Whole-body fasciculation detection in amyotrophic lateral sclerosis using motor unit MRI.

OBJECTIVE: Compare fasciculation rates between amyotrophic lateral sclerosis (ALS) patients and healthy controls in body regions relevant for diagnosing ALS using motor unit MRI (MUMRI) at baseline and 6 months follow-up, and relate this to single-channel surface EMG (SEMG). METHODS: Tongue, biceps brachii, paraspinals and lower legs were assessed with MUMRI and biceps brachii and soleus with SEMG in 10 healthy controls and 10 patients (9 typical ALS, 1 primary lateral sclerosis [PLS]). RESULTS: MUMRI-detected fasciculation rates in typical ALS patients were higher compared to healthy controls for biceps brachii (2.40 ± 1.90 cm-3min-1vs. 0.04 ± 0.10 cm-3min-1, p = 0.004), paraspinals (1.14 ± 1.61 cm-3min-1vs. 0.02 ± 0.02 cm-3min-1, p = 0.016) and lower legs (1.42 ± 1.27 cm-3min-1vs. 0.13 ± 0.10 cm-3min-1, p = 0.004), but not tongue (1.41 ± 1.94 cm-3min-1vs. 0.18 ± 0.18 cm-3min-1, p = 0.556). The PLS patient showed no fasciculation. At baseline, 6/9 ALS patients had increased fasciculation rates compared to healthy controls in at least 2 body regions. At follow-up every patient had increased fasciculation rates in at least 2 body regions. The MUMRI-detected fasciculation rate correlated with SEMG-detected fasciculation rates (τ = 0.475, p = 0.006). CONCLUSION: MUMRI can non-invasively image fasciculation in multiple body regions and appears sensitive to disease progression in individual patients. SIGNIFICANCE: MUMRI has potential as diagnostic tool for ALS.

Motor Unit Magnetic Resonance Imaging (MUMRI) In Skeletal Muscle.

Magnetic resonance imaging (MRI) is routinely used in the musculoskeletal system to measure skeletal muscle structure and pathology in health and disease. Recently, it has been shown that MRI also has promise for detecting the functional changes, which occur in muscles, commonly associated with a range of neuromuscular disorders. This review focuses on novel adaptations of MRI, which can detect the activity of the functional sub-units of skeletal muscle, the motor units, referred to as "motor unit MRI (MUMRI)." MUMRI utilizes pulsed gradient spin echo, pulsed gradient stimulated echo and phase contrast MRI sequences and has, so far, been used to investigate spontaneous motor unit activity (fasciculation) and used in combination with electrical nerve stimulation to study motor unit morphology and muscle twitch dynamics. Through detection of disease driven changes in motor unit activity, MUMRI shows promise as a tool to aid in both earlier diagnosis of neuromuscular disorders and to help in furthering our understanding of the underlying mechanisms, which proceed gross structural and anatomical changes within diseased muscle. Here, we summarize evidence for the use of MUMRI in neuromuscular disorders and discuss what future research is required to translate MUMRI toward clinical practice. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.

Whole Muscle and Single Motor Unit Twitch Profiles in a Healthy Adult Cohort Assessed With Phase Contrast Motor Unit MRI (PC-MUMRI).

