channelsslowandfastK channelsand theactivityoftheNa K pump8Figure1 Withthedevelopmentoftherapidautomatictesting protocolknownas ID: 499068
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(persistentNa + channels,slowandfastK + channels)and theactivityoftheNa + /K + pump[8](Figure1). Withthedevelopmentoftherapidautomatictesting protocolknownas TROND (namesaftera3-daytrain- ingsymposiumheldin1999atTrondheim,Norway) andthethreshold-trackingsoftwareQTRAC(©Institute ofNeurology,QueenSquare,London,UK)thatrunsthe protocol,asetofaxonalexcitabilityindicesaregenerated, thatreflectthebiophysicalpropertiesandmembrane potentialoftheaxon[9](Figure2). Thesenon-invasivetechniquesallowtheassessmentof axonalmembranefunctioninvivoinaclinicalsetting, andprovideinsightintobothnormalnervefunctionand pathophysiologicalmechanismsindisease[10].Overthe years,nerveexcitabilitystudieshavebeenutilizedina diverserangeofconditionsincludingtoxic,metabolic, bothacquiredandinheriteddemyelinatingneuropathies, neurodegenerativedisorderssuchasamyotrophiclateral sclerosis,aswellasprovidinginsightintopathophysio- logicalchangesoccurringattheperipheralnervelevelin disordersofthecentralnervoussystemsuchasstroke, spinalcordinjuryandmultiplesclerosis[7,11-32].In morerecentyears,theuseofnerveexcitabilitystudies haveprovidedfurtherinsightsintothepathophysio- logicalmechanismsunderlyingcerebellardisordersthat includestrokeandfamilialcerebellarataxiassuchasepi- sodicataxiatypes1and2[33-35].Inaddition,thistech- niquemayhavediagnosticandtherapeuticimplications thatmayencompassabroaderrangeofneurodegenerative cerebellarataxiasinyearstocome. Theperipheralnerveexcitabilitychangesobservedin ischemicstrokeinvolvingthecerebellummaybeare- flectionofatransynapticplasticprocessoralterationsin activityofthelimb(s)thatresultfromtheresultantfunc- tionaldeficit[13,15].Downstreamperipheralnerveex- citabilitychangeshavebeenobservedinpost-stroke patientsinvolvingmotorpathwaysinthebrainthatmay reflectalterationsininwardrectifying(I H )andslowK + conductance,suggestingthattransynapticplasticityin peripheralmotoraxonsdevelopinresponsetoaremote lesioninthecentralnervoussystem[14,15],possibly reflectinganalterationordisturbanceinsupraspinalcir- cuitryandtherebyinputtospinalmotoneurons,conse- quentlyresultinginchangesintheiraxonalphysiology [11,36].Assuch,thebiophysicalchangespresentincere- bellarstrokepatientsmaybeaconsequenceofadown- streamtransynapticplasticprocessfollowingchangesin excitabilityreportedtooccurinbothmotorcorticesin cerebellarstroke[37].Additionally,theintricateconnec- tionsthatexistbetweenthedeepcerebellarnucleiand motoneuronsofthecervicalspinalcord,maymeanthat lesionsinvolvingthesedeepcerebellarstructuresmay ultimatelyaffectexcitabilityofdownstreamlowermotor neuronswithinthecircuitry[38-41]. Geneticneuronalchannelopathiescommonlymanifest withparoxysmalsymptomsthatmayvaryconsiderable betweenpatientsrenderingdiagnosisanoftenchallen- gingfeat.Inpatientswithepisodicataxiatype1(EA1), mutationsinKCNA1generesultinalterationsinfastK + channelfunction.Specifically,thegeneencodesforthe Figure1 Diagramofamyelinatedaxonillustratingionchannels,pumpsandexchangersresponsiblefordeterminingaxonalexcitability. TransientNa + channels(Na t )areclusteredathighdensityatthenodeofRanvier,withpersistentNa + channels(Na p )andslowK + channels(K s ) contributingtoexcitabilityandrestingmembranepotential.FastK + channels(K f )arelocatedathighestdensityatthejuxtaparanode,actingto limitre-excitationofthenodefollowinganactionpotential.Internodalconductancesincludevoltage-independent