Neural basis and recovery of spatial attention deficits in spatial neglect

Transcription

1 25 Nture Pulishing Group Neurl sis nd reovery of sptil ttention defiits in sptil neglet Murizio Corett 1 4, Mihelle J Kinde 5, Chris Lewis 2, Arhm Z Snyder 1,3 & Ayelet Spir 1 The syndrome of sptil neglet is typilly ssoited with fol injury to the temporoprietl or ventrl frontl ortex. This syndrome shows spontneous prtil reovery, ut the neurl sis of oth sptil neglet nd its reovery is lrgely unknown. We show tht sptil ttention defiits in neglet (rightwrd is nd reorienting) fter right frontl dmge orrelte with norml tivtion of struturlly intt dorsl nd ventrl prietl regions tht medite relted ttentionl opertions in the norml rin. Furthermore, reovery of these ttention defiits orreltes with the restortion nd relning of tivity within these regions. These results support model of reovery sed on the re-weighting of tivity within distriuted neuronl rhiteture, nd they show tht ehviorl defiits depend not only on struturl s t the lous of injury, ut lso on physiologil s in distnt ut funtionlly relted rin res. Injury to rin re uses ehviorl defiits tht re thought to reflet the lol dysfuntion of neurons t the site of injury. This logi (the lol injury hypothesis) hs een used for over 15 yers y physiins to lolize lesions in the rin. Neuropsyhologists hve uilt on the sme logi to show the independene of mentl proesses (for exmple, see ref. 1). However, s originlly pointed out y Hughlings Jkson, the loliztion of norml funtions (or mentl opertions) my or my not orrespond to the loliztion of ehviorl defiits. A lesion my use dysfuntion in other nodes of funtionl rin network 2,3, impiring proesses other thn those medited y neurons t the site of injury (the distriuted injury hypothesis). Aordingly, reovery of funtion my depend on the restortion nd relning of tivity in struturlly norml, ut funtionlly impired, nodes of tsk-relevnt network. Here, we test whether the distriuted injury hypothesis pplies to sptil neglet, one of the min ttentionl syndromes following injury to the humn rin. Sptil neglet ours in out 25 3% of ll stroke-ffeted individuls (n estimted 3 5 million yer, worldwide) 4,5.Itis omplex syndrome hrterized y filure to ttend to, look t nd respond to stimuli (ojets, food, people) loted on the side of spe or of the ody opposite to the side ffeted y rin lesion 6 8.This sptil is oexists with diffiulties in mintining lertness nd deteting trgets tht re not lterlized to one side of spe nd hs een linked to (non-sptil) defiits in ttentionl pity (sptil nd temporl) nd impired vigilne Over 9% of individuls with sptil neglet hve right hemisphere injury nd neglet of the left side of spe or ody. The most frequent sites of dmge re right inferior prietl, ventrl frontl 12,13 nd superior temporl ortex 14, long with suortil nulei 12,15. Although the ontriution of different regions to the different proessing defiits in neglet is unler (ut see refs. 16 nd 17), it is urrently ssumed tht these regions serve s speilized nodes of network tht medites sptil ttention, visuomotor ehvior (eye-hnd oordintion) nd vigilne 6,8. Notly, the lesion ntomy of sptil neglet does not losely mth the pttern of rin tivtion ssoited with sptil ttention nd visuomotor ehvior. When sujets diret ttention, eye movements or hnd movements to visul ojets tsks on whih individuls with neglet show rightwrd is prietl nd frontl regions re tivted tht re more dorsl thn those ntomilly dmged in neglet (Fig. 1). These regions form ilterl dorsl frontoprietl network (Fig. 1, lue regions) tht governs sptil ttention nd visuomotor ontrol (eye-hnd movement) 18 21, ontins visuotopi mps of ontrlterl spe 22,23 nd is involved in gol-direted stimulus nd response seletion 24. This network is plusile, neurl sustrte of sptil ises in neglet. The lotion of ntomil dmge nd its right hemisphere lterliztion more losely mthes set of ventrl temporoprietl nd frontl regions relted to the detetion of slient sensory events 18,25,26 (Fig. 1). These regions form ventrl ttention network tht redirets the dorsl network to novel nd ehviorlly relevnt stimuli, espeilly when these re unttended 24 (Fig. 1, ornge regions). Dmge to these ventrl regions my diretly medite defiits in non-sptil proesses suh s vigilne or (ttentionl pity 1 )s well s in ttentionl reorienting. We hypothesize tht sptil ttention defiits in neglet rise from the struturl