V1-bypassing
thalamo-cortical
visual
circuits
in
blindsight
and
developmental
dyslexia
Samy
Rima
1and
Michael
Christoph
Schmid
1,2Visionrestsoncomputationsthatprimarilyrelyonthe
parvocellularandmagnocellulargeniculaterelayofretinal
signalstoV1.Secondarypathwaysinvolvingsuperior
colliculus,koniocellularlateralgeniculatenucleusandpulvinar
andtheirV1-bypassingprojectionstohigherordercortexare
knowntoexist.Whiletheymayformanevolutionaryoldvisual
system,theircontributiontoperceptionandvisuallyguided
behaviourremainlargelyobscure.Recentdevelopmentsin
tracttracingandcircuitmanipulationtechnologiesprovidenew
insights.Herewediscusshowsecondaryvisualpathways
mediateresidualvision(blindsight)afterV1injurybyrelaying
signalsdirectlyintohigherordercorticalareas.Wecontrast
thesefindingsonblindsightwithnewstudiesondyslexia
suggestingthatdysfunctionofsecondaryvisualpathways
mightcontributetodyslexic’sperceptualdifficulties.Emerging
fromtheseconsiderations,secondaryvisualpathways
involvingkoniocellularLGNmaybecriticalfordetectionof
visualchange,whereaspulvinarfunctionappearsmorelinked
tovisuomotorplanning.
Addresses
1Universite´ deFribourg,Switzerland
2
NewcastleUniversity,UnitedKingdom
Correspondingauthors:Rima,Samy(samy.rima@unifr.ch), ChristophSchmid,Michael(michael.schmid@unifr.ch)
CurrentOpinioninPhysiology2020,16:14–20
ThisreviewcomesfromathemedissueonVisionphysiology EditedbyAndrewJParkerandKristineKrug
ForacompleteoverviewseetheIssueandtheEditorial
Availableonline11thMay2020
https://doi.org/10.1016/j.cophys.2020.05.001
2468-8673/ã2020TheAuthors.PublishedbyElsevierLtd.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creative-commons.org/licenses/by-nc-nd/4.0/).
V1-bypassing
thalamo-cortical
visual
circuits
In vision, secondary pathways bypass primary visual cortex (V1) and feed retinal information directly into higher visual cortical areas. The relative strength and contribution of each of these subroutes to perception andvisuallyguidedbehaviourvarywithinthemammals of the Euarchontoglires clade [1] (Figure 1), to which modern primates belong. This variation seems to stem
fromspeciespecific retinal ganglioncell(RGC) organi-zationanddistributionthatemergedfromdifferent eco-logical pressures which, in time, moulded the visual system of each specie. This has led some species of the clade to favour diurnal versus nocturnal lifestyles, with different degrees of front-facing eyes (binocular vision)versusside-facingeyes andmore orless visually guidedgrasping[2].
WhiletheoriginofV1-bypassingroutesundisputedlylies intheretina, theprecisetransferpointsinthemidbrain andthalamusremainanareaofintensestudy,asmultiple subroutesexist.Inmacaques,adedicatedsetofganglion cellsprojectsfromtheretinatoreachthesuperficiallayers ofthesuperiorcolliculus(SC)inthemidbrain[3].From theretwomainparallelprojectionsemergethatbypassV1 [4,5]: one is to the ventral koniocellular/intercalated layersofthelateralgeniculatenucleus(LGN)andfrom theretomultipleareasofvisualassociation,most promi-nentlyarea MT [6–9]; a second projection reaches the inferiorandlateralpartsofthevisualpulvinarand simi-larlyprojectstomultipleareasofvisualassociationcortex
[10–12].InadditiontotheseSCmediatedroutes,certain
ganglioncellsalsoprojectdirectly,withouttheSCdetour, toLGNkoniolayers[8,13,14]and inferiorpulvinar and from there on to visual association areas [15], in both macaquesandmarmosets.Thereisanatomicalevidence thatthestrengthofthepulvinarroutemightbe particu-larlypronetodevelopmentalshapinginmarmosets[16– 19].Animportantsetofelectrophysiologicalrecordingsin LGN and pulvinar has influenced our current under-standingofvisualfunctionintheseregions:LGN record-ings in marmosets established that most dorsal konio neurons aresensitiveto short-wavelengthvisualstimuli [20,21],whereas ventralkonioneurons tendto bemore sensitivetoachromaticstimuliwithlowspatialandhigh temporal frequencies [13,14]. Recordings from the pul-vinarin macaquesestablishedawidesetofvisual func-tions, including responses to faces, snakes [22,23] and saccaderelatedactivitydependingonrecordinglocation
[24–26].AdirectfunctionalconfirmationoftheSC-MT
routevia pulvinar hasbeen established byBerman and Wurtz[11,12]inaseminalstudyusing electrophysiologi-cal collision tests in macaques. In addition to these insightsonahealthy,undisturbedvisualsystem,amajor partofourunderstandingaboutthecontributionsofthese subcorticalstructurestovisualfunctionarisesfrom stud-iesin whichtheprimarygeniculo-V1pathwayhasbeen damaged or inactivated permitting the analysis of V1-bypassing route contributions to residual visual
function. In this review, we will first describe recent advances from these studies, before contrasting them with new insights on developmental dyslexia in which a V1-bypassing projection has been found to be compromised.
