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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.
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Esclerosis Amiotrófica Lateral , Biomarcadores , Proteínas de Neurofilamentos , Estimulación Magnética Transcraneal , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/fisiopatología , Persona de Mediana Edad , Masculino , Femenino , Anciano , Estimulación Magnética Transcraneal/métodos , Electromiografía , Potenciales Evocados Motores/fisiologíaRESUMEN
Cryptochromes are essential flavoproteins for circadian rhythms and avian magnetoreception. Flavin adenine dinucleotide (FAD), a chromophore within cryptochromes, absorbs blue light, initiating electron transfer processes that lead to a biological signaling cascade. A key step in this cascade is the formation of the FAD semiquinone radical (FADHâ¢), characterized through a specific red-light absorption. The absorption spectra of FADH⢠in cryptochromes are, however, significantly different from those recorded for the cofactor in solution, primarily due to protein-induced shifts in the absorption peaks. This study employs a multiscale approach, combining molecular dynamics (MD) simulations with quantum mechanical/molecular mechanical (QM/MM) methodologies, to investigate the influence of protein dynamics on embedded FADH⢠absorption. We emphasize the role of the protein's polarizable environment in the shaping of the absorption spectrum, crucial for accurate spectral predictions in cryptochromes. Our findings provide valuable insights into the absorption process, advancing our understanding of cryptochrome functioning.
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Arabidopsis , Criptocromos , Flavina-Adenina Dinucleótido , Simulación de Dinámica Molecular , Teoría Cuántica , Criptocromos/química , Criptocromos/metabolismo , Arabidopsis/metabolismo , Arabidopsis/química , Flavina-Adenina Dinucleótido/química , Flavina-Adenina Dinucleótido/metabolismo , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/metabolismoRESUMEN
The Earth's magnetic field can provide reliable directional information, allowing migrating animals to orient themselves using a magnetic compass or estimate their position relative to a target using map-based orientation. Here we show for the first time that young, inexperienced herring (Clupea harengus, Ch) have a magnetic compass when they migrate hundreds of kilometres to their feeding grounds. In birds, such as the European robin (Erithacus rubecula), radical pair-based magnetoreception involving cryptochrome 4 (ErCRY4) was demonstrated; the molecular basis of magnetoreception in fish is still elusive. We show that cry4 expression in the eye of herring is upregulated during the migratory season, but not before, indicating a possible use for migration. The amino acid structure of herring ChCRY4 shows four tryptophans and a flavin adenine dinucleotide-binding site, a prerequisite for a magnetic receptor. Using homology modelling, we successfully reconstructed ChCRY4 of herring, DrCRY4 of zebrafish (Danio rerio) and StCRY4 of brown trout (Salmo trutta) and showed that ChCRY4, DrCRY4 and ErCRY4a, but not StCRY4, exhibit very comparable dynamic behaviour. The electron transfer could take place in ChCRY4 in a similar way to ErCRY4a. The combined behavioural, transcriptomic and simulation experiments provide evidence that CRY4 could act as a magnetoreceptor in Atlantic herring.
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Criptocromos , Peces , Animales , Criptocromos/metabolismo , Criptocromos/química , Peces/fisiología , Migración Animal/fisiología , Campos Magnéticos , Proteínas de Peces/metabolismo , Proteínas de Peces/genética , Proteínas de Peces/química , Orientación/fisiologíaRESUMEN
It is still a puzzle that has not been entirely solved how migratory birds utilize the Earth's magnetic field for biannual migration. The most consistent explanation thus far is rooted in the modulation of the biological function of the cryptochrome 4 (Cry4) protein by an external magnetic field. This phenomenon is closely linked with the flavin adenine dinucleotide (FAD) cofactor that is noncovalently bound in the protein. Cry4 is activated by blue light, which is absorbed by the FAD cofactor. Subsequent electron and proton transfers trigger radical pair formation in the protein, which is sensitive to the external magnetic field. An important long-lasting redox state of the FAD cofactor is the signaling (FADHâ¢) state, which is present after the transient electron transfer steps have been completed. Recent experimental efforts succeeded in crystallizing the Cry4 protein from Columbia livia (ClCry4) with all of the important residues needed for protein photoreduction. This specific crystallization of Cry4 protein so far is the only avian cryptochrome crystal structure available, which, however, has great similarity to the Cry4 proteins of night migratory birds. The previous experimental studies of the ClCry4 protein included the absorption properties of the protein in its different redox states. The absorption spectrum of the FADH⢠state demonstrated a peculiar red shift compared to the photoabsorption properties of the FAD cofactor in its FADH⢠state in other Cry proteins from other species. The aim of this study is to understand this red shift by employing the tools of computational microscopy and, in particular, a QM/MM approach that relies on the polarizable embedding approximation.