or funtionl dysfuntion of oth dorsl nd ventrl ttention networks. A stroke in ventrl ortex (either frontl or prietl) should interfere with ttentionl reorienting. Moreover, s the ventrl 1 Deprtments of Neurology, 2 Rdiology nd 3 Antomy nd Neuroiology, Wshington University, 66 South Eulid Avenue, St. Louis, Missouri 6311, USA. 4 The Rehilittion Institute of St. Louis, 4444 Dunn Avenue, St. Louis, Missouri 6318, USA. 5 Deprtment of Psyhology, Wshington University, 66 South Eulid Avenue, St. Louis, Missouri 6311, USA. Correspondene should e ddressed to M.C. (mu@npg.wustl.edu). Reeived 13 June; epted 21 Septemer; pulished online 23 Otoer 25; doi:1.138/nn1574 NATURE NEUROSCIENCE VOLUME 8 [ NUMBER 11 [ NOVEMBER

2 25 Nture Pulishing Group L VFC L TPJ Visul ortex IPS-SPL TPJ (IPL-STG) L FEF Reltive derese Reltive inrese Top-down ontrol Stimulus response seletion Dynmi imlne R FEF Funtionl dmge Ventrl ortex dmged VFC (IFg MFg) Struturl dmge Stimulus-driven ontrol Ciruit reker network normlly sends the dorsl network iruit-reking signl during trget detetion, ventrl lesion should lso derese tivity of the (ipsilterl) right dorsl network (Fig. 1). The resulting hemispheri imlne ould produe rightwrd sptil is in visul proessing. A finl predition is tht the reovery of these ttentionl defiits is ssoited with normliztion of tivity in oth dorsl nd ventrl ttention networks. Previous work shows tht the reovery of neglet is ssoited with the restortion of norml tivity in ipsilterl suortil nulei fter frontl dmge in monkeys 27 or in right hemisphere regions fter ortil-suortil dmge in humns 17,28,29. However, no study to dte hs mesured funtionl tsk-evoked rin tivity in reltively numerous nd ntomilly homogenous group of individuls with sptil neglet during oth ute nd hroni stges of reovery nd relted rin tivity to ehviorl performne. Here we show tht sptil ttention defiits in neglet fter right frontl dmge orrelte with norml funtionl tivtion of struturlly intt regions of the dorsl nd ventrl ttention networks nd tht reovery of these defiits orreltes with the normliztion of tivity within these regions. RESULTS To test the ove preditions, we performed prospetive longitudinl study of individuls with sptil neglet (n ¼ 11) following unilterl strokes. Sujets were enrolled on the sis of the presene of extintion to doule simultneous stimultion, omission of trgets during visul serh or evidene of linil neglet in tivities of dily living within the first week of their stroke (see inlusion riteri in Supplementry Methods online). All sujets underwent stndrd rehilittion for t lest 3 months fter stroke. They were tested t the ute (B4 weeks, men ± s.d. ¼ 32 ± 22.8 dys) nd hroni stges of reovery (B39 weeks, men ± s.d. ¼ 39 ± 11.5 weeks) using ttery of FEF Figure 1 Funtionl-ntomil model of ttention. () Dorsl (lue, topdown) nd ventrl (ornge, stimulus-driven) regions of the humn ttention system. Blk, hypothetil ortil lesion in ventrl frontl, insulr nd perisylvin ortex, using sptil neglet. () Antomil model of ttention nd s in reltive tivtion fter ute dmge to right ventrl frontl ortex. Ares in lue (dorsl system) medite top-down stimulus-response seletion nd is the tivity in visul ortex. Ares in ornge (ventrl system) medite stimulus-driven reorienting. The shding in light lue nd red indite, respetively, reltive dereses nd inreses in funtionl tivity. IPS-SPL, intrprietl sulus superior prietl loule; FEF, humn frontl eye field; VFC, ventrl frontl ortex; TPJ, temporoprietl juntion; IFG, inferior frontl gyrus; STG, superior temporl gyrus; MFG, middle frontl gyrus; IPL, inferior prietl loule. neuropsyhologil nd omputerized tsks whih ssessed the presene of sptil or ody neglet, nosognosi, vigilne, sptil ttention nd rehing defiits. Antomy The mjority of sujets (63%, or 7 of the 11) hd lesions entered in the perisylvin region, inluding superior temporl gyrus (STG), frontl operulum, insul nd putmen (Fig. 2,d). The temporoprietl juntion (TPJ), inluding the suprmrginl gyrus (SMG) nd underlying white mtter, ws dmged in 45% of sujets (5 of 11; Fig. 2,), wheres no sujet hd lesions tht extended into dorsl posterior prietl ortex (speifilly, intrprietl sulus, IPS) or frontl ortex (speifilly, frontl eye field, FEF) (Fig. 2). One sujet hd lesion in the prhippompl gyrus, ut otherwise the visul ortex ws ompletely spred. On verge this group ws representtive of the most ommon lesion sites in neglet 