Evidence for Brainstem and Supra-Brainstem Contributions to Rapid Cortical Plasticity in Adult ...

13 Pages·1999·0.9 MB·English

TheJournalofNeuroscience,September1,1999,19(17):7578–7590
Evidence for Brainstem and Supra-Brainstem Contributions to
Rapid Cortical Plasticity in Adult Monkeys
J. Xu and J. T. Wall
DepartmentofNeurobiologyandAnatomy,MedicalCollegeofOhio,Toledo,Ohio43699-0008
Corticalmapscanundergoamazinglyrapidchangesafterinjury spatial properties of representations (i.e., location, continuity,
of the body. These changes involve functional alterations in size) change during the first minutes to hours after injury. The
normal substrates, but the cortical and/or subcortical loca- comparisonsofcuneateandarea3borganizationfurthershow
tion(s)ofthesealterations,andtherelationshipsofalterationsin thatsomecuneatechangesarepreservedinarea3b,whereas
different substrates, remain controversial. The present study othercuneatechangesaretransformedbeforebeingexpressed
usedneurophysiologicalapproachesinadultmonkeystoeval- in area 3b. The findings provide evidence that rapid reorgani-
uatehowbrainstemorganizationoftactileinputsinthecuneate zationinarea3b,inpart,reflectsmechanismsthatoperatefrom
nucleus(CN)changesafteracuteinjuryofhandnerves.These a distance in the cuneate nucleus and, in part, reflects supra-
datawerethencomparedwithanalogousdatafromourearlier cuneatemechanismsthatmodifybrainstemchanges.
corticalarea3bstudies,whichusedthesameapproachesand
acute injury, to assess relationships of cuneate and cortical Keywords:neuronalplasticity;somatosensorycortex;dorsal
changes. The results indicate that cuneate tactile responsive- column nuclei; lemniscal mechanisms; disinhibition; sensitiza-
ness, receptive field locations, somatotopic organization, and tion;tactileprocessing;primatecuneatenucleus
CorticalandsubcorticalsubstratesoftheCNScontainorganized iological approaches were used to evaluate how tactile inputs
maps of tactile inputs from the skin. Long-standing peripheral from the hand and adjacent body are organized in the CN of
injury in adult primates causes map reorganization in cortical adultsquirrelmonkeysafteracutesectionofnerves(medianand
area 3b that, in part, reflects subcortical and cortical anatomical ulnar) to the hand. These data were then compared with corre-
changesthatslowlydevelopovermonthstoyears(Florenceetal., spondingarea3bdatafromourpreviousstudiesofadultsquirrel
1998;JonesandPons,1998).Theseslowchangesareprecededby monkeys that had the same acute injury and that were assessed
functional changes in normal anatomical substrates, the first of using identical approaches (Kolarik et al., 1994). The following
which can be expressed with surprising quickness; for example, questionswereaddressed:howarefeaturesoftactileinputorga-
initial functional alterations of tactile inputs in area 3b begin nizationintheCNofadultprimateschangedinthefirstminutes
withinminutestohoursaftervarioushandinjuries(Merzenichet tohoursafterinjury,andhowarefunctionalchangesinCNand
al.,1983;CalfordandTweedale,1991;Kolariketal.,1994;Silva area3bhandmapsrelatedduringthisperiod?
et al., 1996). In contrast to long-standing changes, there is little
understandingofwhetherorhowsubcorticalalterationscontrib- MATERIALS AND METHODS
utetotheserapidcorticalchanges(forreview,seeFlorenceetal., AllprotocolsfollowedtheguidelinesoftheNationalInstitutesofHealth
1997). The contributions of brainstem substrates remain espe- GuidefortheCareandUseofLaboratoryAnimalsandwereapprovedby
theInstitutionalAnimalCareandUseCommitteeattheMedicalCol-
ciallyunclearbecausestudiesofthecuneate,gracile,andtrigem-
legeofOhio.
inalnucleipresentacontroversialmixofpositive(Dostrovskyet
Samples and animal preparation. All data are from adult squirrel mon-
al., 1976; Millar et al., 1976; Pettit and Schwark, 1993, 1996; keys. Postinjury CN data were derived from five monkeys that had
Panetsosetal.,1995;Fagginetal.,1997)andnegative(McMahon ipsilateralacutesectionsofthemedianandulnarnerves.Datafromthese
and Wall, 1983; Waite, 1984; Northgrave and Rasmusson, 1996; monkeys were compared with preinjury data from these monkeys and
withCNdatafromanadditional10monkeysthathadnormalnerves(Xu
ZhangandRowe,1997)evidenceforacutereorganizationinthe
andWall,1999).InCNstudies,systematicgridsofrecordingsiteswere
brainstem. madearoundrostrocaudallevelswherethenucleusanditsparsrotunda
Arecentstudyindicatesthatfunctionalchangesappearinthe subdivision are largest. These levels contain the main part of the CN
main cuneate nucleus (CN) of adult monkeys within minutes handrepresentation(Florenceetal.,1991;XuandWall,1996,1999)and
thus the main ascending lemniscal substrates for hand inputs. Area 3b
after hand injury (Xu and Wall, 1997a). This finding prompted
data were derived from 12 monkeys, 5 that had contralateral acute
thepresentexperimentstofurtherstudyCNchangesduringthis
sectionsofthemedianandulnarnerves(Kolariketal.,1994)and7that
initial postinjury period and to evaluate whether initial CN and hadnormalnerves(Walletal.,1993;ourunpublishedobservations).