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Criptocromos , Flavina-Adenina Dinucleótido , Criptocromos/química , Criptocromos/metabolismo , Flavina-Adenina Dinucleótido/química , Flavina-Adenina Dinucleótido/metabolismo , Animales , Proteínas Aviares/química , Proteínas Aviares/metabolismo , Oxidación-ReducciónRESUMEN
Marine fish migrate long distances up to hundreds or even thousands of kilometers for various reasons that include seasonal dependencies, feeding, or reproduction. The ability to perceive the geomagnetic field, called magnetoreception, is one of the many mechanisms allowing some fish to navigate reliably in the aquatic realm. While it is believed that the photoreceptor protein cryptochrome 4 (Cry4) is the key component for the radical pair-based magnetoreception mechanism in night migratory songbirds, the Cry4 mechanism in fish is still largely unexplored. The present study aims to investigate properties of the fish Cry4 protein in order to understand the potential involvement in a radical pair-based magnetoreception. Specifically, a computationally reconstructed atomistic model of Cry4 from the Atlantic herring (Clupea harengus) was studied employing classical molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) methods to investigate internal electron transfers and the radical pair formation. The QM/MM simulations reveal that electron transfers occur similarly to those found experimentally and computationally in Cry4 from European robin (Erithacus rubecula). It is therefore plausible that the investigated Atlantic herring Cry4 has the physical and chemical properties to form radical pairs that in turn could provide fish with a radical pair-based magnetic field compass sensor.
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BACKGROUND: Radiobiological experimental setups are challenged by precise sample positioning along depth dose profile, scattering conditions, and practical difficulties that must be addressed in individual designs. The aim of this study was to produce cell survival curves with several irradiation modalities, by using a setup designed at the Danish Centre for Particle Therapy (DCPT) for in vitro proton irradiations using a horizontal beam line and thereby evaluating the setups use for in vitro irradiations experiments. MATERIALS AND METHODS: The setup is a water phantom suitable for in vitro research with multiple irradiation modalities, in particular the pencil scanning proton beam available from a horizontal experimental beamline. The phantom included a water tank of 39.0 × 17.0 × 20.5 cm. Cell survival-curves were produced using the cell line V79 Chinese hamster lung fibroblast cells (V79s) in biological triplicates of clonogenic assays. Cell survival curves were produced with both a 18 MeV electron beam, 6 MV photon beam, and a Spread-Out Bragg Peak (SOBP) proton beam formed by pristine energies of 85-111 MeV where three positions were examined. RESULTS: Survival curves with uncertainty areas were made for all modalities. Dosimetric uncertainty amounted to, respectively, 4%, 3% and 3% for proton, electron, and high energy photon irradiations. Cell survival fraction uncertainty was depicted as the standard deviation between replications of the experiment. CONCLUSION: Cell survival curves could be produced with acceptable uncertainties using this novel water phantom and cellular laboratory workflow. The setup is useful for future in vitro irradiation experiments.
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Fotones , Protones , Animales , Cricetinae , Humanos , Supervivencia Celular , Agua , DinamarcaRESUMEN
Migratory birds possess remarkable accuracy in orientation and navigation, which involves various compass systems including the magnetic compass. Identifying the primary magnetosensor remains a fundamental open question. Cryptochromes (Cry) have been shown to be magnetically sensitive, and Cry4a from a migratory songbird seems to show enhanced magnetic sensitivity in vitro compared to Cry4a from resident species. We investigate Cry and their potential involvement in magnetoreception in a phylogenetic framework, integrating molecular evolutionary analyses with protein dynamics modelling. Our analysis is based on 363 bird genomes and identifies different selection regimes in passerines. We show that Cry4a is characterized by strong positive selection and high variability, typical characteristics of sensor proteins. We identify key sites that are likely to have facilitated the evolution of an optimized sensory protein for night-time orientation in songbirds. Additionally, we show that Cry4 was lost in hummingbirds, parrots and Tyranni (Suboscines), and thus identified a gene deletion, which might facilitate testing the function of Cry4a in birds. In contrast, the other avian Cry (Cry1 and Cry2) were highly conserved across all species, indicating basal, non-sensory functions. Our results support a specialization or functional differentiation of Cry4 in songbirds which could be magnetosensation.