15. The lotion of TPJ dmge mthed the lotion of mximl dmge fter middle ererl rtery strokes 13. Behvior Clinilly, from the ute to the hroni stge of reovery, ll sujets improved on trditionl mesures of sptil neglet (Supplementry Tle 1). Whole-rin funtionl mgneti resonne imging (fmri) of the lood oxygention level dependent (BOLD) signl, n indiret SMG.6 d IFG Insul SFS- PrCeS Figure 2 Lesion ntomy. () Atls rin; right hemisphere, ntomil verge of individul lesions. Color sle indites perentge of sujets with lesion overlpping speifi voxel. Red-yellow res, 5 7% overlp; yellow-green res, 3 5% overlp; purple-lue res, o1% overlp. Dshed lines indite setions t the level of () the TPJ (oronl view; SMG, suprmrginl gyrus), () dorsl frontoprietl regions (trnsverse view; SFS-PrCeS, superior frontl sulus-preentrl sulus: tht is, lotions of FEF nd IPS-SPL) nd (d) ventrl frontl nd insulr ortex (trnsverse view; IFG, inferior frontl gyrus). IPS SPL 164 VOLUME 8 [ NUMBER 11 [ NOVEMBER 25 NATURE NEUROSCIENCE

3 25 Nture Pulishing Group Retion times (ms) Contrlesionl Ipsilesionl Visul field Aute Chroni noninvsive inditor of neuronl tivity, ws quired t 4 weeks nd 39 weeks fter stroke. Sujets were snned while performing Posner visul orienting tsk used to define dorsl nd ventrl frontoprietl ttention networks in norml oservers 24 nd previously used to study sptil neglet 3. Sujets viewed entrl rrow ue tht overtly direted their ttention to left or right lotion on omputer sreen. After rndom dely, trget (n sterisk) ws riefly flshed t one of the two lotions. On 75% of the trils the trget ws presented t the lotion indited y the ue (vlid), wheres on 25% of the trils it ws presented t the opposite lotion (invlid). Sujets pressed key with their right hnd s soon s they deteted the trget, nd ury nd retion times were mesured. Ativity indued y the presenttion of the ue stimulus ws not seprted from tivity indued y the presenttion of the trget. All sujets were tested efore snning to estlish tht they ould see the stimuli, mintin urte fixtion on lrge mjority of trils (49%) nd rry out the tsk. Eye movements were not reorded in the snner. The ehviorl dt were nlyzed with three-wy nlysis of vrine (ANOVA), using stge (ute or hroni), visul field (left or right) nd ue vlidity (vlid or invlid) s ftors. Overll, sujets deteted more trgets t the hroni thn ute stge (87.7% versus 81.1%; F 1,1 ¼ 6.46, P o.5), in the ipsilesionl (right) thn ontrlesionl (left) visul field (87% versus 82%; F 1,1 ¼ 8.35, P ¼.1) nd when the trget ws vlidly ued rther thn invlidly ued (87% versus 81%; F 1,1 ¼ 6.62, P ¼.3). Similr effets were found for the retion time to detet trgets. Reovery ws indexed y two mesures. First, there ws signifint derement in the rightwrd proessing is, s shown y greter improvement in retion time to trgets in the ontrlesionl (left) rther thn the ipsilesionl (right) visul field (two-wy ANOVA of stge visul field; F 1,1 ¼ 4.77, P ¼.53; Fig. 3). Seond, there ws signifint improvement in ttentionl reorienting, expressed s n improvement in the hit rte nd retion time for deteting invlidly ued rther thn vlidly ued trgets (hit rtes for ute vlid nd ute invlid were 87% nd 76%, respetively; hit rtes for hroni vlid nd hroni invlid were 88% nd 87%, respetively; F 1,1 ¼ 14.35, P ¼.4; retion time: F 1,1 ¼ 4.79, P ¼.53, Fig. 3). Rightwrd is nd impired ttentionl reorienting (or the disengge defiit ; ref. 3) re roust mesures of the sptil impirment in neglet nd orrelte with the severity of, nd reovery from, sptil neglet s ssessed y more trditionl mesures 31. Funtionl MRI The norml pttern of rin tivtion on the Posner tsk, s shown previously 18 for group of young dults, involves lrge swths of oipitl, prietl, temporl nd frontl ortex ilterlly, exept in Retion times (s) Vlid Trget vlidity Invlid Figure 3 Behviorl results. () Reovery in ontrlesionl visul field. () Reovery in reorienting to invlid trgets. Aute Chroni right TPJ (Fig. 4). These mps re not diretly omprle to those in the strokeffeted sujets ut provide qulittive seline for omprison. In the neglet group, t 4 weeks fter stroke (Fig. 4), signifint ltertion ws evident in the tivtion pttern. In the dmged right hemisphere, lrge portions of oipitl visul ortex, posterior prietl ortex (espeilly IPS nd superior prietl loule (SPL)) nd dorsolterl prefrontl ortex (DLPFC) showed wek or no tsk-relted tivity, even though these regions were ntomilly