corticalchangesarerelated.Toexaminetheseissues,neurophys- Exceptfordifferencesinsurgeriestoexposethemedullaversuscortex,
allmonkeyswerepreparedwithcomparableproceduresthathavebeen
ReceivedMarch29,1999;revisedMay18,1999;acceptedJune15,1999. describedpreviously(Walletal.,1993;Kolariketal.,1994;XuandWall,
1996,1997a,1999).Briefly,forinitialsurgicalandsubsequentrecording
ThisworkwassupportedbyNationalInstitutesofHealthGrantNS21105.We
thankMarshonnaForguesandJessicaNguyenfortheirtechnicalassistance,and procedures,monkeysweremaintainedatasurgicalplaneofanesthesia
RichardLaneandAndreyStojicforhelpfuldiscussions. with a mixture of ketamine hydrochloride (25–50 mg/kg, i.m.) and
CorrespondenceshouldbeaddressedtoJ.T.Wall,DepartmentofNeurobiology acepromazine (0.4–0.8 mg/kg, i.m.). After the head was secured in a
andAnatomy,MedicalCollegeofOhio,P.O.Box10008,Toledo,OH43699-0008. frame,thedorsalmedullaorparietalcortexwasexposed,coveredwith
Copyright©1999SocietyforNeuroscience 0270-6474/99/197578-13$05.00/0 siliconefluid,andphotographed(30–403).
XuandWall•BrainstemandCorticalPlasticity J.Neurosci.,September1,1999,19(17):7578–7590 7579
Figure1. Shiftsintactilereceptivefieldlocationsand
responsivenessduringthefirstminutesafternervesec-
tion. Top, Transverse plane camera lucida drawings of
reconstructedtracksintheCN(shaded)oftwomonkeys
(A,B).Handpicturesoftheglabrous(left)anddorsal
(right)sidesofthehandindicateabbreviationsfordigits
(D1–D5), palmar pads (P), and the dorsal hand area
oppositethepalm(DH).Bottom,Theindicatedprein-
juryreceptivefields(Pre)wererecordedastwocoupled
electrodes were advanced stepwise from dorsal (i.e.,
sites 1 1 9 in A and 1 1 8 in B) to ventral (i.e.,
immediatelybelowsites8116inAand7114inB)
locationsinthepreinjuryglabroushandrepresentation.
Nerve section was then performed (each nerve was
previously looped with suture to permit simultaneous
sectioning), and postinjury responses (Post) were as-
sessed as the electrodes were immediately retracted
stepwiseupthesametracksoverthesubsequent34–49
min (Min). Note (1) preinjury tactile receptive fields
that were restricted to glabrous skin shifted to dorsal
handskinwithinminutes,(2)shiftsfrequentlyinvolved
changes from the glabrous to dorsal side of the same
and/or adjacent digit(s), and (3) some sites became
unresponsivetotactilestimuli(U).Scalebar,500mm.
Nerveinjury.Transectionofthemedianandulnarnerveswasperformed shiftsof50–70mm,indicatingthatneuronsweresampledoveradiameter
asdescribedpreviously(Kolariketal.,1994).Oneortwoincisionswere of100–140mm(orareaof0.008–0.015mm2).
madealongthewrist,themedianandulnarnerveswerelocalizedand Theproceduresforarea3brecordinghavebeendescribed(Walletal.,
freedfromsurroundingtissue,andaloopofsuturewaspassedbeneath 1993; Kolarik et al., 1994). Area 3b hand maps in four monkeys with
eachnerve.Incisionswereclosedexceptforopeningsforeachloop.Both acutely sectioned nerves and three monkeys with normal nerves were
nervesweresubsequentlyrapidlyandsimultaneouslytransectedbyele- studiedindetail(Walletal.,1993;Kolariketal.,1994).Inthesecases,
vating the loops and cutting the nerves with scissors. From previous recording sites were uniformly spaced ;200–300 mm apart across the
nerverecordings(Walletal.,1993),andfromthelocationsofresidual entirearea3bhandrepresentation.Inoneadditionalmonkeywithacute
fieldsafterinjury(seeResults),thisinjurydenervatedallglabrousskin injuryandfourmonkeyswithnormalnerves,delimitedpartsofthearea
andpartsofthedorsal(hairy)surfaceonthelittlefingerandadjacent 3bhandmapwerestudiedindetail.Inallarea3bstudies,receptivefields
edge of the hand. Radial nerve innervation to the other parts of the weredefinedfrommultiunit,oroccasionallysingleunit,activityencoun-
dorsalhandremainedintact. tered around the middle layers, 400–900 mm below the surface. After
Neurophysiological recording, stimulation, and receptive field definition. recording,selectedsitesweremarkedtopermitreconstructionofrecord-
Tungsten or stainless steel microelectrodes (1–4 MV) were inserted ingsiteswithrespecttothehistologicalbordersofarea3b.
perpendicular to the dorsal surface of the medulla or area 3b, and the Equivalent stimulation procedures and criteria for defining tactile
entrypointsweremarkedonthephotograph.ForCNrecording,upto receptivefieldswereusedintheCNandarea3b.Asdescribedpreviously
fourelectrodesthatwerecoupledinarowwithtipsalignedand100–200 (Walletal.,1993;Kolariketal.,1994;XuandWall,1996,1999),stimuli
mmapartwereusedtosamplemediolateralrowsofrecordingsites.Use werehand-deliveredpunctatecontactsorbrushes oftheskin,hairs,or
of coupled electrodes simplified reconstructions of tracks because dis- deep tissues. To define cutaneous receptive fields, light tactile stimuli
tances between electrodes were fixed and measurable. Receptive fields were presented to activate low-threshold cutaneous inputs directly be-
weredefinedfrommultiunitandoccasionallysingleunitactivityencoun- neaththeprobe.Acutaneousreceptivefieldwasdefinedastheareaof
tered at successive dorsal-to-ventral recording sites. When responses skin from which responses were elicited to light cutaneous stimulation;
indicated that electrodes had advanced below the CN, marking lesions i.e.,bothpreinjuryandpostinjuryfieldsreflectedthetotalskinareathat
weremadeatselectedsites(3–8mA,2–4sec).Theseprocedureswere evoked action potentials. Each field was judged to reflect a maximal,
reiteratedwiththeaimofproducingatransverseplanegridthatsampled low-thresholdcutaneousfieldarea.Thesemaximalfieldsaresomewhat
responsesatintervalsof;50–100mminthedorsoventraland100–200 larger than minimal cutaneous fields as defined in other studies in
mminthemediolateraldimensions.Themultiunitmethodswerecapable squirrelmonkeys(Suretal.,1982;Merzenichetal.,1987).
