LOOK AWAY: THE ANTI-SACCADE TASK AND THE VOLUNTARY CONTROL OF EYE MOVEMENT

Transcription

1 LOOK AWAY: THE ANTI-SACCADE TASK AND THE VOLUNTARY CONTROL OF EYE MOVEMENT Dougls P. Munoz* nd Stefn Everling The nti-sccde tsk hs emerged s n importnt tsk for investigting the flexile control tht we hve over ehviour. In this tsk, prticipnts must suppress the reflexive urge to look t visul trget tht ppers suddenly in the peripherl visul field nd must insted look wy from the trget in the opposite direction. A crucil step involved in performing this tsk is the top-down inhiition of reflexive, utomtic sccde. Here, we descrie recent neurophysiologicl evidence demonstrting the presence of this inhiitory function in single-cell ctivity in the frontl eye fields nd superior colliculus. Ptients dignosed with vrious neurologicl nd/or psychitric disorders tht ffect the frontl loes or sl gngli find it difficult to suppress the utomtic pro-sccde, reveling deficit in top-down inhiition. *Centre for Neuroscience Studies, Deprtment of Physiology, CIHR Group in Sensory Motor Systems, Queen s University, Kingston,Ontrio K7L 3N6, Cnd. Deprtments of Physiology & Phrmcology nd Psychology, University of Western Ontrio, London, Ontrio N6A 5C1, Cnd. Rorts Reserch Institute, PO Box 5015, 100 Perth Drive, London, Ontrio N6A 5K8, Cnd. Correspondence to D.P.M. e-mil: doug@eyeml.queensu.c doi: /nrn1345 One chrcteristic feture of humn ehviour is our ility to ct flexily in response to environmentl events. For exmple, while strolling down crowded sidewlk, you might notice n ttrctive person in the distnce. Under most circumstnces, n dmiring glnce towrds tht person would e pproprite. Except, however, when you re with your prtner. In this instnce, it might e wise to void looking in tht direction nd insted to orient in the opposite direction. This ility to control ehviour flexily, responding utomticlly to stimuli in one sitution nd suppressing this utomtic response in fvour of n lterntive response in different sitution, is the hllmrk of executive control. The SACCADIC EYE MOVEMENT system provides n excellent model for investigting this ility of the rin ecuse eye movements re esy to mesure in the lortory nd ecuse we hve considerle knowledge of the neurl networks tht prticipte in controlling gze (BOX 1). In this review, we descrie how the ntisccde tsk cn e used to investigte the volitionl control of ction nd how this tsk cn e used to understnd the pthophysiology tht underlies vrious neurologicl nd psychitric disorders. The nti-sccde tsk In the lortory, ehviourl prdigms hve een developed to study the ility of the rin to respond flexily to our environment (BOX 2).The nti-sccde tsk 1 hs ecome one of the most populr tsks ecuse it contins mnipultion of stimulus response comptiility tht decouples stimulus encoding nd response preprtion. In this tsk, the prticipnt is instructed tht, fter presenttion of peripherl trget, they must look wy to its mirror position. performnce on this tsk requires two steps. The suject must first suppress the utomtic response to look t the trget (pro-sccde) nd then trnsform the loction of the stimulus into voluntry motor commnd to look wy from the trget (nti-sccde). Performnce on the nti-sccde tsk cn e contrsted with performnce on the pro-sccde tsk in which the loction of the sensory stimulus nd the gol of the sccde re comptile (FIG. 1, left), requiring direct sensory motor trnsformtion. In the ntisccde tsk (FIG. 1, right), stimulus loction nd sccde gol re decoupled: the direct response must e suppressed nd the stimulus vector must e inverted into the sccde vector. We review the neurl mechnisms relted 218 FEBRUARY 2004 VOLUME 5

2 Box 1 Neurl circuitry controlling sccdic eye movements An extensive ody of literture descriing lesion studies, humn ehviourl testing, functionl neuroimging, niml neurophysiology nd detiled ntomy hs identified severl rin res tht re involved in controlling visul fixtion nd sccdic eye movements, including regions in the cererl cortex, sl gngli, thlmus, superior colliculus (SC), rinstem reticulr formtion nd cereellum 48,49,56,96, (see pnels nd ).Visul inputs to the system rise from the retino-geniculo-corticl pthwy to the primry visul cortex nd from the retinotectl pthwy to the superficil lyers of the SC. Visul informtion is processed through severl extrstrite visul res 117 efore it impinges on motor structures to ffect ction. The lterl intrprietl re (LIP) in the posterior prietl cortex is t the interfce etween Indirect pthwy GPe STN Bsl gngli Frontl cortex CN SNpr DLPFC Direct pthwy Suppression (frontl