intt. In the left hemisphere, there ws deresed tivity in oipitl visul ortex nd prefrontl ortex ut roust tivtion in prietl ortex nd sensory motor ortex (SMCX; Fig. 4). At 39 weeks, strong retivtion ourred in mny right hemisphere regions ut lso in mny left hemisphere regions (Fig. 4). Dorsl prietl ortex (IPS-SPL) To determine whih rin regions d their level of tivtion from 4 to 39 weeks, we rried out rndom-effet voxel-wise ANOVA using the MR frme (frmes 1 8) nd stge (ute or hroni) s ftors. One notle pttern ws oserved in dorsl prietl ortex, the posterior ore of the dorsl ttention network (Fig. 5,). In the right hemisphere, dorsl prietl ortex (speifilly, IPS-SPL) ws not tive t the ute stge ut strongly retivted t the hroni stge (pips-spl 23, 73, 51, P ¼.1; ventrl IPS (vips)-preuneus 14, 76, 36, P ¼.5). This retivtion ws independent of the visul field in whih the trget ws presented. In ontrst, in the left hemisphere, dorsl prietl ortex tivity ws stronger t the ute thn t the hroni stge (SPL 21, 6, 58, P ¼.8; IPS 26, 54, 24 F 7,7 ¼ 3.54, P ¼.3). Dorsl prietl ortex ws the only rin region tht showed this interhemispheri push-pull pttern from the ute to the Young dults Neglet ute DLPFC Neglet hroni L SMCX. Visul 1. ortex IPS-SPL R TPJ -SMG -STG IPS-SPL R TPJ -STG Visul. 5.5 ortex FEF R DLPFC Insul IFG DLPFC Figure 4 Funtionl mps of the Posner tsk. () In young dult oservers. (,) In sujets with neglet t () the ute nd () the hroni stge. Antomil revitions s in previous figures. DLPFC, dorsolterl prefrontl ortex; SMCX, sensory-motor ortex. NATURE NEUROSCIENCE VOLUME 8 [ NUMBER 11 [ NOVEMBER

4 25 Nture Pulishing Group Left L SPL L DLPFC 4 L SPL 4 L SPL ( 15, 74, 48) hroni stge. For exmple, prefrontl ortex retivted ilterlly t the hroni stge (left DLPFC: 46, 2, 39, P ¼.9; right DLPFC: 37, 43, 28, P ¼.1; Fig. 5,); left FEF tivity did not, wheres djent lusters in right FEF showed opposite ptterns (right preentrl gyrus: 31, 15, 61, P ¼.2 ute 4 hroni; right preentrl gyrus: 4, 1, 43, P ¼.1 hroni 4 ute). See Supplementry Tle 2 for omplete list of oordintes. To onfirm tht dorsl posterior prietl ortex ws the site of tivity imlne, we rried out regionl ANOVA using regions of interest (ROIs) from the young dult group in IPS (nterior nd posterior) nd FEF (medil nd lterl), regions previously shown to e involved in ontrolling sptil ttention 18. This nlysis onfirmed n imlne in dorsl prietl ortex ut not in the FEF (Supplementry Fig. 1). The interhemispheri push-pull pttern in dorsl prietl ortex is onsistent with the hypothesis tht the lterlized (rightwrd) is in R IPS-SPL 4 R STG R DLPFC 4 Right Hit Miss L SPL ( 21, 6, 58) L DLPFC ( 46, 2, 39) Aute left VF Aute right VF neglet is used y left hemisphere orienting mehnism tht is reltively hypertive 32. If left prietl ortex hypertivity medites the rightwrd sptil is, then greter tivity in left SPL should orrelte with greter numer of missed trgets; this invrily ourred in the left visul spe. A voxel-wise ANOVA identified severl left hemisphere regions tive for missed trgets; one of the most signifint regions ws the left SPL ( 15, 79, 4; Fig. 5). In seond nlysis, we diretly ompred hit nd miss trils in voxel-wise ANOVA. One gin we found signifint effets in left SPL (grph in Fig. 5) where the response ws signifintly stronger for miss thn for hit trils (F 7,7 ¼ 3.85, P ¼.1), espeilly t the ute stge (response stge MR frme; F 7,7 ¼ 3.16, P ¼.6). Finlly, we found positive signifint orreltion etween rightwrd is nd left SPL tivity (r 2 ¼.36, P ¼.51) t the hroni stge (see Supplementry Fig. 2), onfirming tht hypertivity in this region orrelted with poor orienting towrd the left visul field R IPS-SPL (23, 73, 51) R DLPFC (37, 43, 28) Chroni left VF Chroni right VF Figure 5 BOLD orreltes of rightwrd is in prietl ortex. () BOLD s from ute to hroni stge in prietl nd frontl ortex (thresholded t z ¼ 2.5, P o.1 unorreted), superimposed on three-dimensionl tls rin with verge lesion emedded. The dshed lk line indites slie through SPL in pnel. () BOLD signl time ourses for trgets in left nd right visul fields t ute nd hroni stges. () BOLD signls for missed trgets in left SPL. Grph, BOLD time ourse for hits nd misses in left SPL. y = 76 R IPS/SPL Visul ortex Figure 6 BOLD orreltes of rightwrd is in visul ortex. () BOLD s from ute to hroni stge in visul ortex (thresholded t z ¼ 2.5, P o.1 unorreted). Coronl slie t y ¼ 76. () Retinotopi ROIs seleted in young dults: green, ventrl; purple, dorsl. BOLD signl time ourses from left nd right ventrl ROIs in sujets with neglet. (,d) BOLD signl time ourse, in right ventrl visul ortex, for left nd right visul field trgets () in young dults nd (d) in neglet group t ute nd hroni stges. L R Aute Chroni Aute left VF Aute right VF Chroni left VF Chroni right VF d R visul ortex Young dults (n = 13) R visul ortex Neglet (n = 11) Left VF Right VF VOLUME 8 [ NUMBER 11 [ NOVEMBER 25 NATURE NEUROSCIENCE