ofdetectingchangesintactileresponsiveness(e.g.,responsivevsnonre- Theproceduresfordelineatingandmeasuringtactilereceptivefields
sponsive)andextentsorlocationsofreceptivefieldswithrecordingsite onthehandhavebeendescribed(XuandWall,1999).Fieldsweredrawn
7580 J.Neurosci.,September1,1999,19(17):7578–7590 XuandWall•BrainstemandCorticalPlasticity
Figure 2. Postinjury recording sites and related receptive
fieldsforarepresentativeCNtransverseplanemap.Topleft,
Transverse plane camera lucida drawing of the CN (shaded).
Verticallinesindicate15electrodepenetrations,smallblackdots
indicateCNrecordingsites,hashmarksindicatesitesoutside
the CN, and larger black and white circles indicate marker
lesions(dorsal5up;medial5right).Scalebar,1mm.Bottom,
Tactile receptive fields (black areas) for CN sites with corre-
spondingnumber.Numberedsitesforwhichnofieldisshown
were not responsive to tactile stimulation. Note that neurons
withtactilefieldsinvolvingthehandwereincentralCNloca-
tions(e.g.,tracksbelowsites14,26,38,and50),andallhand
fieldswereonthedorsal(hairy)hand.
ondiagramsthatillustratedthebordersofeachhandpartandmeasured criteriawereappliedintheCNandarea3b,thusprovidingameansof
withacomputerizedplanimeter.CNandarea3bfieldswerenormalized comparingspatialsizes,continuities,andadjacenciesofrepresentations
inthesamewaytopercentagesofthetotalhandsurface.Theseproce- of particular skin areas. Areas within borders of representations were
dures permitted comparisons of the relative sizes of CN and area 3b measuredwithacomputerizedplanimeter.Onlyfullymappedrepresen-
fieldswithoutconfoundsattributabletodifferencesinabsolutehandsize. tationsofthehandinarea3bandinCNtransverseplaneswereusedfor
Receptive field data were mainly derived from multiunit responses; analyses of representations (postinjury: CN 5 11 maps, area 3b 5 4
however, single unit fields were also encountered and were similar to maps;normal:CN514maps,area3b53maps).Foranalysesinwhich
multiunitfields. extensivebracketingofrepresentationswasnotnecessary(e.g.,analyses
Histologicalreconstructionsanddelineationandmeasurementofrepresen- ofreceptivefields),datafrommapsthatwereincompletelydefinedwere
tations.Theseprocedureshavebeendescribed(Walletal.,1993;Kolarik usedtosupplementdatafromfullmaps(postinjury:CN56maps,area
etal.,1994;XuandWall,1996,1999).Inbrief,afterrecording,monkeys 3b51map;normal:CN55maps,area3b54maps).
wereoverdosedwithbarbiturateandperfusedwithsalineandparafor- Previous studies of CN organization in normal squirrel monkeys
maldehyde.InallCNexperiments,themedullawasfrozenandcutinto demonstratedthattactileinputsfromallormostofthehandsurfacemap
50-mm-thick transverse sections. All sections were co-processed with ontoatransverseplanethroughtheparsrotundaandthatsimilarorga-
cytochromeoxidase(CO)toidentifyCNbordersandCOdensepatches nizationisrepeatedinplanesatdifferentrostrocaudallevels(Florenceet
in the pars rotunda, and with the Prussian blue method to distinguish al.,1991;XuandWall,1999).Asimilarconceptappliestohandmapsin
irondepositsmadewithstainlesssteelmicroelectrodesfromelectrolytic tangentialplanesparalleltothelayersofarea3b.Thus,two-dimensional
marksmadewithtungstenmicroelectrodes.GridsofCNrecordingsites handmapsthroughtherespectivetransverseandtangentialplanesofthe
werereconstructedusingdepthestimatesfrommicrodrivereadingsand CNandarea3bprovideestimatesofspatialpropertiesofmapsinthese
cameralucidaimagesofhistologicallyobservedtrackartifactsandfidu- structures.Theresultsdefineorganizationintheseplanes.
cialmarks.Inallarea3bexperiments,theparietalcortexwasfrozenand
cutinto50-mm-thickparasagittalsections.Allsectionswerestainedwith
RESULTS
cresyl violet, and the architectonic borders of area 3b were related to
trackartifactsandfiducialmarks.AllCNandarea3bneuronaldatawere CN postinjuryorganization
histologicallyconfirmedtobeinthesestructures.
