title: Stimulation-induced ectopicity and propagation windows in model damaged axons.
abstract: Neural tissue injuries render voltage-gated Na+ channels (Nav) leaky, thereby altering excitability, disrupting propagation and causing neuropathic pain related ectopic activity. In both recombinant systems and native excitable membranes, membrane damage causes the kinetically-coupled activation and inactivation processes of Nav channels to undergo hyperpolarizing shifts. This damage-intensity dependent change, called coupled left-shift (CLS), yields a persistent or "subthreshold" Nav window conductance. Nodes of Ranvier simulations involving various degrees of mild CLS showed that, as the system's channel/pump fluxes attempt to re-establish ion homeostasis, the CLS elicits hyperexcitability, subthreshold oscillations and neuropathic type action potential (AP) bursts. CLS-induced intermittent propagation failure was studied in simulations of stimulated axons, but pump contributions were ignored, leaving open an important question: does mild-injury (small CLS values, pumps functioning well) render propagation-competent but still quiescent axons vulnerable to further impairments as the system attempts to cope with its normal excitatory inputs? We probe this incipient diffuse axonal injury scenario using a 10-node myelinated axon model. Fully restabilized nodes with mild damage can, we show, become ectopic signal generators ("ectopic nodes") because incoming APs stress Na+ / K+ gradients, thereby altering spike thresholds. Comparable changes could contribute to acquired sodium channelopathies as diverse as epileptic phenomena and to the neuropathic amplification of normally benign sensory inputs. Input spike patterns, we found, propagate with good fidelity through an ectopically firing site only when their frequencies exceed the ectopic frequency. This "propagation window" is a robust phenomenon, occurring despite Gaussian noise, large jitter and the presence of several consecutive ectopic nodes.
authors.affiliation: Département de physique, Cégep de l'Outaouais, 820 de la Gappe, Gatineau, Québec, J8T 7T7, Canada, mlachance@cegepoutaouais.qc.ca.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lachance
authors.forename: André
authors.initials: A
authors.lastname: Longtin
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Morris
authors.forename: Na
authors.initials: N
authors.lastname: Yu
authors.forename: Béla
authors.initials: B
authors.lastname: Joós
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000473:pathology*; D020833:Diffuse Axonal Injury / Q000503:physiopathology*; D006801:Humans; D008959:Models, Neurological; D009431:Neural Conduction / Q000502:physiology*; D011901:Ranvier's Nodes / Q000473:pathology
references.citation: Pain. 2000 Apr;85(3):503-521
references.pmid: 10781925
references.citation: J Neurotrauma. 2013 Mar 1;30(5):307-23
references.pmid: 23252624
references.citation: Nature. 2009 May 21;459(7245):379-85
references.pmid: 19458714
references.citation: Curr Opin Neurobiol. 2011 Dec;21(6):880-7
references.pmid: 22054924
references.citation: Phys Rev Lett. 1991 Jul 29;67(5):656-659
references.pmid: 10044954
references.citation: J Comput Neurosci. 2012 Oct;33(2):301-19
references.pmid: 22476614
references.citation: PLoS Comput Biol. 2012;8(9):e1002664
references.pmid: 23028273
references.citation: Front Pharmacol. 2012 Feb 23;3:19
references.pmid: 22375118
references.citation: J Neurophysiol. 2002 Apr;87(4):2009-17
references.pmid: 11929919
references.citation: Lancet Neurol. 2010 Aug;9(8):807-19
references.pmid: 20650402
references.citation: Am J Physiol Cell Physiol. 2009 Oct;297(4):C823-34
references.pmid: 19657055
references.citation: J Neurophysiol. 1996 Aug;76(2):1310-26
references.pmid: 8871238
references.citation: Joint Bone Spine. 2005 Oct;72(5):359-71
references.pmid: 16214069
references.citation: J Vis Exp. 2012 Apr 26;(62):
references.pmid: 22565594
references.citation: Front Comput Neurosci. 2012 Aug 13;6:58
references.pmid: 23060780
references.citation: Annu Rev Neurosci. 2009;32:1-32
references.pmid: 19400724
references.citation: J Neural Eng. 2011 Dec;8(6):065002
references.pmid: 22058273
references.citation: Pain. 2000 Feb;84(2-3):309-18
references.pmid: 10666536
references.citation: J Neurosci. 2001 Mar 15;21(6):1923-30
references.pmid: 11245677
references.citation: Neural Comput. 2013 Oct;25(10):2646-81
references.pmid: 23777525
references.citation: Eur Neuropsychopharmacol. 2012 Feb;22(2):81-91
references.pmid: 21672666
references.citation: Neurol Sci. 2006 May;27 Suppl 2:S179-82
references.pmid: 16688626
references.citation: Acta Pharmacol Sin. 2006 Dec;27(12):1537-46
references.pmid: 17112406
references.citation: J Clin Invest. 2009 May;119(5):1150-8
references.pmid: 19425168
references.citation: Brain Res. 1999 Apr 10;824(2):218-23
references.pmid: 10196451
references.citation: J Neurosci. 2007 Dec 19;27(51):14059-68
references.pmid: 18094245
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17555-60
references.pmid: 23045676
references.citation: J Neurophysiol. 2000 Feb;83(2):735-45
references.pmid: 10669489
references.citation: Brain. 2006 Sep;129(Pt 9):2436-46
references.pmid: 16835248
references.citation: Curr Opin Struct Biol. 2012 Aug;22(4):529-36
references.pmid: 22483432
references.citation: Neuron. 2013 Mar 6;77(5):899-914
references.pmid: 23473320
references.citation: J Neurosci. 2012 May 9;32(19):6682-7
references.pmid: 22573690
references.citation: J Physiol. 2003 Aug 1;550(Pt 3):921-6
references.pmid: 12824446
references.citation: Nat Rev Neurosci. 2007 Jun;8(6):451-65
references.pmid: 17514198
references.citation: J Neurosci. 2002 Feb 1;22(3):1187-98
references.pmid: 11826148
references.citation: Biochim Biophys Acta. 2013 Mar;1828(3):1102-11
references.pmid: 23246974
references.citation: ASN Neuro. 2013 Aug 07;5(3):209-19
references.pmid: 23834220
references.citation: Brain Res. 1993 Apr 30;610(1):62-8
references.pmid: 8518931
references.citation: Brain Res. 1987 Jul 7;415(1):122-36
references.pmid: 3620940
references.citation: J Neurosci. 2009 Oct 21;29(42):13242-54
references.pmid: 19846712
references.citation: Eur Biophys J. 1984;11(2):137-47
references.pmid: 6100544
references.citation: J Neurosci. 2011 Mar 30;31(13):5089-105
references.pmid: 21451046
references.citation: J Neurophysiol. 2000 Jul;84(1):495-512
references.pmid: 10899222
references.citation: J Neurophysiol. 2000 Jul;84(1):205-15
references.pmid: 10899197
references.citation: Acta Neurochir Suppl. 1996;66:81-6
references.pmid: 8780803
references.citation: Pain. 2000 Feb;84(2-3):253-61
references.pmid: 10666530
references.citation: Epilepsia. 2012 Dec;53 Suppl 7:26-33
references.pmid: 23153207
references.citation: J Physiol. 1952 Aug;117(4):500-44
references.pmid: 12991237
references.citation: Pain. 2011 Dec;152(12):2685-2689
references.pmid: 21889261
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2009 Jan;79(1 Pt 1):011904
references.pmid: 19257066
references.citation: J Neurophysiol. 1992 Sep;68(3):734-44
references.pmid: 1331353