Whole Brain Emulation ­ -- State of the Art

Abstract

In the next decade, high performance computing is projected to reach exascale capacity (10 18 floating­point operations per second), a region deemed suitable for emulating one or more continuous­learning spiking neuron models of the human brain in real­time [Markram 2012]. Alternatively, specialized hardware may make an exascale computer system unnecessary. Our human brain contains 86 billion neurons, nearly as many glial cells, 100 trillion synapses and over 100 different chemical neurotransmitters [Herculano­Houzel 2009]. Adequate preservation of the human brain after death such that the potential information represented by all of those parts is not lost is difficult, though progress is being made on several fronts. Capturing the full human brain connectome, with all relevant connectome data of a given person, appears to be very difficult and may remain one of the greatest technological hurdles in the coming years. In 2012, Kenneth J. Hayworth emphasized a specific technique for SEM scanning of brain slices for whole brain emulation [Hayworth 2012]. Hayworth's paper is recommended as a complement to the present paper. Our survey has a more general approach to method and a broader scope. The earlier report on whole brain emulation by Sandberg and Bostrum [Sandberg 2008] recognized the potential importance of body and environment simulations.

Full text

WholeBrainEmulationStateoftheArt
©2015GaryFeierbachandRandalA.Koene

Abstract
Inthenextdecade,highperformancecomputingisprojectedtoreachexascalecapacity(10
18
floatingpointoperationspersecond),aregiondeemedsuitableforemulatingoneormore
continuouslearningspikingneuronmodelsofthehumanbraininrealtime[Markram2012].
Alternatively,specializedhardwaremaymakeanexascalecomputersystemunnecessary.Ourhuman
braincontains86billionneurons,nearlyasmanyglialcells,100trillionsynapsesandover100
differentchemicalneurotransmitters[HerculanoHouzel2009].Adequatepreservationofthehuman
brainafterdeathsuchthatthepotentialinformationrepresentedbyallofthosepartsisnotlostis
difficult,thoughprogressisbeingmadeonseveralfronts.Capturingthefullhumanbrainconnectome,
withallrelevantconnectomedataofagivenperson,appearstobeverydifficultandmayremainoneof
thegreatesttechnologicalhurdlesinthecomingyears.In2012,KennethJ.Hayworthemphasizeda
specifictechniqueforSEMscanningofbrainslicesforwholebrainemulation[Hayworth2012].
Hayworth'spaperisrecommendedasacomplementtothepresentpaper.Oursurveyhasamore
generalapproachtomethodandabroaderscope.Theearlierreportonwholebrainemulationby
SandbergandBostrum[Sandberg2008]recognizedthepotentialimportanceofbodyandenvironment
simulations.
Introduction
Recently,therehasbeenaflurryofnewsconcerningprogressinartificialintelligence(AI).Wesee
possiblesignsofintelligenceinSiri(Apple),Watson(IBM)andtheselfdrivingcar(Google).Atthe
sametime,newtoolsarebeingdevelopedtounderstandbiologicalneuronalnetworks.Here,we
examineprogresstowardsthetwogoalsof(1)acquiringthedatathatrepresentstheneuronalnetwork
ofaspecifichumanbrainand(2)recreatingthatneuronalnetworkinoperationalform,forexampleby
acomputeremulationwithmemories,emotionsandpersonalityintact.Effortsareunderwayinthe
UnitedStatesandintheEuropeanUniontotacklethehumanbrainatthelevelofphysiologyand
neuronalcircuits[EFPL2014,NIH2013,NIH2014].Thebyproductsoftheseefforts,braintissue
preservationandpreparation,neuronandglialcellbehaviorandneuralnetworkunderstandingand
modeling,havedirectbearingonwholebrainemulation.
Thefundamentalsforwholebrainemulationthroughsystemidentificationinneuronaltissuewere
laidoutinpriorwork[Koene2012a],andaroadmapoftechnologicalrequirementswaspostulated
[Koene2012b,Deca2014].Thepresentpaperisconstrainedtoareviewofthestateoftheart,andwe
refertothosepriorpublicationsfordetailsaboutthestructuredapproachforwhichthetechnologies
reviewedbelowareneeded.
Technologyfortissuepreservation,preparation,circuittracingandemulationatthescaleofa
humanbrainarealsodiscussed.Asuccessfulemulationwillneedtobeembodiedwithinputandoutput
ineitheravirtualorphysicalmanner.
Toconstrainthisconcretestudy,wedonotaddressmatterssuchasunderstandinghow
consciousnessworks,definitionsorintuitivenotionsofpersonalidentity,dualistphilosophies(e.g.
'souls'),legalconsiderations,moralconsiderationsoranyothermetaphysicalpoints.Thesemaybe
importantissues,butarewellbeyondthescopeofthistechnologicalsurvey.



InvivoBrainScanning

A.MagneticResonanceImaging(MRI)
Theidealistoobtainahighresolutionscanofthecompleteconnectomeinvivoandwithoutharm.
Toadegree,theHumanConnectomeProject[HCP2012]takesthatapproach,usingahighlymodified
3and7TeslaMRIwithcustomizedheadcoils[Ugurbil2013].Thisyieldsa1.25mmvoxelresolution
andcanidentifyonlylargebundlesofnervefiber(whitematter).Acube1.25mmoneachsidecan
contain170,000neuronsandmillionsofsynapses.MRIresolutionwouldhavetoincreasebyfiveor
moreordersofmagnitudetoseeallofthesedetails(leavingasideotherconstraintsaboutthethings
MRIcanorcannotdetect).Thisresolutionhasbeenusefultolearnabouthowvariousbrainsubsystems
areconnectedandhashelpedresearchersidentifyfunctionalunitsandtosomeextentthepurposeof
thoseunits.9.4TMRImachinesarenowavailableandawholebody11.7Tmachineisexpected
[Wada2010].The11.7Tmachinesareexpectedtoresolve100μmvoxels. 
ResolutionofcurrentMRIimaginghasbeenimprovedbyalmostanorderofmagnitudeby
applyingdiffusiontechniques[Hagmann2007,CohenAdad2012]andfurtherimprovementmaybe
possiblewithbetterMRIdetectionandprocessingalgorithms.AheadonlyMRImachinemight
achievehigherresolutionat25T.MRImachinesfornonhumanuseareavailableupto17T[Wada
2010].InvivoMRIscanshavetodealwithseveraldifficulties[Passingham2013].(1)Movement:
Clampingapersonsheadmayrestrictoverallheadmotiontoamillimeterorlessbutrespirationand
bloodpressurechangescanalsomoveneuronssignificantfractionsofamillimeter,makingitdifficult
toincreaseresolution.(2)Theneedformorepowerfulmagnets:Toreachtherequiredresolution(~40
nm)[Marblestone2013],themagnetswouldrequiretechnologybeyondanythingwecanconceiveof
today.Theeffectsofultrastrongmagneticfieldsonhumanneuronalsystemsareunknown.Magnets
usedincurrentMRIsystemsareneverturnedoffandcaninducesmallcurrentsinneuralcircuitsasa
personisloadedintothemachine.PeoplehavereportedvertigoinandaroundMRImachines,
indicatingpossibleinterferencewiththevestibularsystem.Strongermagnetswillinducestronger
currentsduringmovementwithinthefield,leadingtoincreasedsafetyconcerns.Thehumanbody
consistsof65%water,adiamagnetic.Water’sdiamagneticpropertiesallowpowerfulmagnetsto
levitatesmallmammals.

