Repetitive transcranial magnetic stimulation for ALS_ A preliminary controlled study

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NeuroscienceLetters408(2006)135–140RepetitivetranscranialmagneticstimulationforALSApreliminarycontrolledstudy

VincenzoDiLazzaroa,∗,MicheleDileonea,FabioPilatoa,PaoloProficea,FedericoRanieria,GabriellaMusumecia,FrancescoAngeluccia,MarioSabatellia,PietroA.Tonalia,b

aInstituteofNeurology,Universit`aCattolica,L.goA.Gemelli8,00168Rome,Italy

bFondazioneDonCGnocchi,Roma,Italy

Received15June2006;receivedinrevisedform26August2006;accepted29August2006

AbstractRepetitivetranscranialmagneticstimulation(rTMS)ofbraincanmodulatecorticalneurotransmission,anovelparadigmofrepetitivestimulationtermedcontinuoustheta-burststimulation(cTBS)producesapronouncedandprolongedsuppressionofmotorcortexexcitability.TheaimofthispreliminarystudywastoinvestigatewhethercTBSofmotorcortexcouldhaveanybeneficialeffectinpatientswithamyotrophiclateralsclerosis(ALS).Weperformedadouble-blind,placebo-controlledtrial.TwentypatientswithdefiniteALSwererandomlyallocatedtoblindedactiveorplacebostimulation.Repetitivestimulationofthemotorcortexwasperformedforfiveconsecutivedayseverymonthforsixconsecutivemonths.TheprimaryoutcomewastherateofdeclineasevaluatedwiththeALSfunctionalratingscale.Thetreatmentwaswelltoleratedbythepatients.Fifteenpatients(sevenactiveandeightsham)completedthestudyandwereincludedinthe6-monthsanalysis.Bothactiveandshampatientsdeterioratedduringtreatment,however,activepatientsshowedamodestbutsignificantslowingofthedeteriorationrate.ThoughwecannotbesurewhethertheeffectsobservedcanbeattributedtocTBS,becauseoftherestrictednumberofpatientsstudied,furtherinvestigationonalargergroupofALSpatientsiswarranted.TheresultsofthepilotstudymightopenupanewtherapeuticperspectiveinALSbasedonneuromodulation.©2006ElsevierIrelandLtd.Allrightsreserved.

Keywords:Amyotrophiclateralsclerosis;Magneticstimulation;rTMS;Glutamate

Amyotrophiclateralsclerosis(ALS)isafataldiseasewithnocure.Glutamate-mediatedexcitotoxicityhasbeenproposedasapossiblecauseofcelldeathinALS[22].Glutamatergiccircuitsofthehumanmotorcortexcanbeactivatednon-invasivelyusingtranscranialmagneticstimulation(TMS)ofthebrain[8],andbecausetheexcitabilityofneuralcircuitsinthecerebralcortexisnotstatic,repetitivetranscranialmagneticstimulation(rTMS)canproducechangesinneurotransmissionthatoutlasttheperiodofstimulation[2,4,5,7,12,14,18,19,20,27].RepetitiveTMShasbeenalreadyevaluatedasatherapeu-tictoolinseveralneurologicalandpsychiatricdisorders,suchasParkinson’sdisease[17–24],chronicpainsyndromes[13],dystonia[25],epilepsy[26,28]anddepression[11](seeWasser-mannandLisanby2001forareview[30]).Arecentreview∗Correspondingauthorat:IstitutodiNeurologia,Universit`aCattolica,L.goA.Gemelli8,00168Rome,Italy.Tel.:+390630154435;fax:+390635501909.E-mailaddress:vdilazzaro@rm.unicatt.it(V.DiLazzaro).suggestedthatthebesteffectsoftherapeuticrTMSareseenwhenprotocolsthatdepressnetworkexcitabilityareusedtotreatdisorderscharacterisedbycorticalhyperexcitability[30].Inaproofofprinciplestudy,wefoundthatmotorcortexrTMS,atfrequenciesthatdecreasemotorcortexexcitability,causesaslightslowingintherateofdiseaseprogressioninALSpatients[9].Atendencytowardanincreaseintherateofdis-easeprogressionwasobservedinpatientstreatedwithrTMSatfrequenciesenhancingmotorcortexexcitability[9].IthasbeensuggestedthattheobservedeffectsmightberelatedtotherTMSinducedchangesincorticalexcitatoryneurotransmissionandthatanybeneficialeffectproducedbyrTMSprotocolsthatreducecorticalexcitabilitycouldberelatedtoadiminutionofglutamate-drivenexcitotoxicity[33].ApositiveeffectofmotorcortexstimulationinALShasalsobeensuggestedbyarecentpapershowingthatinvasivechronicmotorcortexstimulationthroughsubduralelectrodesseemstoreducetherateofprogres-sionofthedisease[23].Arecentstudydemonstratedthatexcitabilityofthemotorcortexcanbeeffectivelyreducedafterapplicationofanovel

