Measuring and Modeling of Axon Membrane Properties in Motor Neuron Disorders and Normal Subjects

1 2 1 Measuring and modeling of axon membrane properties in motor neuron disorders and normal subjects Maria Kovalchuk 2 Cover design Picture of a marshalling yard south to Hamburg (Germany) from Google Planet Earth, Inc., adopted by Natalia Solovyeva, Maria Kovalchuk Layout Natalia Solovyeva Printed by Buki Vedi ISBN 978-5-4465-2558-4 Copyright © 2019 M. Kovalchuk All rights reserved. No part of this publication may be reproduced, distributed or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage or retrieval system, without permission in writing form from the author. The copyright of the articles that have been accepted for publication or that have already been published, has been trans- ferred to the respective journals. 3 Measuring and modeling of axon membrane properties in motor neuron disorders and normal subjects Meten en modelleren van axonmembraaneigenschappen bij motor neuron aandoeningen en gezonden (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. H.R.B.M Kummeling, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 19 december 2019 des avonds te 6.00 uur door Maria Kovalchuk geboren op 5 oktober 1984 te Moskou, Rusland 4Promotor: Prof. dr. L.H. van den Berg Copromotoren: Dr. H. Franssen Dr. ir. B.T.H.M. Sleutjes Funding of the studies described in this thesis was provided by the European Federation of Neurological Societies and Prinses Beatrix Spierfonds. 5 The last process of reason is to recognize that there is an infinity of things which transcend it. Blaise Pascal 6 7 CONTENTS CHAPTER 1 9 Introduction and aims of this thesis CHAPTER 2 17 Comparing excitability at 37°C with 20°C: differences between motor and sensory axons CHAPTER 3 33 Simulating perinodal changes observed in immune-mediated neuropathies – Impact on conduction in a model of myelinated motor and sensory axons CHAPTER 4 65 Excitability of motor and sensory axons in Мultifocal Мotor Neuropathy CHAPTER 5 89 Nerve excitability at different target levels in Multifocal Motor Neuropathy CHAPTER 6 97 Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial CHAPTER 7 119 Influence of intravenous immunoglobulin on nerve excitability in Multifocal Motor Neuropathy CHAPTER 8 131 Sodium-potassium pump assessment by submaximal electrical nerve stimulation CHAPTER 9 145 Excitability tests using high-density surface-EMG: A novel approach to studying single motor units CHAPTER 10 163 Warming nerves for excitability testing CHAPTER 11 179 General discussion ADDENDA 189 Summary 191 Summary in Dutch (Nederlandse samenvatting) 19 3 Acknowledgements (Dankwoord) (Благодарность) 195 List of publications 199 Curriculum vitae 200 8 CHAPTER 1 General introduction and aims of the thesis 9 1 1 Introduction and aims of this thesis 10 CHAPTER 1 Motor neuron disorders (MNDs) form a heterogenous group of diseases, characterized by upper and/or lower motor neuron involvement with secondary Wallerian degeneration of motor axons.1 Depending on the level of motor neuron loss, MNDs present with specific types of muscle weakness. Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, where both – upper and lower motor neurons, are affected.2 Spe- cial care should be taken to differentiate MNDs from similar clinical characteristics of potentially treatable disorders, especially when suspecting ALS, dramatically influenc- ing life expectancy.3 Genetical background plays an important role in the pathogenesis of MNDs, being multifactorial and largely unclear.4,5 MNDs share pathogenic pathways and probably overlap with other neurodegenerative diseases6,7,8 and even immune-mediated disorders of the peripheral nervous system, such as multifocal motor neuropathy.9 In multifocal motor neuropathy (MMN) immune-mediated inflammation selectively affects motor fibers, which is clinically presented with slowly progressive, asymmetric distal limb weakness without sensory deficit.10,11 Electrophysiological hallmark of MMN is the presence of conduction block – failure of proper action potential generation and propagation.12,13 Conduction block was suggested to be caused by focal demyelination, altered resting membrane-potential, or dysfunction of Na+ channels at the node of Ran- vier, but the exact mechanism is unclear.14 MMN does not affect life expectancy and up to 90% of patients improve in muscle strength after immunoglobulin (Ig) therapy.15,16 Because of the presence of antibodies against GM1 gangliosides and positive response to Ig MMN is classified as the dysimmune disorder, overlapping