Receptive fields and tactileresponsiveness
CNandarea3bresponseswereusedtodefinerepresentationsofthe
hand and adjacent parts of the body (Wall et al., 1993; Kolarik et al., Median and ulnar nerve section, which denervated the glabrous
1994;XuandWall,1996,1999).Briefly,eachrecordingsitewaslabeled hand, triggered rapid shifts in locations of cutaneous receptive
according to its receptive field location. Borders delimiting groups of fieldsandlossesoftactileresponses.Inexperimentsinwhichthe
recordingsiteswithfieldsonatargetedskinarea(s)(e.g.,digits,dorsal
same or similar neurons were recorded before and after injury,
hand,forelimb)wereplacedeithermidwaybetweensiteswithfieldsthat
did and did not include the targeted area(s) or, alternatively, on sites CNsiteswithpreinjurytactileresponsesonthehandunderwent
havingfieldsthatpartlyincludedthetargetedarea(s).Thesameborder receptivefieldshiftsfromtheglabroustodorsalhand,acrossthe
XuandWall•BrainstemandCorticalPlasticity J.Neurosci.,September1,1999,19(17):7578–7590 7581
Table1.Mean(SD)sizesofrepresentationsaspercentagesofCN
transverseareasinnormalandpostinjuryanimals
Cuneate Normal Postinjury
Totalhand 53.1(9.3) 35.1(14.4)
Glabrous 38.5(8.0) 0
Hairy 14.6(4.9) 35.1(14.4)
Forelimb,trunk,face 38.1(8.8) 37.3(2.8)
Cutaneouslyunresponsive 8.8(5.7) 27.6(14.2)
byconsistentchangesinthelocation,continuity,size,andsoma-
totopicorganizationofCNrepresentationsofthedorsalhand.In
transverse planes of the CN, the representation of the glabrous
handisnormallyalarge,continuousrepresentationoccupyingall
ormostoftheparsrotunda,distinguishedbyitsdenselystained
COpatches;incontrast,therepresentationofthedorsalhandis
normally distributed in discontinuous small areas, mainly along
the lateral, or lateral and medial, edges of the glabrous hand
representation(Fig.3E)(XuandWall,1996,1999).Afterinjury,
the CN dorsal hand representation consistently became more
continuousandenlargedbyapproximately2.4timesfromanor-
mal mean of 14.6% to a postinjury mean of 35.1% of the CN
transverse plane (t[11] 5 4.1; p , 0.002) (Fig. 3, compare E,
A–D,F; Table 1). These enlarged dorsal hand representations
consistently spanned pars rotunda patches in central CN loca-
tionswheretheglabroushandrepresentationisnormallylocated
(Figs.3,4).
The normal CN hand map occupies a mean area of 53.1% of
CN transverse planes (Table 1). Thus, relative to this area, the
dorsal hand representation expanded from a normal mean area
equivalent to 27.4% (i.e., 14.6/53.1) to a postinjury mean area
equivalent to 66.1% (i.e., 35.1/53.1) of the mean size of normal
CNhandmaps(Fig.5).Thesefindings,andtheabovechangesin
Figure3. ConsistentlyobservedfeaturesofhandmapsintheCN(A–F)
andarea3b(G,H).Notethat(1)normallyinboththeCN(E)andarea
3b (G), the glabrous representation (gray) is continuous and large,
whereasthedorsalrepresentation(striped)occupiesadjacent,discontin-
uous,smallpatches,and(2)afterinjury,thedorsalrepresentationinthe
CN(striped)enlargedandbecamecontinuousacrosscentralCNlocations
normally representing glabrous inputs (A–D and F vs E), whereas the
dorsal representation in area 3b also enlarged into area 3b locations
normally representing glabrous inputs, but remained discontinuous and
patchy(striped;HvsG)(seeFig.7forfurtherexamples).ForCNmaps,
dorsal 5 up and medial 5 right. Scale bar, 1 mm. For area 3b maps,
anterior5upandmedial5right.Scalebar,1mm.
dorsalhand,orinfrequently,fromthehandtoforelimb.Preinjury
neuronalresponsesthatwererestrictedtoglabrousskinshiftedto
dorsalskinfieldswithinminutesandremainedapparentorcon-
tinuedtodevelopoverthenextseveralhours(Fig.1).Theseshifts
commonly involved changes from the glabrous to dorsal side of
the same and/or adjacent digit(s), suggesting that preinjury and
postinjuryfieldswereinroughregister(Fig.1A,4,7,8,11;1B,1,
5,6,8).Incontrasttoneuronsthathadshiftedfields,neuronsat
otherCNsiteslosttactileresponsivenessafterinjury(Fig.1)(see
below). Figure 4. Cytochrome oxidase (CO) stained transverse section of the
brainstemshowingtheCN(solidborder)andthepostinjurydorsalhand
The representation of the hand and sizes of receptive fields on representation(areasindicatedby*betweendottedlines).Thepostinjury
thehand dorsal hand representation occupies pars rotunda locations containing
COdensepatchesthatarenormallyassociatedwithglabroushandinputs
In experiments in which CN planes were mapped in high detail
(Xu and Wall, 1999). Arrows indicate marker lesions at the bottoms of
afterinjury(Fig.2),receptivefieldshiftstothedorsalhandwere some of the penetrations made in this transverse plane. Dorsal 5 up;
furtherreflectedbyincreasedincidencesofdorsalhandfieldsand medial5right.
7582 J.Neurosci.,September1,1999,19(17):7578–7590 XuandWall•BrainstemandCorticalPlasticity
Figure6. AnalysesofCNandarea3brepresentationsofsubregionsof
thedorsalhand.A,Enlargementratios(Postinjury/Normal)forrepresen-
tationsofdistal,proximal,radial,andulnarsubregions.Notethatinboth
Figure5. Normalandpostinjurysizesofdorsalhandrepresentationsin
the CN and area 3b, representations of distal (i.e., digit) and radial
theCNandarea3b.ForCNmeasures(left),NORMALMEANindicates
subregions had larger postinjury enlargements than proximal and ulnar
mean and 95% confidence interval sizes of normal CN dorsal hand
subregions.B,C,Examplesofcompositereceptivefieldareas(hatching)
representations[14maps;XuandWall(1999)];POSTINJURY1–11and
that were represented in each of three CN (B) and three area 3b (C)
MEAN indicate postinjury sizes of dorsal hand representations for 11
postinjurymaps.Notethat(1)similarlocationsandextentsofthedorsal
maps and their mean. For area 3b measures (right), NORMAL MEAN
handwererepresentedinindividualmapsatbothlevels,and(2)theulnar
indicates mean and 95% confidence interval sizes of normal area 3b
edge was usually not represented (because of ulnar nerve section). See
dorsal hand representations [3 maps; Wall et al. (1993)]; POSTINJURY
Resultsforfurtherdetails.