Blindsight
While conscious vision in humans is deeply disrupted followingalesionof V1,significantresidualvisual func-tion remains,[27–31]including thecapacity to execute saccadestowardvisualstimulipresentedwithinthe sco-toma [27,28] and to detect visual motion [29]. This ‘blindsight’ phenomenon hasinstigated alively debate aboutwhichcircuitsthatbypassV1areresponsibleforthe residualvision ofthesepatients. Severalnonhuman pri-mateinvestigationshavedemonstratedsignificant resid-ualneuronalactivityinmotionsensitiveareaMTdespite alesionofV1,consistentwithpreservedmotiondetection capacitiesinblindsight[32–35].Anotherextrastriatearea, V4,whichwasinitiallyshowntobesilencedbyV1cooling [36],appears to regainsome residualactivityin chronic V1 lesions [37]and become moresensitive towardsthe detectionofvisualmotion[38] inmacaques.While itis largely accepted that the SC has a critical function in mediating blindsightbyrelayingvisualsignalsto cortex [32,39], the thalamic relays via LGN versus pulvinar remain atopicofrichdebate [40–42].
For a long time, the LGN route appeared an unlikely candidateduetostrongdegenerationcausedbyV1injury. Butevidenceinmacaquesshowsthatasignificantamount
of cells projecting directly towards visual association cortex survivethis degeneration[9,43].Pharmacological inactivationofLGNneuronseliminatedfunctional acti-vation of visual association cortex and visual detection capacities in a monkey model of blindsight [44]
(Figure2b).Similarinactivationsinpulvinarhadnoeffect
on basic vision but induced neglect-like visuomotor symptoms [45] shifting the focus for blindsight-related circuits further to LGN. Indeed, electrophysiological recordingsfromLGNneuronssurvivingV1lesions con-firmed intact visual processing of these neurons [46]. Modern optogeneticmethodsnowenable theCamK-II specific targeting of koniocellular neurons in an intact visualsystemof macaques,howeverso farwithnoclear delineation of visual response characteristics [47,48]
(Figure 2a). Evidence for the involvement of a
geni-culo-extrastriate pathway in blindsight exists also for humans. In 2015, Ajina et al. [49] used psychophysics andconnectivitymeasurestoshowthatpatientswithV1 lesions that could discriminate motion(blindsight posi-tive) had an intact LGN-hMT+ tract, while those that couldn’tdiscriminatemotion(Blindsightnegative)hada severely impaired or no measurable tracts. The other pathways tested,which includedaconnection between hMT+andthesuperiorcolliculus(SC),andwithhMT+ intheoppositehemisphere,didnotshowthispattern.Ina subsequentstudy,Ajinaetal.[50]usedfMRIto demon-strate that blindsight positive patients had intact func-tionalconnectivitybetweentheLGNandhMT+which was not the case for blindsight negative patients. Fur-thermore,theirresultssuggestthatthiswasspecifictothe
Figure1 LGN Pul SC Extra-striate
Rat Squirrel Tree shrew Galago Marmoset Squirrel
monkey Macaque
SC input Less dense SC input
Dense SC projections Topographic SC projections Retinal projections Retinal terminations Pluv projecting LGN projecting Striate cortex Extrastriate cortex Drosal MT projections (primeres only) Caudal MT 5mm 1mm Dorsal Lateral
Current Opinion in Physiology
OrganizationofsubcorticalstructuresandtheirsubdivisioninvolvedinV1bypassingcircuits.AdaptedfromBaldwinandStates[1].Thevisual systeminhumansfollowscloselytheoverallprimateorganisation[2],butdetailedcircuitinformationisstilllacking.