B.MagneticResonanceSpectroscopy(MRS)
MRImachinesat3TandabovecanapplyMagneticResonanceSpectroscopy(MRS)toidentify
neuraltransmitterssuchasgammaaminobutyricacid(GABA),Nacetylaspartatylglutamate(NAAG),
Acetylcholine(Acl),myoinositol,andglutamate/glutamine(Glu)fromsmallmoleculenuclear
resonance[Foerster2013].AsinMRI,thesetechniquesaremanyordersofmagnituderemovedfrom
theresolutionthatisneededfordetailedneuronalcircuittracing,butareusefulfortracinglong
myelinatednervebundlesfromonepartofthebraintoanother.

C.UltrasoundImaging
XiangZhangatLawrenceBerkeleyLabisexperimentingwith10GHzultrasoundimaging,
currentlyusedon2Dmaterialsat1,000timestheresolutionoftypicalultrasoundimaging.Ultrasound
maybecomecompetitivewithMRIforfineneuralstructure.


D.CarbonNanotubeDetectors
JunichiroKonoofRiceandFrançoisLéonardofSandiaNationalLaboratoriesdemonstrate
promisingresultsusingcarbonnanotubeterahertzdetectorsthatmayreplaceMRIformedicalimaging
athigherresolution[He2014].Thetechniqueisalsoaffectedbysmallheadmotionsandchangesin
bloodpressure.Theseeffectsmaybemitigatedbyanesthetizingthesubjectandscanningbetween
carotidpulses.

Someproposalsenvisionusinggeneticallyengineered/modifiedvirusesthatcouldfollowneural
pathwaysandrecordthepathbyextendingDNAwitha‘barcode’,usingsetsofbasepairsforthebars,
tobedecodeduponcollection[Zador2014,Kramer2013,Callaway2008].Atechnologycurrently
usedonsomesmallanimalsistheuseoflightemittingtracers,florescentlabelsandquantumdots
addedtotagneurotransmittersandstructures.Inthiscase,boneandintermediatetissuewithpoorlight
transmittancehastoberemoved.Othertechnologies,suchasfunctionalmagneticresonanceimaging
(fMRI),diffuseopticaltomography(DOT),magnetoencephalography(MEG),singlephotonemission
computerizedtomography(SPECT)andpositronemissiontomography(PET)canbeusedtocorrelate
regionsofthehumanbrainwithparticularmentaltasks,butataresolutionseveralordersofmagnitude
belowthatrequiredfordetailedneuronalcircuittracing.Anewtechnique,usingahighlymodified
longtippedhighspeedatomicforcemicroscope(LTHSAFM),allowsonetowatchthemorphology
ofliveneuralcellschangeundervariousstimuli[Shibata2015].

PostmortemBrainPreservation
Theproblemwithwaitingfordeath,beforecapturingthatperson’sconnectome,isirreversible
braindamagemayhaveoccurredbefore(e.g.Alzheimer'sdisease,stroke)andafterdeath(e.g.
ischemicdamage),orinthebrainpreservationprocess(e.g.icecrystalformation).Ifbraindamagedue
toconditionssuchasAlzheimer'sdiseaseorstrokeoccursthenthereisagreatlyreducedpossibilityof
recreatingthatperson’spriorbrainconnectivity.
Thecurrentpreservationmethodofreplacingbloodwithanagentthatdoesnotformicecrystals
andpreservesbrainconformationhasbeenaccomplishedwithsmallbrains,butitstillfallsshortfor
brainsthesizeofahumanbrain.TheBrainPreservationFoundation(www.brainpreservation.org)has
offereda$100,000challengeforareliablebrainpreservationtechnique.Therearetwoserious
challengersplustwonewmethods,onedevelopedatStanfordUniversitythatreplacesthelipidswitha
hydrogelthathasmetwithsuccessonratbrainstheotherdevelopedatMIT[Chen2015]using
expansionmicroscopy(ExM).
Thefirsttechnique,usedattheMaxPlanckInstitutetopreservedawholemousebrainused
chemicalpreservationandplasticembedding[Mikula2012].Thesecondtechnique,usedby21
st
CenturyMedicine,usescryopreservationfreezingandreplacingbloodandwaterbasedfluidswithan
antifreezetypefluidcalledM22thatdoesn'texpandandformsharpcrystalsonfreezing[Fahy12004,
Fahy22004].ThethirdisStanfordUniversitydevelopedhydrogelmethodcalledCLARITYthat
createsatransparentblockofbraintissuewithlipidmembranesremovedthatiseasiertocircuittrace
[Cheng2013].Theforthandnewestadditionisexpansionmicroscopy[Chen2015]thatenlargesthe
specimenbysynthesizingaswellablepolymernetworkwithinthespecimengivinga4.5linear
expansionin3dimensionsproviding~70nmlateraland~200nmaxialresolutionusingaconfocal
spinningdiskmicroscope.


Therearedifferentgoalsforpreservinginternalorgans.Preservationdowntothemolecularlevelis
necessaryfororgansthataretobetransplanted.Generallycryopreservationhasbeenthemethod
chosenforreanimationofbiologictissueandsomesuccesseswithsmallanimalsandorgansincluding
fishandflyembryos.MorerecentlyFahy[Fahy22004]hashadsuccesswithlowtemperature
vitrificationfollowedbycontrolledthawingandtransplantingofarabbit'skidney.
Inthelastdecade,considerableprogresshasbeenmadeinpreservingthehumanbrainafterdeath,
butthehopeofbringingabrainbacktolifelooksremote.Currently,perfusingthehumanbrainwith
cryopreservationagentsdoessignificantdamageatthemolecularlevel.However,thismaynotmatter
forbrainconnectometracinganddownloading.ForthepurposesofSEM,Clarityorexpansion
microscopyaldehydestabilizedcryopreservation,accordingtoMcIntyreandFahy[McIntyre2015],
enablesindefinitestorageofwholebrainswhilepreservingtheultrastructurewithminimaldistortion
andisscalabletoanysizedbrain.Ifneuralwallstructuresareintactsothatdendrites,neuralcelltypes,
somaconfigurationandaxonscanbetracedalongwiththesynapticjunctionsthenonecanreconstruct
anetwork.Additionally,ifassociatedinformationsuchasneurotransmittertypeandsynapticstrength
areidentified,thenitmaybepossibletoestablishthekeyinformationthatcouldbeusedtoreconstitute
thatperson'smemoryandpersonalitywhenneuroscienceisabletoreliablymapsuchdatatofunctional
representations.