1–4andMEANindicatepostinjurysizesofdorsalhandrepresentations
forfourmapsandtheirmean.SeeResultsfordetails.
inputsfromthedigitstendedtoactivateneuronsatmoredorsal
CN sites, whereas inputs involving more proximal locations on
locationandcontinuityofthedorsalhandrepresentation,suggest the back of the hand usually activated more ventral sites (Fig.
thatapproximatelytwo-thirdsofthenormalCNhandrepresen- 7A–F).(3)Inputsfromtheradialhalfofthedorsalhandusually
tation was taken over by dorsal hand inputs. This postinjury activated neurons at more lateral to lateroventral sites, whereas
expansion was seen in most CN planes; i.e., dorsal hand repre- ulnar inputs usually activated more mediodorsal sites (Fig. 8A–
sentations that were at or above the upper 95% confidence F). (4) CN areas with inputs from different dorsal digits were
intervalsizeofnormaldorsalhandrepresentationswereseenin representedinapartiallyshiftedbutoverlappingmanner.Digit1
9of11postinjuryCNmaps(Fig.5). was represented most lateroventrally, digit 5 (when present) or
Representations of inputs from subregions of the dorsal hand digit4wasrepresentedmostmediodorsally,andinterveningdigit
underwentvariablechangesinsize.Expansionsoftherepresen- representations overlapped in between (Fig. 9A–C). (5) Finally,
tationsofthedigitskinandradial(thumb)halfofthedorsalhand postinjuryCNsomatotopicgradientsfordistal–proximal,radial–
werelargerthanexpansionsofrepresentationsofcomplementary ulnar, and digit inputs were in rough register with somatotopic
regionsontheproximalandulnar(littlefinger)halfofthedorsal gradientsofnormalinputsfromthesehandparts(Figs.7–9).
hand (Fig. 6A). The smaller enlargement of the ulnar, as com- The above changes did not lead to major changes in sizes of
pared with the radial representation, likely reflects the partial CN dorsal hand receptive fields. Postinjury dorsal fields, like
denervation of the ulnar dorsal hand attributable to the ulnar normal dorsal fields, involved one or more digits and/or an
nerveinjury.Consistentwiththis,receptivefieldsineachpostin- adjacent area on the dorsal hand (Fig. 10A,B) and occupied a
juryCNmaptypicallycoveredmost(mean575%)ofthedorsal meanareaof6.7%ofthehandsurface.Thisissimilartothesize
handsurface;however,inputsfromallormostofdigit5and/or of normal dorsal hand fields (mean 5 7.7%; t[11] 5 0.26, p 5
the adjacent ulnar hand, which are commonly part of the ulnar 0.80)(Fig.11)(XuandWall,1999).
nerve innervation territory, were usually not represented in CN
maps (Fig. 6B). The differences in enlargements of representa- Forelimb and otherrepresentations
tionsofdigitversusproximalhandregionsarenotattributableto Preinjury receptive fields on the glabrous hand occasionally
differential denervation because the ulnar sides of both regions shiftedtoforelimblocationsafterinjury;however,thepostinjury
were denervated. Together, these findings suggest that CN rep- sizes of the forelimb and other representations were similar to
resentationsofdorsalhandsubregionsdidnotenlargeuniformly, normal [postinjury: forelimb mean 5 23.4% (SD 5 2.2) and
partly because of denervation gradients and partly because of trunk–face–hindlimbmean513.9%(SD52.1)ofCNtransverse
otherfactorsthatremainlessclear. area; normal: forelimb mean 5 27.6% (SD 5 8.1) and trunk–
Severalfeaturesofsomatotopicorganizationwereconsistently face–hindlimbmean510.5%(SD54.9)ofCNtransversearea
observedinpostinjuryCNrepresentationsofthedorsalhand.(1) (Table 1)]. In addition, postinjury forelimb and other represen-
As described above, acute injury resulted in expression of a tationswereintheirnormallateralandmedialCNlocationsand
largely continuous postinjury dorsal hand representation. This had a normal somatotopic organization, with representations of
decreased the somatotopic fracturing inherent in the normal theforelimb,shoulder,neck,andfacelocatedlateraltothehand
discontinuous, patchy representation of this skin. (2) Tactile representation,andinputsfromtheforelimb,trunk,andproximal
XuandWall•BrainstemandCorticalPlasticity J.Neurosci.,September1,1999,19(17):7578–7590 7583
Figure 7. Somatotopic gradients of re-
ceptive fields on the dorsal digits and
proximal dorsal hand in CN (A–H) and
area3b(I–L)maps.A–F,Withinpostin-
juryCNdorsalhandrepresentations(dark
shading),recordingsiteswithfieldsonthe
digits(E)typicallyoccupiedmoredorsal
locations,whereassiteswithfieldsonthe
proximalhand(F)orthatextendedfrom
thedigitsontotheproximalhand(K)typ-
icallyoccupiedmoreventrallocations.G,
H,NormalCNmapsoftheglabrous(light
shading) and dorsal (dark shading) hand
have a similar gradient. I–L, Analogous
somatotopic gradients across the distal–
proximal dorsal hand are seen in postin-
jury (I–K) and normal (L) dorsal hand
representations(darkshading)inarea3b.