LGN,asbothpatientgroupshadpreservedconnectivity between hMT+, the pulvinar and contralateral hMT+. Observationsinhumansthusconfirmedtheexperimental discoveries in V1 lesioned macaques in which residual visualfunction was abolished if theLGN was silenced whichfurtherstrengthenstheinvolvementofa geniculo-extrastriatepathway in blindsight.Althoughkonio neu-ronscanreceiveinputsfromSCaswellasdirectlyfrom theretina[2],itremainstobedeterminedwhichofthese inputsisessentialfor LGN-dependentblindsight. Recentadvancesinchemogeneticandoptogenetic tech-nologieshavehoweveralsobroughtnewgroundbreaking evidencetothePulvinarcontribution.Kinoshitaetal.[51] in an important new study directly tested the role of superior colliculus to ventrolateral pulvinar (vlPul)
pathwayin blindsightmonkeysusingpharmacogenetics
(Figure2c).Theyfirstconfirmedtheabilityofmonkeys
tomakevisuallyguidedsaccadestohighcontraststimuli inthecontralesionalvisualfield.Then,theymappedthe ventralpulvinar byelectricmicrostimulation of theSC. FollowingtheidentificationofthevPul,theyinactivated itthroughtheinjectionofmuscimol.Theprecisionofthe injectionlocation waslater confirmed through Gadolin-ium-based magnetic resonance imaging. This inactiva-tion severely impaired visually guided saccades to the contralesional visualfield.The authors then used phar-maco-genetics to investigate the role of the SC-vPul pathway in the generation of visually guided saccades tothecontralesional visualfield.Theyinjected 2 retro-gradeviral vectors,one in the SC and theother in the vPul. The goal of these injections was to selectively
Figure2 (a) (c) (b) (d) 100 80 60 40 20 0 7 10 17 40 100 % Contrast Correct detection (%) V1 lesioned + LGN inactivated V1 intact V1 lesioned
HiRet injection site
A8 (Monkey-C) M L V D 15 10 5 0 0 –5 –10 –15 15 10 –5 –10 –15 –15 –10 –5 0 –15 –10 –5 0 Horizontal (degree) V e rtical (degree) V e rtical (degree) Horizontal (degree)
Pre (day – 1) Dox (day 12)
Current Opinion in Physiology
InvolvementofK-MTandSC-PUL-MTpathwaysinblindsight.(a)eYFPfluorescenceofKlayersthatexpressCAMKIIandcalbindin.Adaptedfrom Kleinetal.[47].(b)EffectofLGNinactivationonthecorrectdetectionofrotatingcheckerboardswithascotomainducedbyaV1lesion.Adaptedfrom Schmidetal.[44].(c)Injectionsiteoflentiviralvector(HiRet),whichcarriedeTeNTunderthetetracyclineresponsiveelement.(d)Saccadetrajectories andsaccadeendpointsbeforeadministration(Pre)andduringDoxadministration(Dox).(c)and(d)areadaptedfromKinoshitaetal.[51].
inhibit neurons of the SC-vPul pathway using doxycy-cline.DuringtheoraladministrationofDoxicycline,the accuracy of vision guidedsaccadesto thecontralesional visual field declined and reactiontimes increased.The confirmation of this findingwith similarresultsin mice [52] highlightstheimportanceof thispulvinar routefor re-foveation to high contrast peripheral targets during blindsightacross species.
Thus,thereisgoodevidenceforV1bypassingprojections inblindsightthatimplicateboththeLGNandPulvinar. Intheabsenceofdoubledissociationexperimentsinthe same primatespecies, thereisnoclear-cut answerasto whichofthesesubcorticalpathwaysisultimatelycritical forblindsight.Withpositiveevidenceforeitherroute,the possibility remains that both pathways contribute in parallel with the LGN route possibly more concerned
with basic visual detection and the pulvinar pathway more directlylinkedwithvisuo-motorbehavior.
Developmental
dyslexia
Whilethereisstrongevidencethattheresidualvisualand visuomotorcapacitiesofblindsightrelyonvisualcircuits that bypass V1 into extrastriate cortex, the function of such a circuitry in other clinical contexts – or even everyday vision – remains largely unknown. A recent investigationofsubcorticalcircuitsinsubjectswith devel-opmental dyslexia, however, points to at least one sec-ondary visual pathway bypassing V1 in dyslexia. It is knownthatdyslexicsofdifferentagegroupsandlanguage backgrounds show deficits in visual motion processing [53].Acurrentprominenttheoryascribesthese deficien-cies to a disrupted LGN magnocellular pathway [54].
Figure3
(a)
(c)
(b)
(d) RAN (letters, numbers) Time (s)
Connectivity Index Left V5/MT - LGN
Controls
Dyslexics
Mean functional connectivity (z)
Correlation of timeseries ( r) 0.50 V5 ROI 0.1 0.4 log-normalized nb. streamlines 0.25 0 –0.25 Time 1 Untrained Trained Time 1 Time 1 Time 2 Time 2 –0.50 –0.25 0.00 0.25 0.50 0.75 10 0.15 0.25 0.35 0.45 0.55 0.65 0.75 15 20 25 30 35 Time 2 Controls Dyslexics R2 = .346 p = .045
Trained group
Current Opinion in Physiology
InvolvementofV1bypassingcircuitsinreadingacquisitionandreadingdeficits.(a)DyslexicspresentdecreasedconnectivitybetweenleftLGN andleftareaMT,which(b)negativelycorrelateswithreadingskills.AdaptedfromMu¨ller-axtetal.[56].(c)and(d)Learningtoreadincreases cortico-subcorticalfunctionalconnectivity.AdaptedfromSkeideetal.[66].
