Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis: C9orf72 Repeats

Amyotrophiclateralsclerosis(ALS) isadevastatingdiseaseofthe motornervoussystem.Whilemost casesare sporadic, approximately5%to10%ofcasesare familial andresult frommutation in1ofmorethan25knownALS genes.Thesegenesspanasurprisingly broad range of molecular functions, including RNA metabolism, oxidative stress, axonal transport, autophagy, excitability, and immunity.Oneof thegreatmysteries in the field is thatmotorneurondiseaseresultsasaconvergentphenotypefrommutations in this diverse group of genes. Understanding this puzzle is likely keytooptimizingbothclinicaltrialsandpatienttreatmentbecause differentdrugsmayultimatelybenecessaryfortargetingspecific disease variants. Despitethemolecularheterogeneity, theclinicalmotorneuronphenotypesresultingfromthevariousgeneticmutationsand sporadic casesdifferonlymodestly. So toohasbeen thecaseon theneurophysiological level, inwhichBaeandcolleagues1have performedanimpressiveassemblyofstudiesshowingaxonaland cortical hyperexcitability in ALS. Lowermotor neuron studies useaspecializednerveconductionstudyprotocolcalled threshold tracking,whichwasdevelopedbyMogyoroset al.2Changes instimulus intensitynecessarytogeneratecompoundmotoractionpotentialsofapredeterminedamplitudearemonitoredduring the course of a recording, andprepulses and recovery cycle analysisareusedtomeasuredifferentcomponentsofaxonalexcitability.Cortical hyperexcitability inALShasbeen repeatedly demonstrated using transcranial magnetic stimulation (TMS), bothusing the traditional constant stimulus technique toelicit motor-evokedpotentials (MEPs)andbyadaptingthethresholdtracking approach to TMS. Inthis issueofJAMANeurology,Geevasingaandcolleagues3 extendedtheirobservationstoshowcorticalhyperexcitability in patients with familial ALS due to chromosome 9 open reading frame72(c9orf72)hexanucleotidegenerepeatexpansion,which is themost commongenetic causeofALSand is responsible for about5%ofapparentsporadicALSand40%offamilialALScases. The findings are quite similar to those in sporadic and superoxidedismutase(SOD1)genefamilialALS,with increasedexcitabilitymanifestedmost clearlyusingpaired testing. Short intracortical inhibitionreferstotheincreaseinMEPthreshold(ordecrease inMEPamplitude) resulting fromaconditioningprepulsea few millisecondsbefore a test pulse. In contrast, intracortical facilitationisthereductioninthreshold(orincreaseinMEPamplitude) whentheconditioningprepulseprecedesthetestpulsebyabout 15milliseconds.4The reduction in short intracortical inhibition and increase in intracortical facilitationare2of themostprominentTMSfindings inALS.Otherdisease featuressharedbyboth sporadicandc9orf72 familialALS includereducedrestingmotor threshold, increased MEP amplitude, decreased cortical silent periodduration, and increased centralmotor conduction time. Thecorticalandaxonalexcitabilitystudieshaveshownaremarkableconsistencyof findings inbothpatientswithsporadic ALSandpatientswithfamilialALSand,thus,raisequestionsabout how different molecular mechanisms converge to produce changes inneuronalexcitability inALSandwhether researchers can leverage the consistent neurophysiological hyperexcitabilityphenotypetoreveal informationandpotential targetsthatare broadlyrelevantacrossALSvariants.Theclinical resultssuggest anopportunitytoreexaminehyperexcitabilityusinganimalmodelsandmore-reductionistsystemstoaddressexcitabilitymechanisms.Suchworkcouldpotentially reveal specific ionchannels or cellular pathways that underlie the neurophysiological phenotype.Thecomplexityofdifferentneuronal andnonneuronal cellularsubtypesthatgiverisetoandmodulatethedifferentTMS and nerve conduction study measurements justify additional basic exploration.However, technical considerationshave limited theuseof theneurophysiological techniques inmice, both with regard to challenges inperforming tests aswell as artifacts owing to sedation in interpreting test results. In animalmodels of SOD1 ALS, most studies have supported increased motor neuronactivity5;however,others, includingastudyusinginvivo recordings of specificmotor neuron pools, have not.6 Inmotor neuronsmadefromALS-inducedpluripotent stemcells,hyperexcitability ispresentbut thendecreaseswith longcultureperiods, potentially because of worsening neuronal health and a depolarization-inducedblockofmotorneuronfiring.7-9 Invitro studies have identified roles of persistent sodium currents and delayed-rectifierpotassiumcurrents in increasingmotorneuron excitability in ALS. Futurework using specific channelmodifiers may help elucidate the channels, receptors, andmolecular scaffolding underlying clinical neurophysiological cortical and axonal hyperexcitability. Webelievethebulkoftheevidencesupportshyperexcitability as aprimaryprocess inALSasopposed toanadaptiveone.10 Thepresenceofsignsofhyperexcitability,suchasfasciculations, beforeotherclinicalsymptomsismoreconsistentwithaprimary roleforhyperexcitability.Similarly,thehyperexcitabilityobserved inbothprenatalSOD1motorneuronsandALSstemcell–derived motorneuronsofmultiplegeneticvariants, inwhichdecreasing excitability improvesmotorneuronsurvival andreducesendoplasmicreticulumstressinvitro,bothsupportaprimaryupstream Author Audio Interview at jamaneurology.com