BACKGROUND: Motor units (MUs) control the contraction of muscles and degenerate with age. It is therefore of interest to measure whole muscle and MU twitch profiles in aging skeletal muscle. PURPOSE: Apply phase contrast MU MRI (PC-MUMRI) in a cohort of healthy adults to measure whole anterior compartment, individual muscles, and single MU twitch profiles in the calf. Assess the effect of age and sex on contraction and relaxation times. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Sixty-one healthy participants (N = 32 male; age 55 ± 16 years [range: 26-82]). FIELD STRENGTH/SEQUENCES: 3 T, velocity encoded gradient echo and single shot spin echo pulsed gradient spin echo, echo-planar imaging. ASSESSMENT: Anterior shin compartment (N = 47), individual muscle (tibialis anterior, extensor digitorum longus, peroneus longus; N = 47) and single MU (N = 34) twitch profiles were extracted from the data to calculate contraction and relaxation times. STATISTICAL TESTS: Multivariable linear regression to investigate relationships between age, sex and contraction and relaxation times of the whole anterior compartment. Pearson correlation to investigate relationships between age and contraction and relaxation times of individual muscles and single MUs. A P value <0.05 was considered statistically significant. RESULTS: Age and sex predicted significantly increased contraction and relaxation time for the anterior compartment. Females had significantly longer contraction times than males (females 86 ± 8 msec, males 80 ± 9 msec). Relaxation times were longer, not significant (females 204 ± 36 msec, males 188 ± 34 msec, P = 0.151). Contraction and relaxation times of single MUs showed no change with age (P = 0.462, P = 0.534, respectively). DATE CONCLUSION: Older participants had significantly longer contraction and relaxation times of the whole anterior compartment compared to younger participants. Females had longer contraction and relaxation times than males, significant for contraction time. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Interfacing Motor Units in Non-Human Primates Identifies a Principal Neural Component for Force Control Constrained by the Size Principle.

Motor units convert the last neural code of movement into muscle forces. The classic view of motor unit control is that the central nervous system sends common synaptic inputs to motoneuron pools and that motoneurons respond in an orderly fashion dictated by the size principle. This view however is in contrast with the large number of dimensions observed in motor cortex which may allow individual and flexible control of motor units. Evidence for flexible control of motor units may be obtained by tracking motor units longitudinally during tasks with some level of behavioural variability. Here we identified and tracked populations of motor units in the brachioradialis muscle of two macaque monkeys during ten sessions spanning over one month with a broad range of rate of force development (1.8 - 38.6 N·m·s-1). We found a very stable recruitment order and discharge characteristics of the motor units over sessions and contraction trials. The small deviations from orderly recruitment were fully predicted by the motor unit recruitment intervals, so that small shifts in recruitment thresholds happened only during contractions at high rate of force development. Moreover, we also found that one component explained more than ∼50% of the motor unit discharge rate variance, and that the remaining components represented a time-shifted version of the first. In conclusion, our results show that motoneurons recruitment is determined by the interplay of the size principle and common input and that this recruitment scheme is not violated over time nor by the speed of the contractions.SIGNIFICANCE STATEMENT:With a new non-invasive high-density electromyographic framework we show the activity of motor unit ensembles in macaques during voluntary contractions. The discharge characteristics of brachioradialis motor units revealed a relatively fixed recruitment order and discharge characteristics across days and rate of force developments. These results were further confirmed through invasive axonal stimulation and recordings of intramuscular electromyographic activity from 16 arm muscles. The study shows for the first time the feasibility of longitudinal non-invasive motor unit interfacing and tracking of the same motor units in non-human primates.

In vivo 3D imaging of human motor units in upper and lower limb muscles.

OBJECTIVE: To assess in-vivo cross-sectional and 3D morphology of human motor units in hand, forearm and lower leg muscles using magnetic resonance imaging (MRI). METHODS: Diffusion weighted MRI was used with in-scanner electrical stimulation in healthy controls to image motor units at a single slice in lower leg, forearm and hand muscles (n = 6) and multiple slices in the lower leg for 3D assessment (n = 7). RESULTS: Motor unit cross-sectional area (CSA) and maximum Feret diameter (FDmax) did not differ between the lower leg (CSA: 22.4 ± 8.4 mm2; FDmax: 8.7 ± 2.4 mm), forearm (CSA: 23.6 ± 14.1 mm2; FDmax: 9.0 ± 3.3 mm) and hand (CSA: 26.8 ± 12.8 mm2 and FDmax: 9.6 ± 2.7 mm) (ANOVA; p = 0.487 and p = 0.587, respectively). Lower leg motor units were 8.0 ± 3.8 cm long with largest CSA in the motor unit's middle section. 3D motor unit imaging revealed a complex structure with several units splitting and re-forming along their length. CONCLUSIONS: Motor unit MRI (MUMRI) can be applied to upper limb muscles, and can reveal the 3D structure of human motor units in-vivo. SIGNIFICANCE: MUMRI provides the first in-vivo 2D images of upper limb motor units and 3D images of lower leg motor units. 3D imaging suggest a more complex human motor unit structure than previously thought.