UnderstandingBrainPhysiology
Itmaynotbenecessarytounderstandhowthewholebrainorevensubsectionsofthebrainworkin
ordertoemulateahumanbrain.However,itwillbenecessarytounderstandhowthebasicbuilding
blocks,thevariousneurontypesandmorphologies,workandhowtofunctionallysimulatethem.This
involvesidentifyingandunderstandingneurotransmitters,synapticjunctions,neuronsandtheir
connectivity,theinfluenceofglialcells,etc.Significantprogresshasbeenmadeintheseareasbutnew
detailsandcomplexitiesarebeingrevealedcontinuously.
StartingwithLapicque'sspikingmodelofaneuronin1907[Abbott1999],progresswashampered
bytheinabilitytoprobeneuralnetsofanycomplexitytoascertaintheiractualfunction.Thelasttwenty
yearshavebroughtaboutaremarkablechangeinourabilitytoprobeneurons,circuittraceneural
circuits,understandthefunctioningofalargearrayofneurotransmittersandlightuptheinner
workingsoftheinnermachineryoftheneuron.Methodsforprobingneuralactivityhaveimproved
fromglasspipettestoParyleneCcoatedselfentangledcarbonnanotubeswithtipstrimmedusinga
Ga+focusedionbeam[Yoon2013]forintraandextracellularrecording.Arraysofimplanted
electrodes(upto127)usedforsimultaneousrecordingofupto14brainareasinthemacaquemonkey
havebeendeveloped[Feingold2012]forpermanentimplant.CMOSsensorarraysforextracellular
recordingcannowrecord16Kpixelsataframerateof2kiloframespersecondwithapixelpitchof
7.8μmx7.8μm[Eversmann2003].Thishasbeenusedforimagingactivityinabrainslice.Membrane
currentsgeneratedbyneuronscanbemeasuredinintracellularspace[Nadasdy1998]andthesource
neuronscangenerallybeascertainedwithsomesignalprocessingifanarrayofsensorsareused.
RomainBrette[Brette2009]bringsthespikebasedmodelnearlyuptodatewithcomputer
simulationsandnowwithimprovedtoolssuchasinvitroandinvivoexperiments,multichannel
monitoring,andcomputersimulationonecanshowthatinvivoneuronsappeartoexhibitashorter
timeconstant(afewmillisecondsorless)thaninvitroneurons(afewtensofmilliseconds)anda
neuron’soutputiscorrelatedtothetimingoftheinputpulses.Spikingneuronsaredifferentthanthe
perceptronstylelevelinput(thelevelthoughtofasafunctionofspikerepetitionrate)artificialneuron,

variantsofwhichhavebeenusedinmanyAIneuralnetworks.Computingtheforwardpropagationofa
perceptronnetworkismorethananorderofmagnitudesimplersinceonesetofcomputationscan
representaseriesofspikecomputations.Furthermore,spikingnetworksaresensitivetospike
correlationsontheirinputsindicatingthattheremaynotbeasimpletransformationbetweenspiking
modelsandnonspikingmodels.Ifonewantstoemulatehumanneuralnetworksanduseparameters
derivedfromhumanneuralnetworksthen,itseems,itissafesttousespikingmodelstoachievethe
sameresult.Althoughnotallpropertiesofbiologicalneuronsareimportantforneuralcomputation,
clearlymanyare[Ostojic2009],andtheremaybemanysubtletiesthatcontributetoreplicatinghuman
behavior. 
Weareatatimeofacceleratingdiscoveryandactivityinneuroscience,andcouldsaythatweare
onatrajectorythatresemblesMoore'sLaworBell'sLawphenomena.Recentdevelopmentsin
nanoscaleanalysistools[Alivisatos2013]andinthedesignandsynthesisofnanomaterialshave
generatedoptical,electrical,andchemicalmethodsthatcanreadilybeadaptedforuseinneuroscience.
TheultimateintentoftheBrainActivityMapping(BAM)[Alivisatos2013]projectistobeableto
monitortheactivityofeveryneuroninamousebrainsimultaneouslyat1mssampleresolution.Thisis
currentlybeingtackledwithimproved2Delectrodearrayswithoutcellpenetration,buttheneedfora
“spikesorting”algorithmthatcanhandlerecordingfromalargefractionofthecellsinapieceof
neuraltissueisstillaproblem.New3Dmicrofabricatedelectrodearraysmayovercomesomeofthe
problemsof2Darrays.Thesearrayscanstimulate,aswellasrecordfromneurons.Thisresearch
coupledwithoptical[Micheva2010]andothertechniques,includingneuralnetsimulations,isleading
toanunderstandingofindividualneuronbehavioratthemolecularlevel.Inaddition,thisshouldlead
toanunderstandingofvariousneuralsubsystems.Thisworkisthenverifiedbyneuralsimulation
[Dethier2011]thatshould,ultimately,manifestthesamebehaviorifthenetworkistracedcorrectly
andtheneuronsaremodeledandinitializedcorrectly.
Notallthisresearchisrelevanttowholebrainemulationbutit'stooearlytobesurewhatisand
whatisn't.Currentactiveresearchindicatesthatglia[Fields2013],astrocytesinparticular,
communicateandperformanactivebutnotthoroughlyunderstoodroleinnetworkactivationand
plasticity.

CapturingtheFullConnectomeofaBrain
Thereareseveralmeansforpreparingbraintissueforelectronmicroscopesandsuperresolution
lightmicroscopes.Toidentifythoseparametersnecessaryforconnectomereconstructionand
behavioralsimulationitcurrentlyappearsthat40nmvoxelsarenecessary.Bothelectronmicroscopes
andsuperresolutionlightmicroscopesarecapableof40nmorlessvoxelresolution[Denk2012,
Briggman2012]andbothmaybenecessarytoidentifyeverythingthatisnecessaryfornotonlytracing
theconnectomebutcountingvesicles,identifyingtypesofneurotransmitters,enzymes,anddistribution
ofionchannels.Thetechnologiesinvolvedincludeserialsectionelectronmicroscopy,serialblockface
electronmicroscopyandsuperresolutionlightmicroscopy.
Serialsectionelectronmicroscopyhastwomainsubdivisions,transmissionelectronmicroscopy
(TEM)withsamplespreparedonTEMgrids,andsectionscollectedonsolidsupportforserialelectron
microscope(SEM)imaging.TEMadvantagesinclude:tissuesmaybestainedaftercutting,sectionscan
bereimagedandparallelimagingispossible.TEMhasthehighestlateralresolutionandthefastest
imagingrate.SEMcanuseautomatedsectioncollectionandlargesectionareaswithalowerlikelihood
ofsectionloss.Bothmethodsarecurrentlysubjecttosectionfolding,distortionandloss.Heavymetal
stainingisusedtooutlinemembranousstructures.