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Pájaros Cantores , Animales , Filogenia , Pájaros Cantores/fisiología , Criptocromos/metabolismo , Campos Magnéticos , Migración Animal/fisiologíaRESUMEN
The ability of migratory birds to sense magnetic fields has been known for decades, although the understanding of the underlying mechanism is still elusive. Currently, the strongest magnetoreceptor candidate in birds is a protein called cryptochrome 4a. The cryptochrome 4a protein has changed through evolution, apparently endowing some birds with a more pronounced magnetic sensitivity than others. Using phylogenetic tools, we show that a specific tryptophan tetrad and a tyrosine residue predicted to be essential for cryptochrome activation are highly conserved in the avian clade. Through state-of-the-art molecular dynamics simulations and associated analyses, we also studied the role of these specific residues and the associated mutants on the overall dynamics of the protein. The analyses of the single residue mutations were used to judge how far a local change in the protein structure can impact specific dynamics of European robin cryptochrome 4a. We conclude that the replacements of each of the tryptophans one by one with a phenylalanine do not compromise the overall stability of the protein.
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The primary step in the mechanism by which migratory birds sense the Earth's magnetic field is thought to be the light-induced formation of long-lived magnetically sensitive radical pairs within cryptochrome flavoproteins located in the birds' retinas. Blue-light absorption by the non-covalently bound flavin chromophore triggers sequential electron transfers along a chain of four tryptophan residues toward the photoexcited flavin. The recently demonstrated ability to express cryptochrome 4a from the night-migratory European robin (Erithacus rubecula), ErCry4a, and to replace each of the tryptophan residues by a redox-inactive phenylalanine offers the prospect of exploring the roles of the four tryptophans. Here, we use ultrafast transient absorption spectroscopy to compare wild type ErCry4a and four mutants having a phenylalanine at different positions in the chain. We find that each of the three tryptophan residues closest to the flavin adds a distinct relaxation component (time constants: 0.5, 30, and 150 ps) in the transient absorption data. The dynamics of the mutant containing a phenylalanine at the fourth position, furthest from the flavin, are very similar to those of wild type ErCry4a, except for a reduced concentration of long-lived radical pairs. The experimental results are evaluated and discussed in the framework of real-time quantum mechanical/molecular mechanical electron transfer simulations based on the density functional-based tight binding approach. This comparison between simulation results and experimental measurements provides a detailed microscopic insight into the sequential electron transfers along the tryptophan chain. Our results offer a route to the study of spin transport and dynamical spin correlations in flavoprotein radical pairs.
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Criptocromos , Triptófano , Criptocromos/química , Triptófano/química , Electrones , Transporte de Electrón , Campos Magnéticos , Flavinas/metabolismoRESUMEN
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.
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Esclerosis Amiotrófica Lateral , Enfermedad de la Neurona Motora , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Estimulación Magnética Transcraneal/métodos , Potenciales Evocados Motores/fisiología , Diagnóstico Precoz , Inhibición Neural/fisiologíaRESUMEN
A recent study by Xu et al. (Nature, 2021, 594, 535-540) provided strong evidence that cryptochrome 4 (Cry4) is a key protein to endow migratory birds with the magnetic compass sense. The investigation compared the magnetic field response of Cry4 from migratory and nonmigratory bird species and suggested that a difference in magnetic sensitivity could exist. This finding prompted an in-depth investigation into Cry4 protein differences on the structural and dynamic levels. In the present study, the pigeon Cry4 (ClCry4) crystal structure was used to reconstruct the missing avian Cry4 protein structures via homology modeling for carefully selected bird species. The reconstructed Cry4 structure from European robin, Eurasian blackcap, zebra finch, chicken, and pigeon were subsequently simulated dynamically and analyzed. The studied avian Cry4 structures show flexibility in analogous regions pointing to similar activation mechanisms and/or signaling interaction partners. It can be concluded that the experimentally recorded difference in the magnetic field sensitivity of Cry4 from different birds is unlikely to be due to solely intrinsic dynamics of the proteins but requires additional factors that have not yet been identified.
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Proteínas Aviares , Pájaros Cantores , Animales , Proteínas Aviares/metabolismo , Criptocromos/química , Campos Magnéticos , Modelos Estructurales , Pájaros Cantores/metabolismoRESUMEN
Understanding and predicting the functional consequences of single amino acid changes is central in many areas of protein science. Here, we collect and analyze experimental measurements of effects of >150,000 variants in 29 proteins. We use biophysical calculations to predict changes in stability for each variant and assess them in light of sequence conservation. We find that the sequence analyses give more accurate prediction of variant effects than predictions of stability and that about half of the variants that show loss of function do so due to stability effects. We construct a machine learning model to predict variant effects from protein structure and sequence alignments and show how the two sources of information support one another and enable mechanistic interpretations. Together, our results show how one can leverage large-scale experimental assessments of variant effects to gain deeper and general insights into the mechanisms that cause loss of function.