5 Figure 7 BOLD orreltes of ttentionl reorienting. () Regions involved in the reovery of reorienting. ANOVA (stge vlidity MR frme) intertion mp (expressed s z, thresholded t z ¼ 2.5, P o.1 unorreted). () BOLD signl time ourses for vlid nd invlid trils t ute nd hroni stges, verged over left nd right visul fields. () Correltion ross sujets etween the mgnitude of the BOLD signl nd retion, on invlid trils t the ute stge. Pu, preuneus. L SMG ( 32, 57, 44) R Pu (17, 65, 44) 25 Nture Pulishing Group Visul ortex Neurl models of ttention 24,33 postulte tht posterior prietl ortex interts with visul ortex for the seletion of relevnt ojets. Our hypothesis predited tht tivity in visul ortex should mirror the push-pull interhemispheri pttern oserved in posterior prietl ortex. Mny regions in visul ortex showed signifint s in tsk-relted BOLD tivity from the ute to the hroni stge (Fig. 6). To test this hypothesis, dorsl nd ventrl retinotopi ROIs were seleted from visul ortex in the young dult group (see Supplementry Methods), nd signl time ourses were extrted from these ROIs in the neglet group t the ute nd hroni stges. In oth ventrl nd dorsl retinotopi ROIs, we oserved reltive imlne t the ute stge with more tivity in the left thn right hemisphere, nd relning t the hroni stge with retivtion of the right hemisphere (grph in Fig. 6). This ws onfirmed y signifint intertion of stge (ute or hroni) hemisphere (left or right) time in ventrl visul ortex (three-wy ANOVA; F 7,7 ¼ 2.62 P ¼.2) nd stge hemisphere visul field time in dorsl visul ortex (four-wy ANOVA; F 7,7 ¼ 2.59, P ¼.2). In right dorsl oipitl ortex, the retivtion ws lrger for trgets in the left (ontrlesionl) thn in the right (ipsilesionl) visul field. All results were onfirmed when using only hit trils. We lso oserved disruption of sptilly seletive responses in right visul ortex. In the young dult group (Fig. 6), trgets in the ontrlterl visul field evoked stronger responses thn did trgets in the ipsilterl visul field (F 7.84 ¼ 3.18, P ¼.49), espeilly in the right hemisphere (F 1,12 ¼ 6.4, P ¼.3). In the neglet group (Fig. 6d), norml lterliztion ws oserved in left visul ortex, wheres in right visul ortex, trgets in the left (ontrlesionl) visul field evoked signifintly less tivity thn did those in the right (ipsilesionl) visul field (three-wy ANOVA: MR frme hemisphere visul field; F 1,1 ¼ 4.83, P ¼.5). When ompred to the young dult group, this inversion ws signifint t the ute stge (four-wy ANOVA: hemisphere visul field MR frme group; F 7,154 ¼ 2.38, P ¼.2) ut not t the hroni stge, even though the time ourse of the BOLD signl ws not qulittively different (Fig. 6d). Correltion nlyses showed only mrginl orreltions etween left or right visul ortex tivity nd mesures of rightwrd is (ll omprisons,.5 o P o.1). Temporoprietl juntion The seond index of ehviorl reovery ws the improved ility to reorient to unttended lotions. This funtion is known to orrelte with the reovery of sptil neglet 31 nd is speifilly ssoited with dmge to the STG 16. The TPJ region ws defined in our lortory s the lusters of tivtion in SMG nd STG tht show differentil response to unttended (invlidly ued) versus ttended (vlidly ued) visul trgets (Fig. 1). This region ws dmged in 5 of 11 sujets (Fig. 2). We oserved some retivtion in the ventrl prt of the TPJ from the ute to the hroni stge (right STG: 63, 44, 21, P o.1; right prietl operulum: 57, 35, 35, P o.1; see Supplementry Tle 2), L SMG.3 L STG L SMG RT (ms) L STG RT (ms) Aute vlid Chroni vlid 8 15 Left Right L STG ( 62, 44, 13) R STG (56, 45, 16) Aute invlid Chroni invlid RT (ms).6 R STG RT (ms) ut the degree of retivtion depended on the presene of ntomil dmge (Supplementry Fig. 3). To identify regions whose tivity vried s funtion of oth the stge of reovery nd ttentionl reorienting, s indexed y trget vlidity, we rn voxel-wise ANOVA with MR frme, stge (ute or hroni) nd