with acute motor axonal neuropathy, a form of Guillain-Barré syndrome, although the primary target in MMN is debated.17,18 In animal models this was shown that anti-GM1 antibodies lead to com- plement associated disruption of the node of Ranvier complex.19 Multiple approaches have been used to broaden the knowledge on the pathogenesis of MNDs and MMN: neurophysiological, immunological, pathological, neuroimaging, ex- perimental model.20-29 Each of those has limitations, requiring a combination of methods and new techniques to be implemented to explore distinct levels of damaged structures. Threshold tracking technique is a non-invasive, neurophysiological testing, assessing axonal excitability at the site of stimulation.30,31 This technique provides information on resting membrane potential, sodium-potassium pump and ion currents sustained by voltage-gated ion channels, specifically distributed in the myelinated axon: transient and persistent Na+ channels, fast and slow K+ channels and hyperpolarization-activated cyclic nucleotide-gated channels (Figure 1).32 General introduction and aims of the thesis 11 Figure 1. Diagram of a myelinated axon 1 Figure 1 legend. Nat, transient Na+ current; Nap, persistent Na+ current; Ks, slow K+ current; Kf, fast K+ current; Ih, hyperpolarization-activated cation current; the Na+/K+ sodium-potassium pump; I, node of Ranvier; II, paranode; III, juxtaparanode; IV, standard internode. Excitability properties of the peripheral nerve have previously shown abnormalities both in MMN and ALS.33-37 In ALS few excitability abnormalities were demonstrated: (i) sodium-potassium pump hyperactivity, associated with greater fatigue; (ii) changes in persistent sodium conductance and potassium conductance, potentially contributing to axonal hyperexcitability and fasciculation, related to the functional decline and shorter survival.38-39 Difference in ion channel presentation of motor and sensory axons could be of relevance in selective motor involvement in MMN and phenomenon of cold paresis, characterized by the aggravation of symptoms in cold and specifically attributed to MMN.40-43 The node of Ranvier of motor axons expresses a high density of Na+ channels, which are essential for action potential generation and propagation. Damage to these channels by anti-GM1 antibodies would contribute to conduction block and axonal degeneration in MMN. Considering that specific ion channels contribute to the pathogenesis of the damaged axons in MMN and ALS, the work described in this thesis aims: (i) To highlight the phenomenon of conduction block in MMN from the perspective of physiological differences between motor and sensory excitability and by means of com- puter simulations (chapters 2 and 3). 12 CHAPTER 1 (ii) To explain pure motor involvement, assess sensory excitability of affected nerves and specify the biophysical abnormalities of motor axons in MMN (chapter 4). (iii) To determine the involvement of different types of motor axons in MMN (chapter 5). (iv) To validate excitability testing as a biomarker of hyperexcitability in ALS (chapter 6). (v) To assess effects of the medication on membrane properties in ALS and MMN (chapters 6 and 7). (vi) To implement more sophisticated techniques (a) for the assessment of sodium-potassium pump (chapter 8), (b) to reliably investigate ion channel function in single motor units (chapter 9) and (c) to specify the temperature requirements for a proper excitability testing (chapter 10). General introduction and aims of the thesis 13 REFERENCES 1 1. Desai NP, Olney RK, 2009. Neuromuscular diseases. In: Corey-Bloom, J., David, R.B. (Eds.), Clinical Adult Neurology. 3rd ed. Demos Medical Publishing, New York, pp. 307–333. 2. van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis. Lancet 2017;390:2084-2098. 3. Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med 2017;377:162-172. 4. van Rheenen W, Shatunov A, Dekker AM, et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat Genet. 2016 Sep;48(9):1043-8. 5. Millecamps S, Boillee S, Le Ber I, et al. Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS related genes. J. Med. Genet. 2012. 49, 258–263. 6. Van Damme P, Veldink JH, van Blitterswijk M, et al. Expanded ATXN2 CAG re- peat size in ALS identifies genetic overlap between ALS and SCA2. Neurology. 2011 Jun 14;76(24):2066-72. 7. Burrell JR, Halliday GM, Kril JJ, et al. The frontotemporal dementia-motor neuron disease continuum. Lancet. 2016; 388: 919-931. 8. McLaughlin RL, Schijven D, van Rheenen W, et

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