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Predicción/métodos , Estabilidad Proteica , Análisis de Secuencia de ADN/métodos , Sustitución de Aminoácidos , Animales , Biología Computacional/métodos , Humanos , Aprendizaje Automático , Mutación/genética , Mutación/fisiología , Proteínas/metabolismo , Alineación de Secuencia/métodosRESUMEN
OBJECTIVE: To assess the inter-rater reliability of MScanFit MUNE using a "Round Robin" research design. METHODS: Twelve raters from different centres examined six healthy study participants over two days. Median, ulnar and common peroneal nerves were stimulated, and compound muscle action potential (CMAP)-scans were recorded from abductor pollicis brevis (APB), abductor digiti minimi (ADM) and anterior tibial (TA) muscles respectively. From this we calculated the Motor Unit Number Estimation (MUNE) and "A50", a motor unit size parameter. As statistical analysis we used the measures Limits of Agreement (LOA) and Coefficient of Variation (COV). Study participants scored their perception of pain from the examinations on a rating scale from 0 (no pain) to 10 (unbearable pain). RESULTS: Before this study, 41.6% of the raters had performed MScanFit less than five times. The mean MUNE-values were: 99.6 (APB), 131.4 (ADM) and 126.2 (TA), with LOA: 19.5 (APB), 29.8 (ADM) and 20.7 (TA), and COV: 13.4 (APB), 6.3 (ADM) and 5.6 (TA). MUNE-values correlated to CMAP max amplitudes (R2-values were: 0.463 (APB) (p<0.001), 0.421 (ADM) (p<0.001) and 0.645 (TA) (p<0.001)). The average perception of pain was 4. DISCUSSION: MScanFit indicates a high level of inter-rater reliability, even with only limited rater experience and is overall reasonably well tolerated by patients. These results may indicate MScanFit as a reliable MUNE method with potential as a biomarker in drug trials.
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Esclerosis Amiotrófica Lateral , Neuronas Motoras , Potenciales de Acción/fisiología , Electromiografía/métodos , Humanos , Neuronas Motoras/fisiología , Músculo Esquelético/inervación , Dolor , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: Compare high-resolution ultrasound (HRUS) and electrodiagnostic examination (EDX) in the diagnostic workup of patients with scapulae alatae. METHODS: 27 patients with scapulae alatae and 41 healthy subjects (HS) and underwent a standardized clinical examination (CEX), EDX and HRUS. We measured the thickness of the serratus anterior (SER), rhomboid major and trapezius muscles and the diameter of the long thoracic (LTN), dorsal scapular and spinal accessory nerves (SAN). RESULTS: Twenty patients showed medial winging and six patients showed lateral winging on CEX. One patient had both lateral and medial winging. In patients with medial winging, the SER muscle was thinner and the LTN diameter was larger on the symptomatic side compared with the asymptomatic side and with the dominant side in HS. In this group, both EDX and HRUS detected abnormalities of SER muscle/ LTN with sensitivity of 65%, and with specificity of 100% and 57%, respectively. EDX and HRUS detected abnormalities of the trapezius muscle/ SAN with sensitivity of 60% and 40%, and specificity of 91%, and 86 % a, respectively. There was no significant difference between the two methods. CONCLUSION: HRUS can contribute to the diagnostic workup of scapulae alatae by demonstrating atrophy of muscles and enlargement in nerve diameter. SIGNIFICANCE: HRUS supplements EDX in the diagnostic workup of scapulae alatae.
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Electrodiagnóstico , Enfermedades Neuromusculares/diagnóstico , Escápula/diagnóstico por imagen , Ultrasonografía , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neuromusculares/diagnóstico por imagen , Enfermedades Neuromusculares/fisiopatología , Escápula/inervación , Escápula/fisiopatologíaRESUMEN
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.
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Potenciales Evocados Motores , Corteza Motora , Electromiografía , Humanos , Inhibición Neural , Reproducibilidad de los ResultadosRESUMEN
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.