Empirical datafor themagnocellular theoryof dyslexia saw light in 1991 when Livingstone et al. [55] showed that dyslexic subjects had diminished visually evoked potentials to rapid andlow contrast stimuli,but normal responsestoslowandhighcontraststimuli.Investigation ofthepost-mortemdyslexicLGNbyLivingstonrevealed histological abnormalities in the ventral magnocellular layers, but not the dorsal parvocellular layers. Direct evidencefor adeficientvisualpathway bypassingV1 in dyslexics wasrecentlyprovided byMu¨ller-Axt, Anwan-der, and von Kriegstein, [56]. The authors used ultra-high-resolutionfMRIandtractographytoshow reduced structuralconnectivityfromtheleftLGNtoleftmotion area MT with seemingly intact LGN V1 connections
(Figure3a).Thestrength oftheleftLGNMT
connec-tivity was negatively correlated with the rapid naming abilitiesof dyslexics(Figure3b).Thislateralization cor-roboratesrecentanatomicalevidencethatshowsthatthe sizeoftheleftLGNissmallerindyslexicsascomparedto leftLGNofcontrols[57],andalignswithwithreportsof abnormalities in the areas activated during reading in dyslexics [58,59] which are mostly confined in the left hemisphere.fMRIhasshownthatmovingstimulidonot invokethesameactivityinareaMTindyslexicsasitdoes incontrolsubjects[60]withstrongcorrelationsbetween cortical activity, speed discrimination thresholds, and readingspeed[61].Wehaverecentlypartiallyconfirmed thisfinding:thehighersensitivitytodetectvisualmotion intherighthemifieldseeninskilledreaderswasabsentin individuals with developmental dyslexia [62]. Further-more,transcranial directcurrentstimulationof leftarea V5/MT in dyslexics seemsto lead to improvedreading speedandfluency[63],whiletranscranialmagnetic stim-ulation showed that stimulating left area MT lead to impairmentsin wordrecognition[64]. Thereare there-foregoodreasonstolinktheobservedmotiondeficitsin developmental dyslexia to an altered left-hemispheric motionprocessing systeminthebrainofthesesubjects. However,thereisatthemomentsomewhatofa conun-drum about the LGN involvement which will need to be resolved in future research to determine whether the original magnocellular theory should be extended towards koniocellular function, and to what extent the LGN-MT pathway [8] might consist of a mixture of koniocellularand magnocellularinputs.
Comparedtotheevidenceforadeficientlefthemisphere LGN-MTsystemindyslexia,verylittleisknownabout theinvolvement of theother secondary pathway struc-tures.Deheane’sneuronalrecyclinghypothesisproposes thatreadingmakesuseofbrainareasinitiallydevotedto moreprimitivevisualfunctions,andthatthepracticeof readingwouldcarveoutareading networkinthevisual systemthroughplasticity[65].Evidencefor plasticityof subcortical sensory circuits after reading acquisition comes from a recent resting-state fMRI study [66]. Theauthorsshowed(Figure3candd)that,afterlearning
toread for six months,functional connectivity (SC-Pul, subcortical-cortical,lefthemisphere)increasedfor previ-ously illiterate adults. This increased connectivity also correlated with letter identification and word reading skills on the individual level. While the contributions of the SC and the visual pulvinar to developmental Dyslexia remain largely unknown, there is preliminary evidence for pulvinar disruption[67] in addition to the knownLGNdeficit[55].
ThecommonalitiesintheV1-bypassingcircuitsbetween blindsight and developmental dyslexia are intriguing. Furtherinvestigationsusingcell-specificdouble dissoci-ationexperimentsinprimatesshould helptoclarifythe rolesofthepulvinarversusLGNroutes.Drawingupon ourconsiderationsfromblindsightanddyslexia,we spec-ulatethatanticipatoryvisualprocessinginnormalvision, suchasduringreading,mightinvokethedetection prop-erties of the LGN-MT circuit and saccadic planning functionoftheSC-Pulvinarrouteinconcertastovisually locateupcomingobjectssuchaswords,andfurtherguide thefoveafor analysisathighestacuity.
Conflict
of
interest
statement
Nothingdeclared.
Acknowledgement
ThisworkwassupportedbyERCstartinggrant637638OptoVision.
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