trget vlidity (vlid or invlid) s ftors. We identified severl regions tht showed n intertion of stge vlidity time, inluding left nd right STG (ventrl prt of TPJ), ut lso dorsl regions suh s the right preuneus nd left IPS (Fig. 7 nd Supplementry Tle 3). This reorienting network in stroke-ffeted sujets lrgely overlpped with tht reruited in norml sujets under the sme onditions. Time-ourse nlysis indited tht the intertion ws rried y weker nd delyed response t the ute stge, espeilly for invlid trgets (Fig. 7). This intertion ws very ler in right TPJ when the time-ourse nlysis ompred sujets with nd without ntomil dmge to this region (Supplementry Fig. 3). The modultion of right TPJ y oth the stge of reovery nd ttentionl reorienting (tht is, trget vlidity) ws onfirmed y repliting the stge vlidity time intertion in regionl ANOVA, in whih the ROI ws independently seleted from the R Pu R STG R Pu NATURE NEUROSCIENCE VOLUME 8 [ NUMBER 11 [ NOVEMBER

6 25 Nture Pulishing Group young dult group. Only the hit trils were inluded to void ontmintion from error relted signls. Finlly, we oserved, in TPJ nd other regions of the reorienting network, speifi orreltion t the ute stge etween the mgnitude of the BOLD signl nd the retion time to invlidly ued trgets (left STG: 62, 44, 13, r 2 ¼.73, P o.1; right STG: 56, 45, 16, r 2 ¼.39, P ¼.4; right preuneus: 13, 43, 6, r 2 ¼.54, P ¼.1; Fig. 7). No reltionship ws found for vlidly ued trgets exept in left STG (r 2 ¼.49, P ¼.2), eliminting n effet of time on tsk s n explntion for the orreltion. None of these effets interted with the visul field of the trget (ll omprisons, P 4.5). DISCUSSION We showed tht ttentionl defiits in sptil neglet did not depend just on neuronl dysfuntion t the site of injury, ut were medited y the omined struturl nd funtionl dysfuntion of two interting frontoprietl ttention networks. The reovery of sptil ttention defiits, ordingly, orreltes with the retivtion nd relning of norml tivity within these networks. BOLD signls in humn stroke model There is growing evidene tht BOLD signls my e norml in individuls with stroke; hene n importnt issue is whether our findings might e rtiftul. Mehnisms linking lol neuronl tivity to lol hemodynmi s (lood flow or BOLD) so-lled neurovsulr oupling my e impired fter stroke, even in the unffeted hemisphere Although these findings suggest ution in relting BOLD-fMRI signls to neuronl s in strokeffeted individuls, they nnot explin the urrent findings. First, s in the BOLD response during reovery showed strong orreltion with performne. Seond, lthough in mny res reovery ws ssoited with lrger BOLD responses, in other res reovery indued n ttenution of reltively hypertive response. Third, none of the strokes in our smple were lunr the type ssoited with rtiftul derement in tsk-evoked BOLD response 35.Finlly,mostof the results we report ourred in res tht were distnt from the ore of the lesion where time-dependent s hve een reported 36. Rightwrd is nd reorienting We found different neurl orreltes for two seprte sptil ttention defiits nd their reovery: rightwrd sptil is nd the reorienting defiit. The rightwrd sptil is, reltive impirment in deteting trgets in the left visul field, ws ssoited with reltive funtionl imlne t the ute stge in dorsl prietl ortex (IPS-SPL) nd visul ortex. At the hroni stge, tivity in these regions relned in prllel with ehviorl reovery. Our interprettion is tht the deresed BOLD responses t the ute stge in dorsl prietl ortex reflets the lk of n exittory iruitreking stimulus-driven signl from injured ventrl res during trget detetion (Fig. 1). Under norml onditions this signl reorients the dorsl system to relevnt events, ut fter VFC dmge, its sene indues reltive detivtion of ipsilterl (right) dorsl prietl ortex. The resulting funtionl imlne, t the ute stge, in dorsl prietl nd visul orties is mnifested s reltive hypertivtion on the left nd reltive detivtion on the right (dynmi imlne, Fig. 1). This imlne nd the relning tht ours over time re onsistent with ompetitive (possily ross-inhiitory 37 )intertions etween oppositely lterlized orienting mehnisms for direting ttention nd visul representtions, s previously hypothesized 32. The results of our experiment provide evidene for these ompetitive intertions, lolize the site of ompetition to dorsl prietl ortex nd show ler funtionl intertion etween dorsl prietl nd visul orties. The