Serialblockfaceelectronmicroscopy(SBFSEM)hastwomaingroups,diamondknifecutting
SEMandfocusedionbeamablationFIBSEM[Knott2008,Marblestone2013].Theadvantagesareno
lossofsections,littledistortionandautomatedcuttingandimageacquisition.Thedisadvantageis
sectionsaredestroyedduringcuttingorablation.TheSBFSEMcurrentlyhasaproblemofsometimes
leavingresidueonthenewlycleavedsurface.TheFIBSEMhasthedisadvantageofbeinglimitedto
rectangularblocks12μmononesideduetothedepthoffocusoftheionablationbeam.
Superresolutionlightmicroscopesalsofallintotwogeneralcategories,stimulatedemission
depletionnanoscopy(STED)[Persson2011]andphotoactivationlocalizationmicroscopy(STORMor
PALM)[Huang2008].Also,twophotonexcitationmicroscopy(TPEM)[So2002]isofinterestsince
thesamplesufferslessphotodamagealthoughtheresolutionisn'tasgood.AdvantagesofSTEDand
STORMincludecolortodistinguishdifferentfluorophorestaggingfeaturesofinterestandtheability
togetresolutionsdownto2030nmlateralresolutionalthoughtheaxialresolutionis5060nm.
Disadvantagesincludethedifficultyofgettingasufficientlyhighfluorophoreconcentrationina
section,thesectionthicknessandmultipleimagesaregenerallyrequired.Theseopticalmethodsrival
electronmicroscopyandinsomecasescanbeusedonlivebiologicalsystems.
Automatedtapecollectedlatheultramicrotomy(ATLUM)[Hayworth2012]slicesablockoftissue
intosectionsdownto25nmthick.Largelateralsectionscanbeachievedof2.5x6mm.Thetissue
blockcanbepretreatedwithfluorophoreandmetallicstainingenablinguseofbothopticalandSEM
imaging.Zeiss[ZEISS2013]isdevelopingmultibeamSEMs(mSEM)andwillhavea61beamunit
commerciallyavailablein2015.Thiswillgivea10xprocessingspeedimprovement.Usingassembly
lineprocessingATLUM>STORM>mSEM>imageprocessingwithmultipleassemblylinesit
appearsconceivablethatahumanbraincanbeprocessedinthismannerinareasonabletimeframeof
perhaps3yearswith100processinglinesandexascaledataprocessingandstoragefacilities.This
assumesa50x50x50nmvoxelandonegigavoxelpersecondthroughputperlinecreatingadatabaseof
10petavoxels.
Hayworth[Hayworth2012]hasevaluatedseveralcurrenttechnologieswiththeviewtoward
automatingvariousformsoftissuepreparationanduseofscanningelectronmicroscopes.Hesuggested
thattheplasticembeddedbrainbesubdividedinto3x180mmstrip20μmthick.Thisprocedurewould
create250,000tissuestrips.Thesearethenprocessedinto20x20μm,180mmlongtissuepillars.so
thattheycanbeparceledouttomultipleFIBSEMmachines.Inthiscase,losttissuebetweencylinders,
layeralignmentbetweencylindersanddistortionduetothecuttingprocessmaybeproblems.In
additiontheFIBprocessdestroystissuesoitisoneshot.Itisnotknownwhetherthiscanbecombined
withopticaltechniquesforidentifyingotherkeyelementsoftheconnectomesothatitcanbesimulated
withbehaviorintact.
Kreshuketal.[Kreshuk2013]usedatransmissionelectronmicroscopecameraarray(TEMCA)to
getfasterthroughputwhileusing40x40x40nmvoxels.Theyachievedreasonableresultsonadesktop
(12core3.2GHzXeonES1630CPU)usingrandomforestpatternrecognitionin3Dforsynapse
identification,butitstillfellshortofexperthumanidentificationofconnectomeinformation.
Automatedserialtwophoton(STP)tomography[Ragan2012]hasbeenusedsuccessfullyonwhole
mousebrains.ItisablockfacesetuponanXYZstage,laserscanningandwithabuiltin
vibratingblademicrotome.ThestageelevatesintheZdirectionin50μmstepsforblockfaceslicing
andapiezoelectricallycontrolledobjectiveallowsvoxelsZdimensionsassmallas2.5μm.Awhole
mousebraincanbeimagedbymovingthestageintheXandYdirectiongetting260overlapping
coronalsections.At0.5x0.5μmXYresolutionand2.5μminZ,thewholemousebraincanbe
automaticallyimagedwithin7days.Thiscanbecomplicatedwhenusingmultiplefluorophores.
Further,thedesiredresolution,40nmforcompleteconnectomeinformationanddeterminingsynaptic

strength(e.g.imagingsynapticvesicles)forsimulation,maynotbeattainable.
Anotherwaytocapturetheconnectomeisusingthepseudorabiesvirus(PRV)whichisknownto
travelneuralpathways[Callaway2008,Kramer2013].Othervirusesarealsoknowntospreadinthis
fashionbuttheBarthstrainofPRVspreadsslowerwithreducedcytopathiceffectsanddoesnotaffect
humansorotherprimates.EvidencesuggeststhatPRVmaybeexclusivelytranssynapticmakingit
idealforthispurpose.
Largescaleexperimentsneedtobeconductedtodeterminewhichofthesetechniquesarecapable
ofhighlyparalleloperation,highreliability,automatedimaging/processing,canacquiresynaptictype
(neurotransmitters)andstrengthinformation(synapticvesiclesandreceptordistributions),andcan
makenewconnections(dendriticspines[Bonhoeffer2002]).

PatternRecognitionandCapturingtheConnectome+
Accuratesimulationofthehumanconnectomeinvolvednotjustthemorphologicalneuralmapof
our85billionneuronsbutshouldincludealltheinformationrelatedtotheirtypeandlocality,their
associatedglialcells,synaptictypesandstrengthsandwhateverotherinformationmaybefound
necessaryinthefutureforafullbehavioralsimulation.Thiswillbecalledtheconnectome+.
Currentlymuchconnectomepatternrecognitionattheneuralleveliseitherperformedbycomputer
aidedhumans,byusingpatternrecognitionsoftwareorlabelingneuronswithfluorescentproteins
(Brainbow)[Livet2007].Acrowdsourcedhumanrecognitionofneuralmorphologyusingatoolcalled
EyeWire[Eyewire2014]iscurrentlybeingusedtocreateatrainingdatabaseforwhatwillbecome
fullyautomatedsoftware[Turaga2014,Lang2011].Evenifhumanscouldrecognizeaneuronora
synapticjunctioneveryseconditwouldtakemorethan10billionpersonhourstocompileahuman
connectomeinthismanner.Clearly,thisprocessmustbecomeentirelyautomatedandextremelyfast.
Earliereffortsatneuralcircuittracingfromconfocalimagesusedthefilamenttracersoftwareof
Imaris(Bitplane,Zurich)[Schmitt2004,Evers2005]totracethecenterlineofneuron'snetcomplete
soma,axonanddendrites.AccuracywasimprovedbySchmittetal.byfittingcenterlinesandradiito
thecorrespondingimageofeachsection,constructingaskeletonoftheneuron.Thesurfacewas
createdusingcylindricalsectionsusingtheradiiassociatedwitheachsection.Theprocedurestill
requiredmanualinterventiontocorrecterrorsinbuildingtheskeleton.
Currentpatternrecognitionsoftwareusesanumberoftechniquesthathaverecentlyemergedas
powerfulpatternrecognitionprocedures.Theseincludeconvolutionnets(CN)[Turaga2014],random
forest(RF)[Andres2014],Markovrandomfields(MRF),NeuralNetworks(NN)andanumberof
otherstatisticalandadhoctechniques.Thefirsttaskistopartitionasectionbyconnectingrelated
pixels.Thisiscalledanaffinitygraph.BothTuragaetal.usingCNsandAndres,etal.usingRF
achievedsimilarresultscomparabletohumansandasizableimprovementovertheothertechniques,
butthatstilllefteighttotenpercentofthevoxelsindisagreementwiththehumananalysisofthetest
set.Thisresultisbetterthanonemightexpectbecauseitisjusttheclassificationofindividualvoxels
andnottheoverallpicture.Iftheseareedgevoxelsbetweentwodifferentneurons,thiscouldleadtoa
mergingofthetwoneuronsorapartitioningofonegivingafalseresult.Weareledtotheconclusion
thatmorethanlocalknowledgemightbenecessarytoarriveatanaccurateresult.Forexample,finding
thatanetworkhasmorethanonecellnucleuswouldindicatethatthesenetworkswereincorrectly
combined.Voxelsthatwereweaklyclassifiedasnonboundaryvoxelsthatcouldseparatethenetworks
wouldthenbesuspect.EvenifoneascertainsthefullhumanCNSwithnear100percentaccuracythere
isstilltheproblemoftheadditionalinformationtomaketheemulationofahumanneuralnetfunction
suchassynapsetypesandconnectionstrength.