ForCNmaps,dorsal5upandmedial5
right.Scalebar,1mm.Forarea3bmaps,
anterior5up,medial5right.Scalebar,1
mm.Inallmaps,equaldensityrecording
sitesinwhiteareasarenotindicated.
hindlimb located medial to the hand representation (Fig. 12) representation.Althoughneuronsatthesesiteswerenotrespon-
[comparewithXuandWall(1999)].Takentogether,theseresults sivetotactilestimulationoftheskin,theywereoftenresponsive
suggest that forelimb and other nonhand tactile representations to harder tap stimuli, to stimulation of deep tissues, and/or to
didnotundergomajorchanges.Inviewoftheabovemagnitude movementofjoints.Takentogetherwiththeaboveresultsonthe
andconsistencyofchangesindorsalhandrepresentations,these dorsal hand and forelimb representations, these findings suggest
findingsindicatethattherewasananisotropyinCNreorganiza- that, after injury, approximately two-thirds of the normal CN
tion mechanisms that favored expansion of dorsal hand over hand representation was activated by dorsal hand inputs, and
forelimborother,cutaneousinputs. approximately one-third lost responsiveness to low threshold
cutaneous inputs. In contrast, representations of tactile inputs
Cutaneously unresponsiveareas
fromtheforelimbandotherbodypartseitherdidnotchangeor
Asindicatedabove,injuryledtoalossoflow-thresholdcutaneous hadsmall,lessconsistentchanges.
responsivenessatsomeCNrecordingsites.Normally,ameanof
8.8%oftheCNtransverseplaneareaisoccupiedbysitesthatare Relationships between CN and area 3b
not responsive to low-threshold tactile stimulation of the skin postinjuryorganization
(Table 1). These sites are located outside the hand representa- Immediatepostinjurychangeshavebeendefinedinarea3bafter
tion, usually near the CN borders. After injury, cutaneously thisinjury(Kolariketal.,1994),butnoattemptshavebeenmade
unresponsive areas enlarged to a mean of 27.6% of the CN to relate acute cortical and subcortical organization. As summa-
transversearea,anincrementof18.8%abovenormal(t[11]53.3, rizednext,therewereinterestingsimilarities,anddifferences,in
p 5 0.008) (Table 1). This increment involved CN locations postinjuryorganizationintheCNandarea3b(Table2).
where the glabrous hand is normally represented and locations
Similarities in CN and area 3borganization
aroundpostinjuryrepresentationsofthedorsalhand(Figs.1,12).
Giventhatthenormalhandrepresentationoccupiesameanarea Time course forchanges
of53.1%oftheCNtransversearea(seeabove),thisincrementis AtbothCNandarea3blevels,initialchangesinreceptivefields
equivalent to ;35.4% (i.e., 18.8/53.1) of the normal CN hand wereseenwithinminutes,andrelatedchangesinrepresentations
7584 J.Neurosci.,September1,1999,19(17):7578–7590 XuandWall•BrainstemandCorticalPlasticity
Figure8. Somatotopicgradientsofre-
ceptive fields on the radial and ulnar
dorsal hand in CN (A–H) and area 3b
(I–L)maps.A–F,WithinpostinjuryCN
dorsalhandrepresentations(darkshad-
ing), recording sites with fields on the
radialhand(F)typicallyoccupiedmore
lateral to lateroventral locations,
whereas sites with fields on the ulnar
hand(E)orthatextendedfromthera-
dialtoulnarhand(N)typicallyoccupied
moremediodorsallocations.G,H,Nor-
mal CN maps of the glabrous (light
shading)anddorsal(darkshading)hand
haveasimilargradient.I–L,Analogous
somatotopicgradientsacrosstheradial–
ulnarhandareseeninpostinjury(I–K)
andnormal(L)dorsalhandrepresenta-
tions(darkshading)inarea3b.ForCN
maps, dorsal 5 up and medial 5 right.
Scale bar, 1 mm. For area 3b maps,
anterior5upandmedial5right.Scale
bar,1mm.
were apparent within hours after this injury (Fig. 1) [and see Fig.8A-FvsI-K)handregions.Finally,bothlevelshadpartially
Kolariketal.(1994)].ThesefindingssuggestthatinitialCNand shiftedandoverlappingpostinjuryrepresentationsofdorsaldigits
area3bfunctionalchangesoccurconcurrently(Table2). that were in rough register with normal glabrous digit represen-
tations (Fig. 9). Taken together, these similarities suggest that
Hand receptivefields
somepostinjuryfeaturesofCNdorsalhandrepresentationswere
At both levels, the main postinjury change in tactile receptive consistentlypreservedinarea3b(Table2).
fieldsinvolvedshiftsfrompreinjuryglabroustopostinjurydorsal
handlocations.Postinjurydorsalreceptivefieldsoccupiedsimilar
combinationsofhandregionsatbothlevels(Fig.10B,C). Forelimbrepresentations
Thisinjuryresultedinasmallexpansionofforelimbinputsinto
Handrepresentations
ameanareaof5%ofthearea3bhandrepresentation(Kolariket
Postinjury CN and area 3b representations of the hand were
al., 1994). In the CN, receptive fields occasionally shifted from
similarinseveralways(Table2).First,atbothlevels,enlargement
glabrous hand to forelimb locations; however, postinjury CN
ofthenormallysmalldorsalhandrepresentationwasthepredom-
representationsoftheforelimbwerenotlargerthannormal(see
inantchange.Second,similarlocationsandextentsofthedorsal
above).Giventhisandthesmallextentofthearea3bchanges,it
hand were represented in the postinjury hand representation at
would appear that any differences in enlargements of CN and
eachlevel;inaddition,eachlevelhadrelativelylargerexpansions
ofrepresentationsofthedigitsandradialdorsalhandthanofthe area3bforelimbrepresentationsweresmall.Thus,despitesimilar
complementaryproximalandulnarhand(Fig.6).Third,postin- adjacencies of forelimb and hand inputs at both levels, forelimb
jury dorsal hand representations at both levels had analogous representations did not enlarge like dorsal hand representations
somatotopic gradients. This was reflected, for example, by the (Table 2). This suggests that CN and area 3b reorganizations
distributionsofCNandarea3brecordingsiteswithinputsfrom sharedasimilaranisotropythatledtolargerexpansionsofdorsal
proximal-digit(Fig.7,compareA–F,I–K)andradial–ulnar(e.g., handinputsthanforelimbinputs.