cortex, sl gngli) sensory nd motor processing 118,119.The LIP projects to oth the intermedite lyers of the SC 120 nd the frontl corticl oculomotor res 121,122,including the frontl eye fields (FEF), the supplementry eye fields (SEF) nd the dorsolterl prefrontl cortex (DLPFC). The FEF hs crucil role in executing voluntry sccdes 98, The SEF is importnt for internlly guided decision-mking nd sequencing of sccdes 126,127. The DLPFC is involved in executive function, sptil working memory nd suppressing utomtic, reflexive responses All of these frontl regions project to the SC 28,59,62, ,which is vitl node in the premotor circuit where corticl nd sucorticl signls converge nd re integrted 56,131. The FEF, SEF nd SC project directly to the prmedin pontine reticulr formtion to provide the necessry input to the sccdic premotor circuit so tht sccde is initited or suppressed 59,132,133. Frontl corticl oculomotor res lso project to the cudte nucleus (CN) 66,134,135. GABA (γ-minoutyric cid) neurons in the CN project through the direct pthwy to the sustnti nigr prs reticult (SNpr). Neurons in the SNpr form the min output of the sl gngli circuit: they contin GABA nd project to the intermedite lyers of the SC nd to nuclei in the thlmus tht project to the frontl cortex. Corticl inputs to the direct pthwy led to disinhiition of the SC nd thlmus ecuse these signls pss through two inhiitory synpses. There is lso n indirect pthwy through the sl gngli, in which seprte set of GABA neurons in the CN project to the externl segment of the glous pllidus (GPe). GABA neurons in GPe then project to the suthlmic nucleus (STN). Neurons in the STN send excittory projections to neurons in the SNpr, which in turn project to the SC nd thlmus. Corticl inputs to the indirect pthwy led to inhiition of the SC nd thlmus ecuse these signls pss through three inhiitory synpses 134,136.LGN, lterl geniculte nucleus; SCi, superior colliculus intermedite lyers; SCs, superior colliculus superficil lyers. SEF FEF Thlmus Cereellum Prietl cortex (LIP) Reticulr formtion Voluntry (frontl cortex, sl gngli) Oculomotor ehviour (SC) Premotor circuit (RF) Visul cortex LGN SCi SCs Retin Retinotectl pthwy Sccde Visul reflexive (prietl/occipitl cortex) Retino-geniculo-corticl pthwy Excittory connection Inhiitory connection SACCADIC EYE MOVEMENT A rpid eye movement (with speeds of up to 800 degrees per second) tht rings the point of mximl visul cuity the fove to the imge of interest. to these two processes: suppression of the utomtic response nd vector inversion. Monkeys cn e trined to perform the nti-sccde tsk nd therefore provide n importnt niml model 2,3 in which to investigte neurl processing relted to sccdic suppression nd sensory motor trnsformtion. Pro-sccde nd nti-sccde trils cn e rndomly interleved in lock of trils nd the instruction s to which type of movement to generte cn e conveyed y the colour or shpe of the initil fixtion mrker. In this configurtion, humn 4 6 nd monkey 2,3 sujects produce qulittively similr pttern of ehviour. FIGURE 1 illustrtes the distriution of rection times otined from monkey generting correct pro- nd ntisccdes nd the rection times of direction errors (sccdes triggered in the wrong direction: towrds the trget in the nti-sccde tsk; wy from the trget in the pro-sccde tsk). There re two importnt oservtions. First, if the peripherl trget ppers suddenly nd prticipnts re llowed to move immeditely, correct pro-sccdes re initited erlier thn correct ntisccdes. Second, most direction errors re confined to NATURE REVIEWS NEUROSCIENCE VOLUME 5 FEBRUARY

3 Box 2 Stimulus response mpping The nti-sccde tsk requires the suppression of sccde towrds peripherl stimulus nd the genertion of sccde in the opposite direction. As such, the nti-sccde tsk cn e regrded s clssicl exmple of n ritrry stimulus response (SR) mpping tsk 137,138.In prticulr, the nti-sccde tsk is specil cse of n SR comptiility tsk. A sccde towrds flshed visul stimulus (pro-sccde) represents congruent SR mpping, wheres n ntisccde requires incongruent SR mpping. It is well known from mnul SR comptiility tsks tht involve sptil stimuli nd sptil responses tht rection times re fster nd responses re more ccurte when the stimulus nd the response re comptile rther thn incomptile A relted tsk is the Simon tsk 142,143,in which sujects re presented with different tones in the left or right er nd re instructed to press left or right key depending on the pitch of the tone. Rection times re fster in this tsk when the tone nd the key re comptile in sides. Kornlum 137 proposed tht the rection time enefit