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Esclerosis Amiotrófica Lateral , Enfermedad de la Neurona Motora , Esclerosis Amiotrófica Lateral/diagnóstico , Diagnóstico Precoz , Electromiografía , Potenciales Evocados Motores , Humanos , Enfermedad de la Neurona Motora/diagnóstico , Estimulación Magnética TranscranealRESUMEN
OBJECTIVE: In patients with chemotherapy-induced peripheral neuropathy (CIPN), demonstration of small fibre (SF) damage is important to understand chronic late effects. METHODS: Thirty patients having complaints compatible with possible CIPN following treatment with oxaliplatin or docetaxel were compared with 27 healthy subjects. All subjects were evaluated with quantitative sensory testing (QST) assessing SF function and laser evoked potentials (LEP). In addition, SF-damage was assessed using cutaneous silent periods evoked with electrical (El-CSP) and laser (Ls-CSP) stimuli. RESULTS: For LEP, N2P2 amplitudes were significantly smaller in patients than controls in both upper (P = 0.007) and lower extremities (P = 0.002), and the N1 amplitude in upper extremities of patients were significantly smaller than in controls (P = 0.001). SF-QST, LEP, Ls-CSP, and El-CSP were abnormal in 10 (33.3%), 16 (53.3%), 19 (63.3%), and 24 (80%) of CIPN patients, respectively. CONCLUSIONS: In patients with possible CIPN, El-CSP and Ls-CSP were more often abnormal than LEP and QST. This is probably because El-CSP and Ls-CSP inform mainly about peripheral nociceptive fibres, while LEP and QST inform about peripheral and central nociceptive pathways together. SIGNIFICANCE: LEP and QST are established methods to detect SF-damage. El- and Ls-CSP might help clinicians in diagnosing SF-damage.
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Antineoplásicos/efectos adversos , Potenciales Evocados por Láser/fisiología , Fibras Nerviosas/fisiología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Adulto , Anciano , Estudios Transversales , Docetaxel/efectos adversos , Electromiografía/efectos de los fármacos , Electromiografía/métodos , Femenino , Humanos , Potenciales Evocados por Láser/efectos de los fármacos , Masculino , Persona de Mediana Edad , Fibras Nerviosas/efectos de los fármacos , Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/diagnósticoRESUMEN
OBJECTIVES: To obtain normative high-resolution ultrasound (HRUS) data for thickness of the serratus anterior, the trapezius and the rhomboid major muscles and diameter of their corresponding nerves, the long thoracic, the spinal accessory and the dorsal scapular nerve. Moreover, we aimed to examine intra- and inter-examiner agreement of the HRUS measurements. METHODS: We included 41 healthy subjects. Muscle thickness and nerve diameter were measured bilaterally, resulting in 82 ultrasound measurements for each structure. Normative data were calculated using regression equations for the lower limit of muscle thickness and upper limit of nerve diameter, taking into account various variables. For intra- and inter-examiner agreement, ten subjects underwent two extra ultrasound examinations and Bland-Altman plots were calculated. RESULTS: This normative data set showed significant correlations between decreasing muscle thickness with increasing age and height and increasing muscle thickness with increasing weight and with male sex. Muscle thickness was larger on the dominant side compared to the non-dominant side for the trapezius and rhomboid muscles, whereas the opposite was found for the serratus anterior muscle. For all nerves, significant correlations were found between decreasing nerve diameter with increasing age and height. Intra-examiner agreement was acceptable in all sites. Inter-examiner agreement was acceptable for all sites but one site for the serratus anterior muscle and long thoracic nerve, and not acceptable for five out of six sites for the trapezius muscle. CONCLUSION: This study provides HRUS normative data and intra- and inter-examiner agreement data for muscle thickness and nerve diameter for the muscles stabilizing the scapulae and their corresponding nerves. SIGNIFICANCE: The normative HRUS data reported may be useful in future studies investigating neuromuscular disorders.
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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 1-7â¯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 2â¯ms (pâ¯<â¯0.05) but did not differ at other ISIs. Intra-subject variability did not differ between coils, but mean inhibition from 1-3.5â¯ms was less variable between subjects with the figure-of-8 coil (SD 7.2% vs. 11.2% RMT, pâ¯<â¯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, pâ¯<â¯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.
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Corteza Motora , Estimulación Magnética Transcraneal , Adulto , Potenciales Evocados Motores , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Inhibición Neural , Reproducibilidad de los ResultadosRESUMEN
Electrodiagnostic testing for polyneuropathies is a large part of the diagnostic workup in all electrodiagnostic laboratories. Guidelines on examination and diagnostic strategies and classification of polyneuropathies are crucial for standardization of electrodiagnostic testing and best clinical practice. Several guidelines have been suggested on pathophysiological classification, particularly for the definition of inflammatory neuropathies, whereas for axonal polyneuropathies, the literature is sparse. Similarly, there are a few recommendations on examination and diagnostic strategies. This review will cover the existing guidelines on electrodiagnostic testing of large fiber polyneuropathies including examination and diagnostic strategies and pathophysiological classification. In addition, the diagnostic criteria for Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and hereditary neuropathies are summarized.