The muscle twitch profile assessed with motor unit magnetic resonance imaging.

Localised signal voids in diffusion-weighted (DW) images of skeletal muscle have been postulated to occur as a result of muscle fibre contraction and relaxation. We investigated the contrast mechanism of these signal voids using a combination of modelling and experimental measurements by employing DW and phase contrast (PC) imaging sequences. The DW signal and PC signal were simulated for each time point of a theoretical muscle twitch. The model incorporated compaction (simulating actively contracting muscle fibres) and translation (simulating passively moving surrounding fibres). The model suggested that the DW signal depended on contraction time and compaction whereas the PC signal depended on contraction time, compaction and translation. In a retrospective study, we tested this model with subgroup analyses on 10 healthy participants. Electrical nerve stimulation was used to generate muscle twitches in lower leg muscles; the resulting force was measured using an MR-compatible force transducer. At current levels causing a visible muscle twitch (~13 mA), the width of the first signal drop in the DW signal (mean ± SD: 103 ± 20 ms) was comparable with the force contraction time (93 ± 34 ms; intraclass correlation coefficient [ICC] = 0.717, P = .010). At current levels activating single motor units (~9 mA), the contraction time determined from the DW signal was 75 ± 13 ms and comparable with the PC contraction time (81 ± 15 ms; ICC = 0.925, P = .001). The maximum positive velocity was 0.55 ± 0.26 cm/s and the displacement was 0.20 ± 0.10 mm. Voxel-wise analysis revealed localised DW changes occurring together with more widespread phase changes. In conclusion, local signal attenuations in DW images following muscle fibre activation are primarily caused by compaction. The PC sequence also detects translating muscle tissue being passively pulled. The magnitude of the changes in DW and PC images depends on the twitch's contractile properties and percentage contraction. DW imaging and PC imaging can therefore measure twitch profiles of skeletal muscle fibres.

Non-invasive imaging of single human motor units.

OBJECTIVE: To determine the size, shape and distribution of single human motor units in-vivo in healthy controls of different ages. METHODS: A novel diffusion-weighted magnetic resonance imaging (MRI) technique was used in combination with in-scanner electrical stimulation to quantify the shape, cross-sectional area, and dimensions of individual motor units in 10 healthy subjects. RESULTS: Thirty-one discrete motor units were studied. The majority were elliptical or crescent shaped, but occasional split motor units were observed. The mean motor unit cross sectional area was 26.7 ± 11.2 mm2, the mean maximum dimension was 10.7 ± 3.3 mm, and the mean minimum dimension was 4.5 ± 1.2 mm. Subjects aged over 40 had significantly larger maximum dimensions than those below this age (p < 0.05). CONCLUSIONS: Motor unit MRI (MUMRI) is a novel technique capable of revealing the size, shape and position of multiple motor units in human muscles. It is reproducible, non-invasive, and sufficiently sensitive to detect physiologically relevant changes in motor unit morphology with age. SIGNIFICANCE: To our knowledge, these results provide the first imaging assessment of human motor unit morphology. The technique shows promise both as a diagnostic tool and as a biomarker in longitudinal studies of disease progression.

Functional magnetic resonance imaging of human motor unit fasciculation in amyotrophic lateral sclerosis.

A novel diffusion-weighted magnetic resonance imaging protocol sensitive to contraction of individual skeletal motor units was developed. We applied this technique to the lower limb muscles of 4 patients with confirmed amyotrophic lateral sclerosis (ALS) and 6 healthy controls. A 3-minute scan revealed florid fasciculation in ALS patients, involving both superficial and deep muscles, and at a frequency higher than in healthy controls. This novel imaging technique reveals hitherto unobtainable information on human motor unit structure and function, which may allow earlier diagnosis and recruitment to clinical trials. ANN NEUROL 2019;85:455-459.