0304-3940/$–seefrontmatter©2006ElsevierIrelandLtd.Allrightsreserved.doi:10.1016/j.neulet.2006.08.069136V.DiLazzaroetal./NeuroscienceLetters408(2006)135–140paradigmofrepetitivetranscranialmagneticstimulationtermedcontinuoustheta-burststimulation(cTBS)[5,12].PreliminaryclinicalobservationsinapatientwithhemichoreasuggestthatcTBSmightbeausefulapproachinthetreatmentofhyperkineticdisorderscausedbymotorcortexhyperexcitability[6].TheaimofthispreliminarystudywastoinvestigatewhethercyclesofcTBSofthemotorcortexcanhaveanybeneficialeffectinALS.TherationalefortryingcTBSinthisdisorderisbasedontheevidencethatitinducesalong-lastingdecreaseofmotorcortexexcitabilitythatcouldtheoreticallyantagonizeglutamateexcitoxicityinALSbyreducingtheresponseofcorticospinalcellstoglutamatergicexcitatoryinputs.Ontheotherhand,ithasbeenalsodemonstratedthatrTMSmaymodulateplasmalevelsofbrain-derivedneurotrophicfactor(BDNF)inhumans[1,31,32].TheBDNFisapotentsurvivalfactorformotoneu-ronsthathasbeenevaluatedasapotentialtherapyforALS.Aneuroprotectiveeffectofhigh-frequencyrTMSisalsosuggestedbyarecentstudyusinganexperimentalmodeloftransientbrainischaemiaingerbilsthatdemonstratedthatthedeliveryofrTMSathighfrequency2–5daysbeforecommoncarotidarteryocclu-sionhasaprotectiveeffectagainstdelayedneuronaldeathofhippocampalneurons[10].AlltheabovepreliminaryobservationssupportanevaluationoftheeffectsofcTBSinALSpatients.ThispreliminarystudywasapprovedbytheethicscommitteeoftheMedicalFacultyoftheCatholicUniversityinRomeandpatientsgavetheirinformedconsentbeforeparticipation.Eligi-blepatientshadadiagnosisofdefiniteALSaccordingtotheElEscorialrevisedcriteria[3]withclearclinicalupperandlowermotorneuronsigns,nomorethan24monthsofdiseaseduration.Asmallsampleofpatientswasstudiedbecauseourpreliminarystudy[9]suggeststhatameasurableeffectcouldbedetectedeveninverysmallsamples.Twentypatients(10menand10women;meanageyears61.2±10.7S.D.)withdefiniteALS[3]wereenrolledandwereallocatedtothetreatment:10activeand10shamstimulation.Patientswererandomlyallocatedbyoneoftheauthors(VD)notinvolvedinfollow-upevaluationsanddataanalysis.Stratifiedblockrandomisationwasperformedsuchthatthetwotreatmentgroupswereevenlybalancedfordis-easeseverity,asevaluatedwiththerevisedALSfunctionalratingscale(ALSFRS-R)[meanALSFRS-R38.3±7.5(S.D.)activeand37.93±7.9(S.D.)sham,P>0.05(unpairedt-test)],andduration[meanduration(months)15.3±8.2(S.D.)activeand14.8±8.9(S.D.)sham,P>0.05(unpairedt-test)].Thepatientsandtheneurologistsassessingtheoutcomeswereblindedtogroupassignment.Allpatientsweretakingriluzole.Patientswereevaluatedatthebeginningofthetreatmentandeverymonthuntiltheendofthestudyat6months.Ateachvisit,patientswereevaluatedusingtheALSFRS-Randmanualmuscletesting(MMT).MMTtestingwasperformedbymeansoftheMedicalResearchCouncil(MRC)Scale.ToobtainanestimateoftheoveralllimbmusclestrengthwecalculatedaMRCcompoundscorebyaddingtheMRCscoresofeightupperlimbmusclesandfivelowerlimbmusclesforeachsideanddividingthesumbythenumberofmusclestested(26muscles).Wetestedthefollowingmuscles:bicepsbrachii,deltoid,triceps