leak conductances(Lk)and hyperpolarization-activatedcationconductance(I H ).TheNa + K + pump(Na + /K + -ATPase)utilisesenergytomaintaintheelectrochemicalgradient necessaryforimpulseconductionbyremoving3Na + ionsforevery2K + ionspumpedintotheaxon.TheNa + Ca2 + exchangerexportsCa2 + ions andimportsNa + ,drivenbytheelectrochemicalNa + gradient.Paranodalmyelinterminalloopsaredepictedwithanchoringproteinstoformparanodal junctionsattheparanodalregion. HuynhandKiernan Cerebellum&Ataxias (2015) 2:4 Page2of5 subunitoftheK v 1.1channel.Withsuchchannelsalso presentatthejuxtaparanodalregionofperipheralaxons, aspecificpatternofnerveexcitabilityabnormalitiesin patientswithEA1havebeenobservedwhichdonotap- peartobedifferentamongstthedifferentmutations [34].Moreover,therearepatientswithEA1whopresent withapredominantlyperipheralphenotypebutwithtyp- icalEA1changesobservedinnerveexcitabilityparame- tersrenderingthisapotentialusefuldiagnostictoolin identifyingthosepatientswithanatypicalpresentation [33].Offurtherrelevance,thechangesinparametersin EA1differfromthoseseeninacquiredautoimmuneneu- romyotonia(Isaac ssyndrome)whichisachannelopathy affectingthesameK + channels,suggestingapathophysio- logicallydifferenteffectonthesechannelsalongtheaxon betweenthetwoconditions.Studiesonpatientswith episodicataxiatype2(EA2)havealsoshownaunique patternofnerveexcitabilityalterations.Mutationsof theCACNA1AgenethatencodestheCa v 2.1subunitof thevoltage-gatedCa 2+ channelsrepresentthegenetic defectunderlyingthisdisorder,andthechangesobserved inaxonalfunctionarepostulatedtohavebeenaresultof Ca 2+ channeldysfunctionwhichconsequentlyaffectthe functionofslowK + channels[35]. Studieshaveshownchangesinvoltage-gatedK+chan- nelkineticspresentinthecerebellumofmurinemodels withspinocerebellarataxiatype3(SCA3)thatprecede theonsetofPurkinjecellloss [42].Basedontheseprelimin- aryobservations,futurestudie sutilizingnerveexcitability inhumanpatientswiththespinocerebellarataxiamay Figure2 Plotsofexcitabilityparametersrecordedfromabductorpollicisbrevisinasinglesubjectobtainedfromautomatedprotocol. (A) Charge-durationrelationship,inwhichinter ceptonstimuluswidthaxisgivesstrength-dur ationtimeconstantandslopegivesrheobase. (B) Threshold electrotonusfor100mspolarizingcurrents,±40%ofthreshold.Responsestodepolarizingcurrentsstartabovethelineandthosetohyperpolarizin g currentsbelowtheline. (C) Recoverycyclefollowingsupramaximalstimulation. (D) Current-thresholdrelationship. HuynhandKiernan Cerebellum&Ataxias (2015) 2:4 Page3of5 allowforthedevelopmentofadiagnosticelectrophysio- logicalbiomarker. Takentogether,nerveexcitabilitystudiesmayprovide forasensitivetechniquethatcanbeappliedinaquick andnon-invasivemannertofacilitatethediagnosisofa rangeofacquiredautoimmuneorneurodegenerativeas wellasgeneticcerebellardisorders. Studiesofnerveexcitabilityinchemotherapy-induced neurotoxicityhaveprovidedi nsightintothep athophysio- logicalmechanismsinvolvedan denableearlyidentification ofneurotoxicitytherebyopti mizingtreatmentstrategies andimprovingpatientqualityoflifeincancerpatients[43]. Assessmentofmotorandsensorynervefunctioninmany chemotherapy-inducedneuropathiesusingconventional NCShasrevealedsignificantreductionsincompound sensoryactionpotential(CSAP)amplitudewhilst CMAPandconductionvelocitiesareoftenpreserved, consistentwithasensoryneuropathyoftheaxonaltype [20,44].Studiesofsensorynerveexcitabilityhavedemon- stratedadirecteffectofoxaliplatinonnerveexcitability, withchangesinsensoryaxonsimmediatelyfollowinginfu- sionsimilartothoseseenwiththeNa + channelblocker tetrodotoxin[19],suggestingpartialblockadeofaxonal Na + channels[9,20,22].Longitudinalassessmentofaxonal excitabilityhaveshownthatbe foreeachsuccessi veoxalipla- tintreatment,progressivechangesinnerveexcitabilitywith increasedcumulativedosingwereobserved[45].There weresignificantchangesinthresholdelectrotonusand recoverycycleindices.Importantly,progressivechanges insensorynerveexcitabilityacrosstreatmentcycles occurbeforereductionsinpeakCSAPamplitudearede- tected[46].Thissuggeststhatsuchchangesmaybeable toidentifyat-riskpatientspriortothedevelopmentof chronicneuropathy[47,48]. Indiabeticneuropathypatient,studiesofnerveexcit- abilityhavedemonstratedalterationsinthresholdelectrot- onusconsistentwithreductionsinNa + /K + pump function,thatsubsequentlyimprovedfollowingstrictgly- cemiccontrol[23,49].Otherstudieshavesuggested changesinonNa + channelfunctionwithalterationsinre- coverycycleparameters[50].Recentstudieshavealso shownmarkedimprovementinnerveexcitabilityparame- tersinpatientstreatedwithcontinuousinsulintherapycom- paredtootherregimens[51].Moreimportantly,changesin nerveexcitabilityprecededthedevelopmentofneuropathy indiabeticpatientsthusprovidingapromisingbiomarker fordetectingpreclinicalneuropathyinsuchpatients[52,53]. Furthermore,inthosepatient swithtypicalneuropathic symptomsthatmayreflectsmallfibreneuropathyand hencenormalresultsonconventionalnerveconduction studies,nerveexcitabilitytechniquesofferamoresensitive waytoestablishthepresenceofalterednervefunction underlyingthesesymptomsandprovidingapotentialbio- markertoaidthetreatmentofsymptomsinthesepatients. Excitabilitystudiesinpatien tswithchronickidneydisease andneuropathyhavedemonstratedsignificantchanges consistentwithaxonaldepolarizationdrivenbyhyperkale- miapriortodialysisthatnormalizedfollowingsuchrenal replacementtherapies[21,54].Suchtechniqueshavealso providedinsightintothedifferentialeffectsofvarious haemodialysisregimensonnervefunction[55],aswellas potentialneurotoxiceffectsofvariousimmunosuppressants followingrenaltransplant[56],allowingfortheappropriate selectionofmanagementstrategiesinvolvedinrenal replacement. Insummary,nerveexcitabilitytechniquesareapowerful andnovelnon-invasivemeansofdetectingalterationsin axonalbiophysicalpropertiesthatmaypotentiallyexpand thecurrentarmamentariumavailabletotheclinicalneuro- physiologist.Therecentdevelopmentofcommercially availablesoftwareandhardwarerepresentasteptoward implementingthesetechniquesasaclinicaldiagnostic tool.Thesemeasurementsarenotonlyimportant ininvestigatingthepathophysiologyofdisordersofthe peripheralandtoalesserdegreethecentralnervoussys- tems,theywillplayasignificantroleinchartingdisease progress,anddetectingsubclinicalalterationsinnerve functioninneuropathiesandduringtreatmentwithpo- tentiallyneurotoxicdrugs.Thisinturnwillaidinthe developmentofnoveltherapiesfordisordersofthener- voussystem. Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. Authors contributions WHprepared,draftedandeditedmanuscript.MKeditedthefinalmanuscript draft.Bothauthorsreadandapprovedthefinalmanuscript. 