Glissandi: transient fast electrocorticographic oscillations of steadily increasing frequency, explained by temporally increasing gap junction conductance.

PURPOSE: We describe a form of very fast oscillation (VFO) in patient electrocorticography (ECoG) recordings, that can occur prior to ictal events, in which the frequency increases steadily from ≈ 30-40 to >120 Hz, over a period of seconds. We dub these events "glissandi" and describe a possible model for them. METHODS: Four patients with epilepsy had presurgical evaluations (with ECoG obtained in two of them), and excised tissue was studied in vitro, from three of the patients. Glissandi were seen spontaneously in vitro, associated with ictal events-using acute slices of rat neocortex-and they were simulated using a network model of 15,000 detailed layer V pyramidal neurons, coupled by gap junctions. KEY FINDINGS: Glissandi were observed to arise from human temporal neocortex. In vitro, they lasted 0.2-4.1 s, prior to ictal onset. Similar events were observed in the rat in vitro in layer V of frontal neocortex when alkaline solution was pressure-ejected; glissandi persisted when γ-aminobutyric acid A (GABA(A)), GABA(B), and N-methyl-d-aspartate (NMDA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were blocked. Nonalkaline conditions prevented glissando generation. In network simulations it was found that steadily increasing gap junction conductance would lead to the observed steady increase in VFO field frequency. This occurred because increasing gap junction conductance shortened the time required for an action potential to cross from cell to cell. SIGNIFICANCE: The in vitro and modeling data are consistent with the hypothesis that glissandi arise when pyramidal cell gap junction conductances rise over time, possibly as a result of an alkaline fluctuation in brain pH.

Impact of medical audit on electrodiagnostic medicine in polyneuropathy.

OBJECTIVE: The aim of the study was to investigate whether experienced physicians' electrodiagnostic practice and criteria can be influenced by international collaboration involving peer review medical audit. METHODS: Data was obtained from the ESTEEM project, an ongoing collaboration since 1991 among European neurophysiologists concerned with quality improvement in electrodiagnostic medicine. Three sets of the physicians' polyneuropathy examinations performed with intervals of 2-4 years were analysed. RESULTS: Changes towards increased homogeneity among the physicians were found in (1) the average number of studies performed per patient and the number of abnormal studies required for accepting the diagnosis of polyneuropathy, with the most pronounced changes seen for abnormal motor nerve segments, abnormal F-wave studies, and electromyographic studies, and (2) the agreement on pathophysiological interpretation of nerve conduction studies and classification of polyneuropathy. CONCLUSIONS: Changes towards increased homogeneity contributed to years of participation in peer review medical audit, were seen among a group of experienced physicians. Peer review medical audit as carried out here is however difficult to scale up. Therefore guidelines or minimal criteria should ideally supplement a medical audit process to disseminate the results obtained to a larger audience. SIGNIFICANCE: These results support the role of international peer review medical audit in quality improvement of electrodiagnostic medicine.

Variation in the neurophysiological examination of amyotrophic lateral sclerosis in Europe.

Our objective was to analyse how patients with amyotrophic lateral sclerosis (ALS) are examined neurophysiologically at different European centres in order to identify possible areas with variation or disagreement in the neurophysiological examination of ALS. Ninety-three prospectively collected examinations from six out of seven neurophysiologists in the European ESTEEM project were analysed. All examinations were peer reviewed with an electromyographic consensus diagnosis of motor neuron disease and the diagnosis of ALS confirmed by clinical follow-up. The examinations were analysed for differences among the physicians in EMG techniques and number and distribution of examined and abnormal muscles and nerve segments. Considerable variation was found among the physicians regarding the average numbers of performed and abnormal EMG and nerve conduction studies per patient, the EMG techniques used, and the topographical distribution of the examined muscles. The existence of two different examination approaches, one with quantitative EMG analyses and relatively few muscles studied, and one with more muscles studied using qualitative methods was clearly confirmed in the present study. The large variation among the physicians indicates that different criteria were used, or that criteria were used inconsistently.