SEMsarepowerfultoolsbuttheyprovideverylimitedinformationineachvoxel,sevenbitsof
intensitylevel.Oneoftenneedopticalmethodsusingfluorescenttagstoprovideinformationon
neurotransmitters,vesicles,neuraltypes,etc.thatcanbecorrelatedwithEMsections.Tapedsections
thatcanbefeedthroughbothatwophotonmicroscopeandanSEMappearstobetheonlywaytodo
this.Thisdoesn'tnecessarilyruleouttheuseofFIBSEMsandSBFSEMsiftheelectronbeamand
photonbeamcansharethesamemountedsample.Theproblemisboththeelectrongunandthe
microscopeobjectivelenshavetobequiteclosetothesection.Apossiblesolutionistorotatethe
sampleholderbetweentwostops.Gravitationaldistortionshouldbeminimalforcylindricalsamplesof
afewmillimeterssquare.
Opticalmethodscanbeusedtotraceneuralfibersinmyelinsheathsusingpolarizedlightimaging
(PLI)[Palm2010].Thepolarizedlight,duetothebirefringenceofthemyelinsheathsofthenerve
fibersrevealsathirddimensionforplacingthefibersina3Dspace.ChristophPalm,etal.wasableto
usethistotracenervefibers1μmto20μmindiameterbundles.
Anoveltechniqueistophysicallyexpandthesampleasmuchas4.5foldlinearexpansionusinga
polyelectrolytegel[Chen2015]todosuperresolutionmicroscopybyincreasingthespeedofvoxel
captureusingdiffractionlimitedmicroscopesinstead.Onecanalsoincreasethepossibleresolutionof
superresolutionmicroscopyusingthismethod. 
Thereisthepossibilitythatoneoracombinationoftechniqueswillbeabletorisetotheoccasion
sincemostofthesuperresolutionopticaltechniquesareveryrecentdevelopments.Onewouldexpecta
combinationoftechniquesusingsuperdefinitionopticalmicroscopywillhavethecapabilitytocircuit
traceandimagealltheparametersnecessaryforneuralemulationintenyearssinceanorderof
magnitudeofopticalresolutionhasbeenattainableinthelastdecadeandmajorimprovementsarestill
possible.
Indetailedstudiesofsmallsectionsofthehumanbrain(e.g.cerebralcortex)weknowweare
dealingwithrepeatingpatternsofneuralconnections.Thereareloadsofexceptionstotherepeating
patternsbutthegeneralstructureinagivenareacanbearoughguidecombinedwithotherinformation
forbothdecidingwhetheragivensynapseshouldbeinhibitoryorexcitatoryandthetypeof
neurotransmittersinvolved.
Dependingontheresourcesmadeavailablethetimeframeforthefirsthumanbraintobefaithfully
capturedcouldrangefromacoupleofdecadestomanydependingonwhetheritbecomesanational
priority.Duetotheincrediblecomplexityofthehumanbrainonemustassumetherewillbeseveral
yearsoffailuresbutthesefailuresshouldteachusagreatdeal.Success,withinthistimeframe,
dependsonwhethertheinformationnecessaryforemulationisknownorobtainableusingreasonable
extensionsofcurrenttechnology.Furthermore,itdependsonexceedinglyaccurateconnectome+
captureandemulationbecausesmallerrorsincriticalplacesmaycausepoorresults.

BrainEmulation 
In2008Koggeetal.[Kogge2008]laidouttherequirementsandproblemstobuildanexascale
computersystem.ThisbecameapriorityfortheUSgovernmentforavarietyofapplicationsranging
fromparticlesimulationsofstarformationtoquantumchemistry[Hopkins2011].Inanotherdecade
weshouldhavesupercomputersthatwillprocessexaflops(10
18
floatingpointoperationseachsecond).
TheplansofIntelandAMD[Intel2012,AMD2014,Tirias2014]targetprocessorsinthe2020time
framethatwillhave25timestheenergyefficiencyofcurrentprocessors.Energyefficiencyisakey
factorsinceIntel[Sodani2011]statedthatthethencurrent(2011)supercomputersystemsinthe10
petaflops/secondrangeburn12megawattsofpower.Theyseeanexaflopmachinein2020usingnot

morethan20megawatts(thehumanbrain,bycomparison,consumesbetween2540watts).In2013
KoggeandShalf[Kogge2013]pointedoutthatanotherchallengeforexascalesystemsisdatalocality.
Shufflingdataathighspeedandlowlatencybetweenprocessorsonchip,betweenchipsandbetween
circuitboardswillbecomemoreimportantthatjusttherawprocessingpower.Theyalsopointedout
thatbuildingcompilersthatrearrangedataandprocessingpowertoachievemoredatalocalitywill
becomevitalassystemsscalewithanordersofmagnitudemoreprocessorcores.Theexafloptargetis
importantsincesuchmachineswillbeabletoemulateone[Markram2012]ormorehumanbrains
usingspikingneuralmodelsinrealtimeandaverysophisticatedvirtualworldaswell.Thiswill
probablyhappenusingthesamesiliconbasedCMOS(ComplementaryMetalOxideSemiconductor)
processorpathwe'vefollowedsincetheRCA1802(COSMAC)microprocessorin1976.
Transistorcircuitshavebeenmadewithcarbonnanotubes[Bachtold2001,Sun2011]],graphene
[Liu2013]andMoS
2
[Mak2013]thatmaybecapableofverylowpowerandhighperformance.These
technologiesmaybetenyearsoutbeforereachingusefullevelsofintegrationandspeedorenduplike
siliconcarbide,diamond,galliumarsenideandgermaniumwithlimitedapplicationspaces.
Inthelastdecade,therehasbeenmanynewdevicesthatmayhavearoleinfuturebrainemulators
includingthememrister(HP),ReRAM(UniversityCollegeLondon),correlatedoxidediode(Harvard
University),32Gbittwistedradiobeams(UniversityofSouthernCalifornia),phasechangematerials
(PCMs)andmanygraphenestylenanomaterialsthathavememoryandswitchproperties.Verylow
powerismoreimportantthanspeedsinceitlimitsthepackingdensityandoperatingcostsofan
emulator.Connectivityanddevicesonchiphavemanyordersofmagnitudehigherreliabilitythanoff
chipconnectionsanddevices,sothemoredevicesonecanputonasubstratethebetterthechanceof
buildingareliablelargescalesystem.
Currentneuralsimulationmodels(theBrianprogram)[Goodman2008]usethebasic
Hodgkin–Huxleymodelwithasynchronoussystemclock.Thereis,infact,evidencethatspiking
correlationisusedforretinaandothertimevaryingsensoryinputfordatainterpretationandmaybea
fundamentalaspectoftheirutility.Therearemanycurrenteffortstomakeneuralnetworksimulations
thatarebiologicallyrealistic.PietroMazzonietal.[Mazzoni1990]showedthatspikingneuralmodels
couldlearnusingreinforcementratherthanthebiologicallyunrealisticbackpropagation.Asimple
modelofspikingneuronsthatreproducedtherichbehaviorofbiologicalcorticalneuronswas
demonstratedbyEugeneIzhikevich[Izhikevich2003].Thismodelreproducedspiking,bursting,
mixedmodefiringpatterns,postinhibitory(rebound)spikesandbursts,continuousspikingwith
frequencyadaption,spikethresholdvariability,bistabilityofrestingandspikingstates,and
subthresholdoscillationsandresonance.TchumatchenkoandClopath[Tchumatchenko2014]
demonstratedhowinhibitoryinterneuronsinthepresenceofasubthresholdresonanceselectively
amplifiesfiringrateresponsetoselectfrequenciesalreadypresentinisolatedneurons.Othermodels
andframeworksincludeGENESIS2.4,LFPy,MvaSpike,PyNN,NeuroML,NineML,SpineML
[Richmond2013].
It'snotclearthataspikingmodelwillbenecessaryforallneuralcircuitsbutcurrentlythereisno
clearcircuitandweightmappingformulafromspikingtononspikingtoachievethesameresultant
behavior.Thereis,infact,evidencethatspikingcorrelationisusedinmanyneuralcircuits[Goodman
2008].Currentnonspikingimplementationsofneuralnetsareapproximately100timesless
computationallyintensive.Othersimplificationmayalsobepossiblebyreplacingsomeneuralcircuits
withothermoreefficientcomputationalalgorithmsthatachievethesamefunctionality.
Muchcurrentemphasishasbeenonthehumanneocortexformachinelearningalgorithm
development[Numenta2011,Schmidhuber2013].Numenta'spurposeistodistilloutprinciplesfor
developingalgorithmsfromthewaythehumanneocortexseemstowork.Theirgoalisnottoreplicate