XuandWall•BrainstemandCorticalPlasticity J.Neurosci.,September1,1999,19(17):7578–7590 7585
Figure9. SomatotopicorganizationofdigitrepresentationsintheCN(A–D)andarea3b(E–H).A–C,Shadingandlabelingofareasinthreepostinjury
CNmapsindicatepostinjuryrepresentationsofdorsaldigits(DorD)1,3,and,whereseen,5inthefirstcolumn,andofdorsaldigits2and4inthesecond
column.Note(1)thepartiallyshiftedandoverlappinglocationsoftheserepresentationsfromD1lateroventrallytoD5(or4)mediodorsallyand(2)their
roughin-registerrelationtonormalglabrousdigitrepresentations(D).E–G,Shadingandlabelingofareasinthreepostinjuryarea3bmapsindicate
postinjuryrepresentationsofdorsaldigits1and3inthethirdcolumnand2and4inthefourthcolumn.Notethat,similartotheCN,postinjuryarea
3brepresentationsofdorsaldigitsoccupiedareasthatwerepartiallyshiftedandoverlappingfromD1laterallytoD4mediallyandwereinroughregister
withnormalglabrousdigitrepresentations(H).ForCNmaps,dorsal5upandmedial5right.Scalebar,1mm.Forarea3bmaps,anterior5upand
medial5right.Scalebar,1mm.
Differences in CN and area 3borganization ofthedorsalhandnormallyoccupiesameanareaof15%ofthe
Sizes of hand receptivefields area 3b hand representation, whereas the CN representation
normally occupies a mean area of 27% of the CN hand repre-
ThesizedistributionsofpostinjuryCNandarea3bdorsalhand
sentation (Fig. 5). After injury, the mean dorsal hand represen-
fieldsoverlapped;however,area3bfieldsweresmallerintermsof
mean (3b: 4%; CN: 6.7%; t[7] 5 2.7; p , 0.03), mode (3b: 2%; tationsexpandedbyapproximately2.5timesatbothlevels,which
resultedintheseinputsbeingrepresentedinameanareaequalto
CN: 5%), and upper 95% confidence interval (3b: 11.6%; CN:
66% of the normal CN hand map area but only 37% of the
16.3%)sizes(Fig.13).Inaddition,area3bhadalowerincidence
ofmultidigitdorsalfields(3b:mean523.9%;CN:mean548%; normal area 3b hand map area (Fig. 5). Thus, postinjury dorsal
t[7]53.8;p,0.007).Takentogether,thesefindingsindicatethat handinputsintheCNactivatedalargerpercentageofthehand
map space than the same inputs in cortex (Table 2). With few
postinjuryfieldsonthedorsalhandtendtobesmallerinarea3b
exceptions, this difference was consistently seen. For example, 9
(Table 2). This suggests that postinjury tactile fields undergo
of11CNpostinjurydorsalhandrepresentationswerelargerthan
sharpeningtransformationsbetweentheCNandarea3b.
the largest postinjury representation in area 3b (Fig. 5). These
Handrepresentations findings suggest that relatively large and continuous postinjury
PostinjuryCNandarea3bdorsalhandrepresentationsdifferedin CNrepresentationsofthedorsalhandwereattenuatedorincom-
the following ways (Table 2). First, representations in area 3b pletely expressed as relatively smaller, less continuous represen-
were consistently discontinuous, occupying three to six patches, tations in area 3b. Thus, some features of CN hand representa-
whereasCNrepresentationsweremorecontinuous(Fig.7,com- tionsweretransformedbeforebeingexpressedinarea3b.
pare I–K, A–F). Under normal conditions, the dorsal hand rep-
resentation is discontinuous at both levels (Fig. 7G,H,L); thus, Cutaneously unresponsiveareas
injuryresultedingreaterCNthanarea3bmergingofthenormal Denervation of the glabrous hand resulted in acute losses of
discontinuous representation of the dorsal hand (Table 2). Sec- tactileresponsesatbothlevels;however,differentextentsofloss
ond,alargerpercentageofthehandmapwasactivatedbydorsal occurredateachlevel.Neuronsatallrecordingsitesinthearea
handinputsintheCNthaninarea3b.Thearea3brepresentation 3bhandrepresentationarenormallyresponsivetotactileinputs,
7586 J.Neurosci.,September1,1999,19(17):7578–7590 XuandWall•BrainstemandCorticalPlasticity
Figure 10. Tactile receptive fields on the hand, as
seeninnormal(A)andpostinjury(B)conditionsin
the CN and in the postinjury condition in area 3b
(C).SeeResultsfordetails.
whereas after injury a mean area of 58.5% (SD 5 8.3) of this handfieldsor,lessfrequently,losttactileresponsiveness.Second,
representationbecameunresponsivetotactileinputs(Kolariket the dorsal hand representation enlarged, became more continu-
al., 1994). In contrast, the CN had postinjury increments in ous, and occupied CN locations where the glabrous hand is
tactilely unresponsive sites that involved a mean area equal to normally represented. Third, enlarged dorsal hand representa-
35.4% of the normal CN hand map (see above), indicating that tionsweresomatotopicallyorganized,withdistal-to-proximalin-
CN maps underwent less extensive losses of tactile responsive- putsactivatingdorsal-to-ventralCNlocations,radial-to-ulnarin-
ness than area 3b maps (Table 2). These results further support putsactivatinglateral-to-mediallocations,andrepresentationsof
the view that changes in CN tactile input organization were not dorsaldigitsactivatingpartiallyshiftedbutoverlappingareasthat
fullyexpressedinarea3b. were in rough register with normal representations of glabrous
digits. Fourth, other representations did not undergo major
DISCUSSION
changes,indicatingthattherewereanisotropiesinthecapacities
TheresultssuggestthattheCNofadultmonkeysundergoesrapid
ofhandandothertactileinputstoreorganize.Finally,thisinjury
functionalchangesafterhandinjuryandthatconcurrentchanges deprived ;74% of the CN hand map of normal tactile inputs;
in area 3b reflect preservations and transformations of CN
approximately two-thirds of the map became driven by radial
changes. These findings, their limitations, and their significance
nerveinputsfromthedorsalhand,whereasaboutone-thirdlost
arediscussedinturn.
