Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.

This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.

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.

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).

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.

Neuromuscular junction involvement in inherited motor neuropathies: genetic heterogeneity and effect of oral salbutamol treatment.

Objectives: Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of diseases. Several recently identified genes highlight the overlap between peripheral neuropathies and congenital myasthenic syndromes (CMS). The beta-2 adrenergic receptor agonist salbutamol has been shown to provide symptomatic benefit in CMS, while improving structural defects at the NMJ.

Ultrasound-guided motor unit scanning electromyography.

Introduction/aims: Measuring the spatial dimensions of a single motor unit remains a challenging problem, and current techniques, such as scanning electromyography (EMG), tend to underestimate the true dimensions. In this study we aimed to estimate more accurately the dimensions of a single motor unit by developing a clinically applicable scanning EMG protocol that utilizes ultrasound imaging to visualize and target a transect through the center of a single motor unit.

Methods: Single motor unit twitches in the tibialis anterior muscles of healthy volunteers were elicited via stimulation of the fibular nerve, visualized with ultrasound, and targeted with an intramuscular EMG electrode.

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 (FD) did not differ between the lower leg (CSA: 22.

Electrical cross-sectional imaging of human motor units in vivo.

Objectives: In many neuromuscular diseases, weakness results from a disruption in muscle fibres' arrangement within a motor unit. Limitations in current techniques mean that the spatial distribution of fibres in human motor units remains unknown.

Methods: A flexible multi-channel electrode was developed and bonded to a clinical electromyography (EMG) needle.

Forecasting stroke-like episodes and outcomes in mitochondrial disease.

In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource.

The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia.

Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well-tolerated and precise antiepileptic drugs that can target glutamate receptors.

Taking Optogenetics into the Human Brain: Opportunities and Challenges in Clinical Trial Design.

Optogenetics, the use of light to control the activity of suitably sensitized cells, has led to major advances in the field of basic neuroscience since it first emerged in 2005. Already, the technique has entered clinical trials for conditions such as Retinitis Pigmentosa. A major focus of interest is the use of optogenetics within the brain, where the ability to precisely control the activity of specific subsets of neurons could lead to novel treatments for a wide range of disorders from epilepsy to schizophrenia.

Neuromuscular Junction Abnormalities in Mitochondrial Disease: An Observational Cohort Study.

Objective: To determine the prevalence of neuromuscular junction (NMJ) abnormalities in patients with mitochondrial disease.

Methods: Eighty patients with genetically proven mitochondrial disease were recruited from a national center for mitochondrial disease in the United Kingdom. Participants underwent detailed clinical and neurophysiologic testing including single-fiber electromyography.

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 role of novel motor unit magnetic resonance imaging to investigate motor unit activity in ageing skeletal muscle.

Sarcopenia is a progressive and generalized disease, more common in older adults, which manifests as a loss of muscle strength and mass. The pathophysiology of sarcopenia is still poorly understood with many mechanisms suggested. Age associated changes to the neuromuscular architecture, including motor units and their constituent muscle fibres, represent one such mechanism.

W:Ti Flexible Transversal Electrode Array for Peripheral Nerve Stimulation: A Feasibility Study.

The development of hardware for neural interfacing remains a technical challenge. We introduce a flexible, transversal intraneural tungsten:titanium electrode array for acute studies. We characterize the electrochemical properties of this new combination of tungsten and titanium using cyclic voltammetry and electrochemical impedance spectroscopy.

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.

Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome.

The β-adrenergic agonists salbutamol and ephedrine have proven to be effective as therapies for human disorders of the neuromuscular junction, in particular many subsets of congenital myasthenic syndromes. However, the mechanisms underlying this clinical benefit are unknown and improved understanding of the effect of adrenergic signalling on the neuromuscular junction is essential to facilitate the development of more targeted therapies. Here, we investigated the effect of salbutamol treatment on the neuromuscular junction in the ColQ deficient mouse, a model of end-plate acetylcholinesterase deficiency.

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.

Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo mutation.

Objective: To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases.

Methods: We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing.

Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

Purpose: To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.

Methods: We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.

The beta-adrenergic agonist salbutamol modulates neuromuscular junction formation in zebrafish models of human myasthenic syndromes.

Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of disorders, termed congenital myasthenic syndromes (CMS). Therapies acting on the sympathetic nervous system, including the selective β2 adrenergic agonist salbutamol and the α and β adrenergic agonist ephedrine, have become standard treatment for several types of CMS. However, the mechanism of the therapeutic effect of sympathomimetics in these disorders is not understood.

Congenital myasthenic syndrome with episodic apnoea: clinical, neurophysiological and genetic features in the long-term follow-up of 19 patients.

Background: Congenital myasthenic syndrome with episodic apnoea (CMS-EA) is a rare but potentially treatable cause of apparent life-threatening events in infancy. The underlying mechanisms for sudden and recurrent episodes of respiratory arrest in these patients are unclear. Whilst CMS-EA is most commonly caused by mutations in CHAT, the list of associated genotypes is expanding.

Drosophila studies support a role for a presynaptic synaptotagmin mutation in a human congenital myasthenic syndrome.

During chemical transmission, the function of synaptic proteins must be coordinated to efficiently release neurotransmitter. Synaptotagmin 2, the Ca2+ sensor for fast, synchronized neurotransmitter release at the human neuromuscular junction, has recently been implicated in a dominantly inherited congenital myasthenic syndrome associated with a non-progressive motor neuropathy. In one family, a proline residue within the C2B Ca2+-binding pocket of synaptotagmin is replaced by a leucine.

Seizure self-prediction: Myth or missed opportunity?

Purpose: Many patients report being able to predict their own seizures, and yet most seizures appear to strike out of the blue. This inherent contradiction makes the topic of seizure self-prediction controversial as well as difficult to study. Here we review the evidence for whether this ability exists, how many patients are capable of self-prediction and the nature of this capability, and whether this could provide a target for intervention.