aparticularhumanneocortexbuttocreateacomputationalmodelforAIuse.Whattheyhaverealized
isthesparsedistributedrepresentationencodingandneuralnethierarchiesleadtowhattheyterm
HierarchicalTemporalMemory(HTM)fortheirclassofmodels.Thenextstepwastomakethebottom
layerneuralnetsrecurrent(RNN)orbidirectionalrecurrentneuralnets(BRNN)[Karpathy2014]since
thiscausedthelowerlevelstobecomemorestableandlongtermrecognizers.Thisclassofmodelshas
beenabreakthroughinAIandgivesusasimplifiedunderstandingofwhatgoesonintheneocortexbut
itisnotcurrentlypurposedforconvertinganactualhumanneuralnetwithassociatedsynapticweights
foremulation.
Anotherapproachistomakehardwarethatisarchitecturallydesignedtoemulateneuralnetworks.
ThishasbeenaccomplishedatIBM[Merolla2014,Cassidy2014]witha5.4billiontransistorchip
(TrueNorth)thatemulates4096neurosynapticcores.Ithandles1millionspikingneuronsand256
millionconfigurablesynapses.Thesechipscanbetiledin2dimensionsanduseonly65milliwattsor3
ordersofmagnitudelesspowerthanusingstateoftheartgeneralpurposemicroprocessors.Thisisa
verysignificantsteptowardadedicatedneuralemulatorandmaybeabetterfitthanageneralpurpose
supercomputer.However,itmaybesomewhatlessversatilewhenotheralgorithmsareavailableto
replacesomebrainparts.Anotherproblemisthischipismodeledonacorticalcolumnofamacaque
cerebralcortex.Ahumanequivalentcorticalcolumnismorecomplexbutshouldbereachablesince
thischipwasimplementedin28nmCMOSandthecurrentstateoftheart(Intel)is14nmCMOS.
TherearestillsomeproblemareassincePurkinjecellscanbranchouttoadendriticarborof200,000
fibersandapyramidalcellreceives30,000excitatoryinputsand1700inhibitoryinputs.Thereisstill
theproblemofhowglialcellsmodulateneuralactivity.Thisapproachhaspromisebutmayrequirea
piggybackmemoryandconnectionchiptoemulatetheselargerhumancellsandtheirconnectivity.To
reduceexternalchipconnectionsonereallyneedanentirehumancorticalstack(hypercorticalcolumn)
emulatedononechip.Itmaytakeastackofpiggybackchipsormoreactivesiliconlayerstodothat.
GeneralVisionhasacommerciallyavailablechipandboardsetsfeaturingoneormoreoftheir
CM1Kchipsthatcontain1024‘neurons’.Ratherthanaspikingneuronmodelthischipusesnumerical
valuesforinputsmakingitusefulforAIapplicationsbutprobablylessusefulforreplicatinghuman
neuralnetworks.
Otherspecializedneuralsimulationsystemsincludeamixedanalogdigitalmultichipsystem
(Neurogrid)[Benjamin2014],theUniversityofManchesterprojectSpiNNaker,theIBMSyNAPSE
project(GoldenGateChip),andtheHeidelbergUniversityBrainScaleproject(HICANNchip).Of
these,theNeurogridusestheleastchipareaandtheleastpowerandisonaparwithTrueNorthabove.
Currentlyitmakessensetomakesurethatthevarioustypesofhumanhypercorticalcolumns,and
otherlowerbrainsystemsoperatethesameinageneralpurposesupercomputersasinvivo.The
flexibilityofgeneralpurposecomputersisneededtomakesurethateverythingnecessaryforafaithful
simulationcanbeincludedthenspecialpurposesystemscanbedevelopedtoreplicatethosesimulated
features.Unfortunately,mostAIemphasisisjustonthecerebralcortexandthehypercorticalcolumns
ortheirmammaliancorticalcolumnancestors.Forthepurposesofbrainemulationtheentirehuman
brainisimportant,notjustthecerebralcortex.

VirtualEmbodiment
Initially,emulatedindividualsmayliveinasimulatedenvironmentinwhichtheycaninteractwith
eachotherandalsointeractwiththerealworldviatheInternet[Abrash2014].Evenwithtoday's
technology,suchanenvironmentwillbefarricherthanSecondLifebutwouldcurrentlyfallshortofa
realworldsensualexperience.Theresolutionofvariousvirtualworldsisincreasingatarapidratein

linewithcomputingpowerandisreachingthegeneralpublicintermsofinteractiveonlinegaming.
Sensoryandhapticbodysuits,omnidirectionaltreadmillsandsophisticatedheadgeararebeginningto
emergealongwithsupportingsoftware.Theemulatedhuman'sneuralinterfaceshouldbeabletotake
advantageofthesamevirtualinterfacethatrealhumanswouldbepluggedinto.
Realistic3Dvirtualreality(VR)worldsmaybecomewidespreadwiththeOculusRiftandother
VRviewersavailabletoconsumers.Theseviewerscanoffersufficientresolution,accuratetranslation
andlowpersistencetoavoidpreviousmotionsicknessproblemsforhumanviewers.Atfirst,
applicationswillbeprimarily3Dgamingbutlateritmaybeenvironmentswithhighlyevolvedcitiesin
virtualspacewithrealisticavatarsspeakingintheuser’svoiceoracopyoftheuser’svoice
synthesized.Thiswillbeaspaceformeetingpeopleprivatelyorpublicly,forshopping,recreationand
sightseeing.Eventuallyuserwillbeabletobecomeabirdorotheranimal,mythicalorrealinthis
world.Asavirtualperson(brainuploaded)thereisnoreasononecannotbeinthisworldwiththe
additionoffullsensoryfeedbacktothepersonsvirtualneuralsystem.Therealdangerofsuchavirtual
worldisbecominghabituatedtoitandhavingtherealworldseemblandbycomparison.