tactileresponsiveness.Thus,CNtactileresponsiveness,receptive
How do features of CN tactile input organization fields, somatotopic organization, and properties of representa-
change immediately afterinjury? tions(i.e.,location,size,continuity)clearlychangedwithinmin-
SeveralCNchangesemergedafterthisinjury.First,CNneurons utes to hours after this injury. We add the cautionary note that
lostglabrousreceptivefieldsandwithinminutesacquireddorsal these changes were defined in a limited number of CN maps;
XuandWall•BrainstemandCorticalPlasticity J.Neurosci.,September1,1999,19(17):7578–7590 7587
Figure11. PostinjuryandnormalCNreceptivefieldsonthedorsalhand
were similar in size. Flower petal graph on the left shows sizes of all
postinjury dorsal hand receptive fields in five monkeys (1 petal in each
flower51receptivefield).Thebottomlineindicatesmeansize,andthe
top line indicates the upper 95% confidence interval distinguishing the
main part of the sample from outlier fields. The histogram on the right
indicatesmeanand95%confidenceinterval(CI)sizesfornormaldorsal Figure 12. Postinjury CN representations of tactile inputs from the
handfieldsfrom10monkeys. forelimb–trunk–faceintwomaps(A,B).Top,Cameralucidatracingsof
twoCNs.Dorsal5up;medial5right.Scalebar,1mm.Stipplingindicates
CN areas that contained recording sites with forelimb, trunk, and face
however, they appeared consistently in maps of different mon- receptivefields.Theseareasarelocatedlateralandmedialtothedorsal
keys.ThesefindingsextendpreviousresultsthatindicatethatCN handrepresentation(white)andadjacenttoareaswithrecordingsitesthat
handrepresentationsinmonkeysrapidlychangeafterinjury(Xu were not responsive to tactile stimulation of the skin (black). Middle,
Compositeofthereceptivefieldareasofallrecordingsiteswithforelimb–
andWall,1997a).
trunk–facefieldsthatwerelocatedinthearealateraltothehandrepre-
Thereissubstantialdisagreementabouthowacuteperipheral sentationfortheaboveCN.Ineachcase,notethatthisskinincludedthe
manipulations in adults affect CN organization. In this regard, forelimb, shoulder, neck, and face. Bottom, Composite of the receptive
acutelossofCNtactileresponses,butnoreceptivefieldreorga- field areas of all recording sites with forelimb–trunk fields that were
locatedmedialtothehandrepresentationfortheaboveCN.Ineachcase,
nization, occurred after lidocaine block of nerves to fingers of
notethatthisskinincludedtheforelimb,trunk,andproximalhindlimb.
raccoons(NorthgraveandRasmusson,1996)andaftercoldblock
of forepaw nerves in cats (Zhang and Rowe, 1997). In the only anatomical findings that afferents from each finger terminate in
previous study of acute injury, Zhang and Rowe (1997) tested separate CN compartments (Rasmusson, 1988; Northgrave and
several CN neurons after section of forepaw nerves and got Rasmusson, 1996). Thus, injury of glabrous inputs in monkeys
similarnegativeresults.Thesefindingsareconsistentwithlosses may leave normally unexpressed dorsal inputs as available sub-
of tactile responses in the present study. In contrast, Pettit and stratesforCNsynapticchangemechanisms,whereasblockadeof
Schwark(1993,1996)assessedCNtactileresponsesaftersubcu- inputs from a finger in raccoons may leave no comparable sub-
taneous forepaw injections of lidocaine or capsaicin and found strates. Other factors, including the nature of the peripheral
rapid field changes in all tested neurons. These changes are manipulations,mayalsocontribute(NorthgraveandRasmusson,
consistent with the present shifts in fields [for similar mixed 1996;ZhangandRowe,1997).
resultsinthegracileandtrigeminalnuclei,seeDostrovskyetal. The present findings provide insight into normal mechanisms
(1976); Millar et al. (1976); McMahon and Wall (1983); Waite of CN processing of hand inputs. For example, the rapid field
(1984);Panetsosetal.(1995,1997);Fagginetal.(1997)]. shiftssuggestthatnormalglabrousfieldsarenot“hardwired”but
There currently is no explanation for the above differences in are constructed physiologically by sharpening mechanisms that
results. Taken together with other data, the present findings suppress dorsal hand inputs. At the scale of representations, the
suggest that one factor in acute CN reorganization is how the replacementoftherepresentationoftheglabroussurfacewitha
manipulationinteractswithresidualCNafferents.Inthisregard, colocalized large, continuous, somatotopic, and roughly in-
thepresentfindingsofrapidglabrous-to-dorsalfieldshiftscorre- register representation of the dorsal surface suggests that CN
late with anatomical and functional findings that dorsal and substrates contain overlapping representations of both surfaces
glabrousafferentsnormallyterminateincloselyadjacentCNCO thatareinaflexiblestatebutnormallysettoexpresstheglabrous
patches (Florence et al., 1991; Xu and Wall, 1999). Moreover, representation. There is a recognition that the CN normally
preliminary findings further indicate that terminations of dorsal transforms,ratherthansimplyrelays,tactileinformationfromthe
hand afferents span larger extents of the CN than normal func- hand; however, these transformations are not understood. The
tional representations of these afferents, thus suggesting that presentfindingssuggestthatCNtransformationssharpenrecep-
some dorsal afferents are normally not functionally expressed tive fields and, on a larger scale, selectively promote (e.g., gla-
(XuandWall,1997b).Incontrast,thelackofrapidfieldchanges brous) and suppress (e.g., dorsal) full expression of
afterblockadeofinputsfromafingerinraccoonscorrelateswith representations.