A nonsynaptic mechanism underlying interictal discharges in human epileptic neocortex.

Very fast oscillations (VFOs, >80 Hz) are important for physiological brain processes and, in excess, with certain epilepsies. Putative mechanisms for VFO include interneuron spiking and network activity in coupled pyramidal cell axons. It is not known whether either, or both, of these apply in pathophysiological conditions. Spontaneously occurring interictal discharges occur in human tissue in vitro, resected from neocortical epileptic foci. VFO associated with these discharges was manifest in both field potential and, with phase delay, in excitatory synaptic inputs to fast spiking interneurons. Recruitment of somatic pyramidal cell and interneuron spiking was low, with no correlation between VFO power and synaptic inputs to principal cells. Reducing synaptic inhibition failed to affect VFO occurrence, but they were abolished by reduced gap junction conductance. These data suggest a lack of a causal role for interneurons, and favor a nonsynaptic pyramidal cell network origin for VFO in epileptic human neocortex.

High-frequency network oscillations in cerebellar cortex.

Both cerebellum and neocortex receive input from the somatosensory system. Interaction between these regions has been proposed to underpin the correct selection and execution of motor commands, but it is not clear how such interactions occur. In neocortex, inputs give rise to population rhythms, providing a spatiotemporal coding strategy for inputs and consequent outputs. Here, we show that similar patterns of rhythm generation occur in cerebellum during nicotinic receptor subtype activation. Both gamma oscillations (30-80 Hz) and very fast oscillations (VFOs, 80-160 Hz) were generated by intrinsic cerebellar cortical circuitry in the absence of functional glutamatergic connections. As in neocortex, gamma rhythms were dependent on GABA(A) receptor-mediated inhibition, whereas VFOs required only nonsynaptically connected intercellular networks. The ability of cerebellar cortex to generate population rhythms within the same frequency bands as neocortex suggests that they act as a common spatiotemporal code within which corticocerebellar dialog may occur.

A prospective multicentre study on sural nerve action potentials in ALS.

OBJECTIVE: To evaluate sensory nerve conduction studies in ALS in a prospective multicentre study involving 7 neurophysiologists from 6 European countries. METHODS: Bilateral sural potentials were obtained in 35 ALS patients and 35 age-matched controls according to a standardised examination protocol using antidromic surface technique. The recordings from the right sural nerve of the controls were used for reference values. A reduction from the mean of controls greater than 2 SDs was considered abnormal. RESULTS: Reduced sensory nerve action potential (SNAP) amplitude or reduced conduction velocity (CV), or both, was found in 6 ALS patients (17%). Decrease in CV was the most frequent finding, and was observed in 8 nerves from 5 patients. Reduced SNAP amplitude was found in 2 nerves from 2 patients. All changes were minor ranging from -2.1 to -3.2 SDs. CONCLUSIONS: This is the first standardised multicentre study on sensory potentials in ALS. It confirms that although normal sensory findings should be expected in the majority of ALS patients, minor abnormalities are not uncommon. SIGNIFICANCE: Mild sensory abnormalities do not necessarily exclude a diagnosis of ALS.

Influence of peer review medical audit on pathophysiological interpretation of nerve conduction studies in polyneuropathies.