AndroidEmbodiment
Portableroboticsisadvancingatafairratebutisn'tfollowingMoore'sLawbyprogressingatan
exponentialrate.Therearenowwalkingrobotswithhighdexteritybutportablepowerandcompact
lowpowerhighefficiencyartificialmuscleshavebeenaproblem.Thefirstandroidsforbrain
emulatedindividualswillhavetobeRFlinkedtoasupercomputerfortheirbrainpowerandmayalso
haveapowertetherforlocomotion.Formoreportability,powercouldbesuppliedbyaplutonium238
radioisotopethermoelectricgenerator(RTG).RTGs,althoughtheyfoundwideuseinthe1970s,are
nowonlysuitedtospacecraftduetotheirexpense,threatofradioactivecontaminationafter
decommissioningandthescarcityofplutonium238.Adirectethanolfuelcellisadistinctpossibility
givenafewmoreyearsofdevelopment.Ifchemicalrechargeablebatterytechnologyimproves
markedlythenwellplacedfastrechargingstations,chairsorbedscouldsolvethisproblem.Atotally
independentandroidexistencemayinvolvereducinganexascaleoralternativecustomsupercomputer
andpowersourcetofitsomewhereinahumanbodysizeframecompletewithalltheotherpartsthat
wouldmaketheandroidrobotlifelikeandacceptabletotheuploadedhumanandtothoseheorshe
willinteractwith[Ishiguro12010,Ishiguro22010].Humansturnedandroidwillwanttolookandfeel
ashumanaspossibleandwillwantothertoreacttothemwithoutvisitingtheuncannyvalley(aterm
coinedbyMasahiroMoritodescribetheuncomfortablefeelingonehaswhenencounteringsomething
nearhumanlookingbutnotquitehumaninmotionorlikeness).
Hapticfeedbacktofeelvirtualheat,pressureandtexturearestillveryrudimentary[Varalakshmi
2012].Currentlygaming,robotics,surgicaltraining(laparoscopy,endoscopyandendovascular
procedures),telemanipulationandartificiallimbsprovidethemotivationforresearchinthisarea.For
thepurposeofhumanbrainemulationjustthedevelopmentofsensorsthatreplicatethehumansensory
systemsisimportant.Thesenseoftouchforanartificialhandisupto20sensors[Tan2014].The
majordrawbackisnotthesensorsbutconnectingthesetoappropriatenervesintheupperarm.Of
course,thisisnonissueinanandroidconnectedtoawholebrainemulator.Thehumanbodyhasfive
typesofcutaneousreceptors:LayeredcapsulePaciniancorpuscle(vibration),Layeredcapsule
Meissnercorpuscle(touch),thincapsuleRuffiniending(pressure),nonencapsulatedathairroot
(touch),andnonencapsulatedMerkelendings(touch).Afreenerveendingsensespain,temperature
andtouch[Nolte1999].Thesensordensityvariesfrom200MeissnerandMerkelunits/cm
2
onthe
fingertips,tongueandlipstoabout40onthepalmsandface.Organicfilmtransistorsandsensors
shouldallowthisdensityofsensorsinmaterialsthatcanbeformedintofingersandlipswithin5years

buttherehastobeaneedwithsufficientfinancingtodevelopthetechnology.
Humanmusclesarecompactandfairlyefficient;seeTable1from[Mirfakhrai2007].Thereare
manytypesofactuatorsthatcanactasartificialmusclesincludinghydraulic,pneumatic,thermal
shapedmemoryalloys,linearandrotarymotors,piezoelectricpolymers,ferroelectricpolymersand
manyothers.Tomakeandroidscordlessartificialmusclesneedactuatorsthataremorecompactand
uselesspowerthatcurrenttechnology.Astepinthatdirectionincludesrecentworkwithelectroactive
polymers(EAPs),conductivepolymers,carbonnanotubes(CNTs)[Mirfakhrai2007]andtwistedfibers
[Baughman2014,Haines12014,Haines22014,Lima2012].Aninexpensivenylonversionoftwisted
fibers,heatactivated,isfarmorepowerfulthanhumanmusclebyweightandsize.Usingcarbon
nanotubefilamentyarnyieldsanevenmorepowerfulcontractileforce.Asourceofheatisrequiredto
makethisworksothatisabitinconvenient,otherwise,thesmoothactionandsizemakesitidealfor
androidfacialandhandmuscles.

Table1Propertiesofmammalianskeletalmuscles

Property
TypicalValue
MaximumValue
Strain(%)
20
>40
Stress(MPa)
.01(Sustainable)
0.35
Workdensity(kj/m
3
)
8

Density(kg/m
3
)
1037

StrainRate(%/s)

500
Powertomass(W/kg)
50
200
Efficiency(%)

40
CycleLife

10
9
Modulus(MPa)
10to60


Visionandhearingcanuseofftheshelftechnologywithconventionaltechnologytoconvertthis
intoappropriateneuralspiketrains.Speechcanuseavocaltractsimulator.Thehumansenseoftaste
includessalt,bitter,sour,sweetandumami[Trivedi2012].Smellmayconsistofasmanyas1000
differentkindsofolfactoryneurons,allsimilarbutwitheach'binding'andifferentarrayofodorants.
Althoughhumantastehasbeencrudelyreplicated,smellhasbeenmorechallenging.Inthelastdecade
nanocompositesensortechnologieshaveadvancedtothepointthatcompanieslikeSensigentsellsa32
sensorarraysensitivetoawideassortmentofvolatileorganiccompounds.Moresensitivesensorsuse
metalligandbondingcolorimetric5x5and6x6sensorarrays[Suslick2004].Thisisbasedonthe
strongandrelativelyspecificbondingbetweentheanalytesandachemoresponsivedye.Sensitivityof
subppmsensitivityisreadilyrealizablewiththistechnologyusinganinexpensiveCMOSorCCD
imagingarrayorscanner.