for congruent versus incongruent mpping rules occurs t the response stge. When the stimulus overlps with the response, the presenttion of the stimulus will utomticlly ctivte its corresponding response. If the utomticlly ctivted response is correct then it is executed. When the SR mpping instruction requires n incomptile response, this utomtic response is orted nd the correct response is prepred nd executed. This ort process is time-consuming nd leds to the longer rection times for incongruent responses. Support for this hypothesis hs come from single neuron recordings in the primry motor cortex 144,145 nd premotor cortex 146 in monkeys tht show utomtic ctivtion of the congruent, ut erroneous, response on incongruent SR trils. Similrily, the initil responses of visuomotor neurons in the superior colliculus nd frontl eye fields on ntisccde trils could e regrded s utomtic ctivtion of the congruent, ut incorrect, pro-sccde. There re lso prllels etween these sptil SR mpping tsks nd tsks tht require n ritrry SR mpping. In the Stroop tsk 147,sujects re presented with the nmes of colours printed in colours nd re instructed to nme the print colours nd ignore the words. Rection times re fster when the print colours nd colour nmes re comptile rther thn incomptile 148,149.In the Eriksen flnker tsk 150,sujects re shown letter string with the instruction to press key sed on the centrl letter. Rection times re fster when the centrl letter nd the flnking letters re comptile. VISUAL GRASP REFLEX Flexive orienting response towrds novel visul stimulus. FRONTAL EYE FIELD An re in the frontl loe tht receives visul inputs nd produces movements of the eye. the nti-sccde tsk nd these errors re initited erlier thn correct responses. Sccdic suppression ility cn e chllenged in these tsks y ltering the fixtion stte t the time of trget ppernce. Removl of the fixtion mrker t lest 200 ms efore the trget ppers forces disenggement of ctive fixtion efore trget ppernce 7 nd leds to reductions in rection time for oth prond nti-sccdes nd to n increse in direction errors in the nti-sccde tsk 4,8. Closer exmintion of the distriution of rection times (FIG. 1) revels tht, in the pro-sccde tsk, there is imodl distriution. The initil pek of short-ltency sccdes, termed express sccdes 9 11, is significntly elevted in the gp condition nd represents the ehviourl mnifesttion of the VISUAL GRASP REFLEX 12.The ltency of these express sccdes pproches the minimum fferent nd efferent conduction delys 13. Express sccdes re elieved to e triggered y the direct trnsformtion of the incoming visul signl into the motor commnd to drive the eyes to the stimulus However, it would not e helpful for every visul signl to trigger sccde, nd so time is required etween sensory nd motor processing to mke decision regrding whether sccde is wrrnted. Therefore, most sccdes re triggered t regulr ltencies. In the nti-sccde tsk, the pttern of imodlity hs different shpe. The initil pek of express sccdes comprises, lmost exclusively, direction errors nd the correct responses hve longer rection times. Direction errors re most prevlent in the nti-gp condition, when the exogenous fixtion mrker hs een removed efore trget ppernce (FIG. 1c). Most direction errors re corrected fter short intersccdic intervls 17,reveling tht errors re not the result of n inility to generte the voluntry nti-sccde. Rther, direction errors re the result of filure to suppress the visul grsp reflex 3,18.They result from the incoming sensory signl triggering n immedite orienting sccde to the trget. Models hve een developed to ccount for the stochstic vriility in rection times Among them, the ccumultor model hs een prticulrly useful for interpreting neurophysiologicl nd ehviourl dt tht re relted to sccdic eye movements 13, These models suppose tht, to initite movement, neurl ctivity must ccumulte t some rte from seline until it surpsses threshold, therey triggering the movement. Vritions in seline, threshold or the rte of rise cn theoreticlly influence rection time. Neurophysiologicl studies hve determined tht the rte of rise of ctivity mong sccde neurons in the FRONTAL EYE FIELDS (FEF) nd superior colliculus (SC) tht occurs fter trget ppernce cn ccount for t lest some of the stochstic vriility in sccdic rection times 23,24,26.Other studies hve reveled tht the ctivity level of sccde neurons in the FEF nd SC t the time of trget ppernce (the seline level) cn lso ccount for vriility in sccdic rection times 15,27,28. From these oservtions we cn conclude tht oth prend post-trget processing influences the ccumultion of ctivity towrds threshold to trigger movement. In the nti-sccde tsk, there re two processes rcing towrds threshold 1 : process tht is initited y the ppernce of the trget tht serves to initite the utomtic prepotent response nd nother process tht is initited y the inversion of the stimulus vector to initite voluntry nti-sccde. To perform the tsk correctly, processes relted to the initition of the utomtic pro-sccde must e hndicpped in some wy to llow time for the voluntry nti-sccde response to 220 FEBRUARY 2004 VOLUME 5