OBJECTIVE: To evaluate the possible influence of peer review medical audit on experienced physicians' pathophysiological interpretation of nerve conduction studies in polyneuropathy patients. METHODS: Since 1992, 7 European neurophysiologists have collected samples of their patient examinations for regular review where the physicians interpret each other's cases electronically and subsequently discuss them at regular workshop meetings (i.e. a form of medical audit). Two sets of 100 polyneuropathy examinations interpreted with an interval of 4-6 years were selected. The sets contained 1456 and 1719 nerve conduction studies, each given a pathophysiological test conclusion by each individual physician. Inter-physician agreement on interpretation of demyelination and axonal loss of the nerve, as well as neuropathic and unspecific findings, was estimated using kappa statistics. RESULTS: Increased agreement from set 1 to set 2 was found on interpretation of demyelination of the nerve (set 1: kappa=0.22; set 2: kappa=0.45), and of neuropathic (set 1: kappa=0.46; set 2: kappa=0.64) and unspecific findings (set 1: kappa=0.35; set 2: kappa=0.54). No changes were found on interpretation of axonal loss (set 1: kappa=0.26; set 2: kappa=0.31) and normal findings (set 1 and set 2: kappa=0.90). CONCLUSIONS: Participation in regular peer review medical audit resulted in increased agreement on interpretation of nerve conduction studies for 6 of the 7 participants. The study further highlights the need for better definition of criteria for identification of demyelinating, and in particular, axonal peripheral neuropathies. SIGNIFICANCE: International collaboration involving peer review medical audit may contribute to development of practice guidelines and, in turn, to increased quality of electrodiagnostic medicine.

Pathophysiology inferred from electrodiagnostic nerve tests and classification of polyneuropathies. Suggested guidelines.

OBJECTIVE: To present criteria for pathophysiological interpretation of motor and sensory nerve conduction studies and for pathophysiological classification of polyneuropathies suggested by a group of European neurophysiologists. METHODS: Since 1992 seven neurophysiologists from six European countries have collected random samples of their electrodiagnostic examinations for peer review medical audit in the ESTEEM (European Standardized Telematic tool to Evaluate Electrodiagnostic Methods) project. Based on existing criteria in the literature, the experience with a patient material of 572 peer reviewed electrodiagnostic examinations, and productive discussions between the physicians at workshops, the collaboration has produced a set of criteria now routinely used at the centres involved in the project. RESULTS: The first part of the paper considers pathophysiology of individual nerve segments. For interpretation of motor and sensory nerve conduction studies, figures showing change in amplitude versus change in conduction velocity/distal latency and change in F-wave frequency versus change in F-wave latency are presented. The suggested boundaries delimit areas corresponding to normal, axonal, demyelinated, or neuropathic nerve segments. Criteria for motor conduction block in upper and lower extremities are schematically depicted using the parameters CMAP amplitude and CMAP duration. The second part of the paper suggests criteria for classification of polyneuropathies into axonal, demyelinating, or mixed using the above-mentioned criteria. CONCLUSIONS: The suggested criteria are developed during many years of collaboration of different centres and may be useful for standardization in clinical neurophysiology. SIGNIFICANCE: Consistent interpretation of nerve conduction studies is an important step in optimising diagnosis and treatment of nerve disorders.

Influence of medical audit on electrodiagnostic evaluation of polyneuropathy. A multicentre study.

OBJECTIVE: Since 1992, 7 European neurophysiologists have participated in the ESTEEM project concerned with improvements in electrodiagnostic medicine. This study assesses whether the collaboration that includes peer review medical audit has influenced the involved physicians' electrodiagnostic criteria for polyneuropathy (PNP) diagnosing and classification. METHODS: Two sets of each physician's PNP examinations performed early and late in the study were examined for changes in (1) number of studies with abnormal electrophysiological findings required for diagnosing PNP, and (2) agreement between the classifications given by the individual physicians and the peer review group. RESULTS: The average number of abnormal motor nerve segments per patient increased from 4.6 to 6.4 during the study. Although most individual changes were minor, the second set of examinations showed an increased homogeneity among the physicians in the number of abnormal motor nerve segments and abnormal F wave studies, and a tendency towards increased homogeneity in the number of abnormal sensory nerve segments. There was also an increased agreement on pathophysiological PNP classification in the second set of examinations compared to the first set. CONCLUSIONS: The participation in the ESTEEM project seems to have impacted the physicians' clinical routine, possibly as they have accustomed themselves to apply criteria more strictly. SIGNIFICANCE: This study support that international collaboration is a useful step towards improvements in electrodiagnostic medicine.