reltionship etween tivity s in dorsl prietl ortex nd the rightwrd sptil is ws supported y two independent nlyses. There ws reltively higher response in left SPL in sujets who deteted fewer trgets in the left visul field nd in those who responded more slowly to left, s ompred to right, visul field trgets. Notly, the shpe of the BOLD response, in left SPL, to missed trgets ws sustined nd outlsted the response to deteted trgets (Fig. 5), suggesting tht the orienting is in SPL ws toni nd endogenous. Toni oulomotor ises tht re independent of visul stimultion hve een desried in neglet 38. The response in right visul ortex, espeilly t the ute stge, not only ws deresed ut lso did not show norml lterliztion tht is, stronger response to ontrlterl (left) thn to ipsilterl (right) visul trgets (Fig. 6). One interprettion of these results is tht unlned top-down modultion from dorsl prietl ortex deresed oth stimulus-evoked responses nd sptil seletivity of visul neurons, wekening the reltive sliene of stimuli presented in the left visul field. Tht is, the rightwrd sptil is my reflet oth norml orienting medited y imlned IPS-SPL tivity nd norml sensory proessing of stimuli in the left visul field. However, s there ws no ler reltionship etween BOLD response in visul ortex nd rightwrd is, the role of visul neurons in mediting the rightwrd is will require further tests, suh s the seprtion of uend trget-relted tivity or the orreltion, tril y tril, of rin tivity nd ehviorl performne. A seond key defiit in sptil neglet is the inility to reorient to ehviorlly relevnt stimuli presented t unttended lotions: the solled disengge defiit 3. Our sujets with neglet showed good reovery of reorienting, with fster nd more urte responses over time to unttended trgets. Previous work orrelted stimulus-driven reorienting with right hemisphere dominnt ventrl nd dorsl network, inluding TPJ 24. Here, we found tht reorienting defiits nd their reovery lso orrelted with funtionl s in similr network. In sujets with lesions restrited to ventrl frontl ortex nd relted suortil strutures (Supplementry Figs. 2 nd 3), right TPJ retivted from the ute to the hroni stge (Supplementry Fig. 3), nd this retivtion ws modulted y whether the trget ws ttended or unttended (Fig. 7). For trgets presented t unttended lotions, BOLD signls in right nd left STG ( suregion of TPJ) were delyed t the ute stge s ompred to the hroni stge (Fig. 7 nd Supplementry Fig. 3). Moreover, t the ute stge, sujets with stronger STG tivity responded more slowly to trgets t unttended lotions. One interprettion is tht signls in the TPJ indexed the time it tkes to reorient to novel lotion of interest, proess tht ws delyed t the ute stge. A new ntomil model of sptil neglet These results provide new frmework for thinking out the pthophysiology of sptil neglet nd reonile funtionl neuroimging results with the ntomy of neglet. Ventrl lesions in frontl or temporoprietl ortex use dysfuntion of dorsl prietl res tht seem to medite rightwrd is during sptil ttention. However, isolted dmge to these dorsl res does not typilly use neglet, even though it n produe defiits of eye movements, ttention nd visuomotor hnd oordintion 39,4. Therefore, dmge (funtionl or struturl) to oth dorsl nd ventrl ttention networks is neessry for neglet to our. This result rules out the possiility tht sptil neglet results from the ritil dysfuntion of one rin re VOLUME 8 [ NUMBER 11 [ NOVEMBER 25 NATURE NEUROSCIENCE

7 25 Nture Pulishing Group The TPJ region is ruil euse it provides signl tht mrks sensory events of interest for the dorsl system, espeilly when they re unttended. Dmge to TPJ produes two effets tht ontriute to neglet. First, it dereses the overll detetion pity tht is, the pity ross the visul field 11. Seond, it ises ompetitive intertions etween orienting mehnisms in dorsl prietl ortex 32. Therefore, stimulus in the left visul field will e t disdvntge, s ompred to stimulus in the right visul field, on two ounts: (i) deresed stimulus-driven pture resulting from dmge of right TPJ nd (ii) top-down is ginst exploring leftwrd lotions, owing to imlned orienting mehnisms in left nd right IPS. The ide tht non-sptil proessing defiits ontriute to sptil neglet nd my exerte sptil ises hs een suggested efore 9,1, ut we provide new ntomil frmework in whih to think out these intertions. The right hemisphere dominne of sptil neglet hs previously