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HuynhandKiernan Cerebellum&Ataxias (2015) 2:4 Page5of5 EDITORIALOpenAccess Peripheralnerveaxonalexcitabilitystudies: expandingtheneurophysiologist sarmamentarium WilliamHuynh * andMatthewCKiernan Abstract Nerveexcitabilitystudieshaveemergedasarecentnovelnon -invasivetechniquethatofferscomplementaryinformation tothatprovidedbymoreconventionalnerveconductionstudies,thelatterwhichprovideonlylimitedindicesof peripheralnervefunction.Suchnove ltoolsallowfortheassessmentofperipheralaxonalbiophysicalproperties thatincludeionchannels,energy-dependentpumpsandmem branepotentialinhealthanddisease.Withimprovements intechniqueanddevelopmentofprotocols,atypicalstudycanbecompletedinashortperiodoftimeandrapid measurementofmultipleexcitabilityindicescanbeachievedthatprovideinsightintodifferentaspectsofperipheral nervefunction.Theadventofautomatedprotocolsfortheassessmentofnerveexcitabilityhaspromotedtheirusein previousstudiesinvestigatingdiseasepathophysiologysuchasinmetabolic,toxicanddemyelinatingneuropathies, nerveexcitabilitystudieshaveadditionallyprovidedinsightsintothepathophysiologicalmechanismsunderlyingcerebellar disordersthatincludestrokeandfamilialcerebellarataxiassuchasepisodicataxiatypes1and2.Moreover,thistechnique mayhavediagnosticandtherapeuticimplicationsthatmaye ncompassabroaderrangeofneu rodegenerativecerebellar ataxiasinyearstocome.Intheforeseeablefuture,thistech niquemayeventuallybeincorporatedintoclinicalpractice expandingthecurrentlyavailablearmamentariumtotheneurophysiologist. Keywords: Nerveexcitability,Cerebellarataxia,Cerebellardisorders Conventionalnerveconductionstudies(NCS)remainan importanttoolandinmanyrespects,anextensionofthe clinicalassessmentinpatientswithneurologicaldisor- ders,particularlythosepertainingtotheperipheralner- voussystem[1].However,suchtechniquesthatemploy supramaximalstimulitomeasureamplitudeandvelocity ofcompoundsensoryormotoractionpotentials,provide informationononlythenumberofconductingfibresand conductionvelocityofthefastest,andhenceonlylimited indicesofperipheralnervefunction. Inmorerecentyears,anoveltechniqueofaxonalexcit- abilityhasemergedandprovidecomplementaryinforma- introductionofthresholdmeasurementstostudyhuman motoraxonsin1970[3]anditsfirstapplicationinaclinical settingondiabeticpatients[4],thetechniquehasunder- gonemodificationsandrefinementovertheyearswiththe developmentofprotocolstoallowtherapidmeasurement ofmultiplenerveexcitabilit yparametersinashortspaceof timeandhenceincreasingthetechnique spracticalitywhen appliedinaclinicalenvironment[5]. Axonalexcitabilitytechniquesprovideinformationre- latedtoactivityofavarietyofionchannels,energy- dependentpumpsandionexchangeprocessesactivated duringimpulseconductioninperipheralaxons.While axonalmembranepotentialcannotbedirectlymeasured inintacthumanaxons,indirectevidencemaybeobtained throughassessmentofthechangesinaxonalexcitability measuredthroughalterationsincurrentrequiredtoelicit anactionpotentialofadefinedsize[6]. Threshold refers tothestimuluscurrentrequiredtoproduceapredeter- minedtargetcompoundmuscleactionpotential(CMAP) response(e.g.,40%ofmaximum)andcanbethatcanbe tracked ) duringdifferentmanoeuvers(e.g.,subthresholdcondi- tioning)tofollowchangesinnerveexcitability[7]. Measurementofthresholddependsonandthereforepro- videsanindirectmeasureofrestingmembranepotential. Furthermore,restingmembranepotentialisdetermined byacomplexnetworkofaxonalmembraneionchannels *Correspondence: w.huynh@neura.edu.au BrainandMindResearchInstitute,UniversityofSydney,Sydney,Australia ©2015HuynhandKiernan;licenseeBioMedCentral.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/4.0)whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycredited.TheCreativeCommonsPublicDomain Dedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle, unlessotherwisestated. HuynhandKiernan Cerebellum&Ataxias (2015) 2:4 DOI10.1186/s40673-015-0022-2