Summary
Therearethreeinterdependentareasthatwillrequirethemostfocus,agoodunderstandingofbrain
physiologyatthelocallevel(corticalcolumn,etc.)pertinenttoemulation,highreliabilitybraintissue
scanningautomationandfast3Dpatternrecognitionthat'sconsiderablymoreaccuratethanhuman
recognition.
Therearemanyneurontypes,synapsetypes,synapsegrowthmechanisms,neurotransmittersand
variousglialcellsthatneedtobefuntionallyunderstood.Patternrecognitionsoftwaremustrecognize
andrejectjunksuchasdamagedordeadneuronsandganglia,plaques,tumors,lesions,calcium
deposits,vascularanomalies,bloodclots,strokedamage,unimportantglialcellsandotherirrelevant
cellularmaterialorforeignmatter.Itwasn'tuntilthelate80sandearly90sthatnitricoxide(NO),
hydrogensulfide(H
2
S)andcarbonmonoxide(CO)wererecognizedaslocalbroadcasttype
neurotransmitters[Dawson1994].Beforethatnoonesuspectedthatgasescouldbeneurotransmitters.
JustrecentlyFieldshasobservedatypeofglialcell(astrocyte)communicationusingcalciumion
wavesbetweenthemselvesandnearbyneuronsthepurposeofwhichisstillnotwellunderstood[Fields
2013].Anotherunsuspectedinconvenienceisthatsomehippocampalpyramidalneuronshavebeen
discoveredwithdendritesthathavegrowntheirownaxons[Thome2014]thatfireindependentlyofthe
pyramidalcell.It'sbeenacardinalrulethataneuronhasoneandonlyoneaxonforacenturybutthese
recentdiscoveriesdemonstratethatneuralbiologystillhasfundamentalsurprises.
Thesecondareaofconcernishighlyreliableautomatedsectionpreparationsystemwithlowtissue
distortionandnolossofthefeatureinformationnecessaryforsimulation.Thisalsoinvolvesreliable
marking,dyingandcataloging(ifsampleisnotdestroyed)andstoragetechniques.Beyondthis,highly
parallelscanningmicroscopesmustbedevelopedalongwithmultiexabytestoragefacilitiesforthe
datathatwillbecollected(30x30x30nmvoxelforanaveragehumanmalebrainofvolume1260cm
wouldrequire4.7x10
19
bytesat1bytepervoxel).Notethattheentiredatabasewouldhavetobesaved
tomakecorrectionsbasedonadditionalinformation,betterpatternrecognitionalgorithmsoralgorithm
learning.
Thethirdhurdleisthepatternrecognitionofallfeaturesandinterconnectivityrelevanttoafaithful
reproductionoftheindividualhuman'sconnectome.Itisdifficultforawelltrainedhumantocircuit
traceevenaverysmallneuralnet.Ittookyearstoteaseoutthestructureofthe302(hermaphrodite)
and384(male)neuronwiringdiagramofnematodeC.elegans.Notethatjustrecently[Li2014]itwas
discoveredthatoneoftheneuronsinC.eleganswasactuallyprovidingtwodifferentoutputs:
locomotionspeedanddirection.Thisshowsthatapparentlysimpleneuralsystemscancontain
unsuspectedcomplexity.
HenryMarkram’sBlueBrainProjecthassimulatedajuvenilerat’ssomatosensorycortexconsisting
of31kneuronsand37millionsynapses[Markram2015].Thisisbasedonpatchclampstudiesthat
identified55layerspecificmorphologicaland207morphoelectricalneuronsubtypes.Thecapturing
ofahumancorticalcolumn(~100kneurons)thoughttobe700to1000minicolumnsisinprogress.
Capturingthecerebralcortexofanindividualisordersofmagnitudemoredifficultsinceinvivo
studiesaredifficultandasinotheranimalseverycorticalcolumnnetworkisdifferent(thoughmany
areverysimilar)sothisindicatesthattheremaybeagenericbiologicallyapproximatedsimulated
artificialintelligencewellbeforeanindividualbraincanbeuploaded.Onewouldexpectthatthe
humancorticalcolumnnetworkwouldprovideabettermodelforAIusethaneitheraratora
macaque’scorticalcolumn.
Inareaswherethefunctionofagroupofneuronscanbefullycharacterizedanalgorithmic

replacementmightbemadeandcommittedtodigitallogic.Aprosthesisreplacementforpartofthe
hippocampusisbeingdevelopedinTheodoreBerger’sLab[Berger2012]atUniversityofSouthern
California.Theintentionistodevelopabiomimeticmicroelectronicdevicetorestorelostmemory.
Otherbiomimeticdeviceslikethecochlearimplantforthedeafhavebeenaroundformanydecades.
Areaslikeseeing,movement/intentionarealsounderbiomimeticmicroelectronicdevelopmentat
variousuniversitylabswithprototypedevicesinafewhumansubjects.Thiscanworkwellforareas
wherelittleornoadultlearningisinvolvedsotheI/Oresponseisbasicallystatic.
TherearemanycriticsofboththeEuropeanandUScurrenteffortsinlargebudgetbrainresearch
dealingwithlargescalecomputersystemsforsimulations[Fregnac2014]sincemanybasicscience
neuroscientistsfeltleftoutoftheprocessandthecurrentroadmap.Thecriticsclaimthiswilldelay
resultsusefulforcuringbraindiseases.Ifthecriticshavetheirwayitwilllikelydelaybotheffortsat
extractingwhatisusefulforAIandwholebrainemulation.Thisissimilartotheuproaroverthehuman
genomeprojectbegunin1990thatfeltmappingthehumangenomewouldnotleadtocuresfordisease.
Insteadithadprovideduswithabigpictureunderstandingofgeneticdiseases,geneticpredispositions
tovariousdiseasesandopenedtodoortomodernepigeneticsthatwouldhavepreviouslybeenwritten
offasLysenkoism.
Table2containsguesstimatesofwheneachbenchmarkmaybeaccomplished.Thisassumes
fundingisavailable.The“CapturingIndividualHumanBrainConnectome”entryisdependentonthe
priortableentriesandthewill(andmoney)tocreateasectioningandscanningfactory.
Akeypartoftheproblemwasnotincludedintheguesstimatesorinthedetaileddiscussioninthis
paper:Theproblemofbuildinganemulatorthatcontainstherightfunctions,arrangedintheright
manner,withsufficientlycorrectfunctionparametersderivedbysometransformationfromthevarious
measurementsmadeinabrain.Atpresent,thereisnosuchemulator,noristhereamethodfor
populatingsuchanemulatorwithparametervalues.Itisacrucialareathatdemandsfurtherresearch
anddevelopment.

DevelopmentLeadTimes
HumanBrainPreservationsufficientforstorageand
uploading
1015years
UnderstandingBrainPhysiologyatdepthnecessary
forbehavioralemulation
10–15years
AutomatedBrainsectioningandscanning
1015years
CapturingIndividualHumanBrainConnectome
2550years*
ComputationPotentialforHumanBrainEmulation
(LevelOutput).Probablywon'tworkbutusefulforAI
Currentmultipetaflopsupercomputers
ComputationPotentialforBrainEmulation(Spiking
Output)
10–20years(ExascaleSuper
Computers)orSpecializedarchitectures
VirtualWorldExistence(~computationalpower)
Possiblenow,mixofAIsandgamers
AndroidExistence(RFlinkandpartiallytethered)
1015Years

IndependentAndroidExistence(selfcontained)
2550years
*AnApollolikeprojectcouldgetearlyresultsbuteconomicandpoliticalconsiderationscoulddelayresultsformany
years.
Table2
References
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BrainResearchBulletin,Vol.50,Nos.5/6,pp.303–304,1999
[Abrash2014]MichaelAbrash,“WhatVRcould,should,andalmostcertainlywillbewithintwo
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[Baughman2014]RayBaughman,“SpinningYarnintoMuscles”Science20February2014
[Benjamin2014]BenVarkeyBenjamin,etal.,“Neurogrid:MixedAnalogDigitalMultichipSystem
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