een explined y theories tht emphsize hemispheri symmetries in sptil mps, with right prietl ortex oding for oth sides of spe nd left prietl ortex oding predominntly for the ontrlterl (right) spe 6,8,41. However, reent studies, in norml oservers, tht mpped visuotopi responses in frontl nd prietl orties hve not reveled ny hemispheri symmetry in sptil representtions or orienting signls 22,23. In ontrst, there is ompelling evidene for right hemisphere dominnt ventrl ttention system, inluding TPJ (reviewed in ref. 24). Therefore, our urrent hypothesis is tht the higher frequeny of left-sided neglet is funtion of the right hemisphere dominne of non-sptil proesses medited y right TPJ, oupled with their physiologil impt on ipsilterl sptil proesses medited y IPS- SPL. Implitions regrding mehnisms of reovery of funtion These results show tht neurologil defiit fter fol rin injury does not reflet only lol dysfuntion t the site of injury, ut lso is determined y the distriuted impirment of onneted neurl systems tht re struturlly intt 2,3. This dysfuntion my e refleted neurlly not just y dishisis t rest, s shown in previous studies 17,27,28 ut lso y detivtion, hypertivity or interhemispheri imlne during tsk proessing, s shown here. Although this distriuted impirment priniple hs een demonstrted here for sptil neglet, it is likely to pply to other defiits suh s phsi or sensory-motor defiits, nd thus hve widespred implitions for the fields of neuropsyhology nd neurology. For exmple, the loliztion of speifi neuropsyhologil syndromes on the sis of ntomil informtion should e re-exmined y omining oth ntomil nd funtionl informtion. Tht ehviorl defiit reflets distriuted dysfuntion does not imply tht different nodes of funtionl network do not perform speilized opertions. The notion of distriuted injury is neutrl with respet to the issue of whether ognitive opertions in the intt rin re rried out in speilized nodes (one-to-one mpping) or over mny nodes (one-to-mny), or whether different opertions re mpped to the sme node s funtion of tsk demnds (mny-toone). Nonetheless, in our se the evidene strongly indites reltive speiliztion of different nodes s in the se of IPS-SPL for direting ttention or TPJ for reorienting ttention. The notion of ompetition etween hemispheres nd the negtive influene of tivity in the intt hemisphere is emerging s n importnt priniple t the systems level to understnd reovery of funtion, not only in sptil neglet, ut lso in studies of motor nd lnguge reovery 42,43. Modultion of these ompetitive intertions either y inresing the exitility of the ipsilesionl ortex or y deresing the exitility of the intt ortex should hve enefiil effet 44. For exmple, we predit tht in individuls with hroni neglet who show persistent rightwrd is despite extensive rehilittion, there should e persistent left SPL hypertivtion; reduing tht hypertivity should e enefiil. This hypothesis hs een tested with some suess in TMS studies tht hve rodly trgeted the left prietl ortex of individuls with neglet 45. Our results suggest more speifi site where TMS tretment might hve fvorle therpeuti effet. METHODS Prtiipnts were eleven ptients (men ge 6 yers; 8 mle) with right frontoprietl stroke nd linil neglet. Both ehviorl testing nd fmri were onduted first in the ute stge (3 4 week post-stroke) nd then t the hroni stge (46 months post-stroke). Individul lesions were segmented (in tls spe) using supervised fuzzy lss-mens proedure on the sis of o-registered T1- nd T2-weighted struturl dt quired in the hroni stge. The Posner tsk ws implemented during fmri s previously desried 18,24. Detils of funtionl snning proedures (sequene prmeters nd dt nlysis tehniques) re s previously desried 18,21. Additionl tehnil detils re given in the Supplementry Methods. Note: Supplementry informtion is ville on the Nture Neurosiene wesite. ACKNOWLEDGMENTS We thnk G.L. Shulmn for disussions nd omments. Supported y the J. S. MDonnell Foundtion, the J. S. MDonnell Center for Higher Brin Funtion nd the Ntionl Institute of Neurologil Disorders. COMPETING INTERESTS STATEMENT The uthors delre tht they hve no ompeting finnil interests. Pulished online t Reprints nd permissions informtion is ville online t reprintsndpermissions/ 1. Crmzz, A. Some spets of lnguge proessing reveled through the nlysis of quired phsi: the lexil system. Annu. Rev. 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