICI, smaller sample sizes were calculated for equally powered interventional studies. CONCLUSION: The close relationship between conventional and T-SICI suggests that both techniques reflect similar cortical inhibitory mechanisms. Threshold-tracking measurements of SICI may be able to improve reproducibility, to shorten acquisition time and to reduce sample sizes for interventional studies compared with the conventional technique.

Patterns of acute whiplash-associated disorder in the Lithuanian population after road traffic accidents.

OBJECTIVE: To investigate acute whiplash-associated disorder in the Lithuanian population who are unaware of the phenomenon. DESIGN: Controlled cohort study. SUBJECTS/PATIENTS: Seventy-one patients were enrolled from the emergency departments of the Kaunas region of Lithuania following road traffic accidents, examined within 3-14 days after the accident, and compared with 53 matched controls. METHODS: Clinical neurological examination, including range of motion and motion-evoked pain or stiffness in the neck; spontaneous pain and pain pressure threshold. Questionnaires: Quebec Task Force questionnaire (QTFQ); Disability Rating Index (DRI); Cognitive Failures Questionnaire (CFQ); Hospital Anxiety and Depression Scale (HADS) and health perception. RESULTS: Sixty-six of 71 (93%) patients developed acute symptoms. The most frequent symptoms found after road traffic accidents were neck or shoulder pain; reduced or painful neck movements, including decreased range of motion; multiple subjective symptoms according to QTFQ and significantly reduced pain threshold. Perceived health status was decreased and DRI was increased, while HADS showed a significantly higher risk of developing anxiety. Higher grade whiplash-associated disorder was linked with a greater reduction in range of motion and more prominent neck pain. CONCLUSION: Road traffic accidents induce whiplash-associated disorder in patients who seek help, but who are unaware of the condition whiplash-associated disorder. Whiplash-associated disorder should be considered and treated as an entity per se.

Importance of pain evaluation for more accurate diagnosis of painful diabetic polyneuropathy.

UNLABELLED: Pain is a common problem in diabetic neuropathy, but relatively little has been published regarding the extent to which it needs to be addressed in clinical practice. OBJECTIVE: To assess neuropathic pain profile and its association with quantitative sensory testing in painful diabetic polyneuropathy. MATERIAL AND METHODS: Altogether, 61 consecutive diabetic inpatients with symmetric neuropathic complaints were enrolled. Clinical neurological examination and quantitative sensory testing (QST) were performed. Patients were interviewed using the Neuropathic Pain Scale (NPS) and filled in the McGill Pain Questionnaire (MPQ). RESULTS: Of all patients, 49 (80.3%) had clinical diabetic polyneuropathy. Only 17 of these patients complained of lower extremity pain on an initial interview, while 27 marked it in the MPQ. The intensity of deep and superficial pain did not differ, but patients rated deep pain as more unpleasant than superficial (6.27±2.37 vs. 4.30±1.42 on the NPS, P=0.034). Superficial pain NPS items tended to correlate with QST results, while deep pain items did not. Only female gender (OR=7.87) and lower glycosylated hemoglobin level (OR=0.65) were predictive of pain in case of diabetic neuropathy. CONCLUSIONS: Standard pain questionnaires were useful in identifying pain sufferers. At the same intensity, deep neuropathic pain was more unpleasant than superficial. Pain manifestation was associated with female gender and lower level of glycosylated hemoglobin.