4 Percent of sccdes c Eye position Fixtion point Trget Pro Anti-gp Percent of sccdes Anti 200 ms Overlp 200 ms Figure 1 The nti-sccde tsk. The colour of centrl fixtion mrker cn e used to instruct the suject to generte either pro-sccde (left) or n nti-sccde (right). Distriution of rection times from monkey for correct (ove sciss) nd error (elow sciss) responses in the pro-sccde tsk (left) nd the nti-sccde tsk (right). If the fixtion mrker remins lit during trget ppernce (overlp condition top pnels), rection times re incresed nd direction errors re uncommon, compred with when the fixtion mrker is sent t trget ppernce (gp condition ottom pnels). c Representtive eye position trces recorded from monkey performing the nti-sccde tsk in the gp condition. responses re in red nd error responses re in lue. Modified, with permission, from REF. 27 (1999) Society for Neuroscience Gp ccumulte towrds threshold. How re these two processes of sccdic suppression nd voluntry response genertion represented in the rin nd how re they hndicpped in the nti-sccde tsk? Neurophysiologicl findings in monkeys Mny corticl nd sucorticl structures re involved in the suppression nd/or genertion of sccdic eye movements (BOX 1).Single-neuron ctivity hs een recorded in numer of these rin res in monkeys performing the nti-sccde tsk, including the dorsolterl prefrontl cortex (DLPFC) 29,30, the lterl intrprietl re 31 34, the supplementry eye fields (SEF) 35 37, the FEF 28,38 nd the SC 18,27. The SC forms vitl node in the sccde network (BOX 1) ecuse it receives convergent input from lmost ll of the corticl nd sucorticl structures tht re involved in controlling sccdes. Together with the FEF, the SC projects directly to the prmedin pontine reticulr formtion to provide the necessry input to the sccdic premotor circuit for sccde initition 39. Therefore, understnding how neurons in the SC nd FEF prticipte in the suppression of utomtic responses nd the genertion of gol-directed sccdes is crucil for explining ehviour in the nti-sccde tsk. Suppression of the utomtic pro-sccde. The SC nd the FEF contin distinct popultions of fixtion nd sccde neurons 40 whose dischrges re modulted in reciprocl mnner in the nti-sccde tsk 27,28 (FIG. 2). Fixtion neurons re toniclly ctive during visul fixtion nd they cese to dischrge during the execution of sccdes. Sccde neurons hve reciprocl pttern of ctivity; they re silent during fixtion nd dischrge high-frequency urst of ction potentils for sccdes to certin region of the contrlterl visul field tht defines their response field. It hs een hypothesized tht network of inhiitory interneurons prticiptes in shping the reciprocl dischrges of fixtion nd sccde neurons 41,56. Let us consider the gp condition when the stimulus ppers in the right visul field, so tht rightwrd sccde is required in the pro-sccde tsk (lue trces in FIG. 2), nd leftwrd sccde is required in the ntisccde tsk (red trces). During fixtion of the centrl fixtion mrker, which lso serves s the instructionl cue to perform either pro- or n nti-sccde, fixtion neurons in the FEF nd SC re toniclly ctive, nd sccde neurons hve little or no ctivity (timepoint in FIG. 2). Compred with pro-sccde trils, ctivity of fixtion neurons is enhnced on nti-sccde trils (red trces ove lue trces), while the ctivity of sccde neurons is reduced (red trces elow lue trces). This reciprocl pttern of ctivity is pprent efore the trget ppers nd explins the nti-effect: longer rection times on nti-sccde trils thn on pro-sccde trils 1,6. Around 100 ms into the gp period (timepoint in FIG. 2), there is drop in fixtion neuron dischrge 7 nd slow uildup of low-frequency ctivity mong suset of sccde neurons in oth the SC 15,42 nd the FEF 28,43.This drop in fixtion ctivity nd the uildup of ctivity in sccde neurons during the gp period cn ccount for the gp effect the reduction in sccdic rection times tht occurs when gp period is introduced etween fixtion point disppernce nd trget ppernce The ppernce of the visul stimulus in the right visul field leds to phsic ctivtion of the visully responsive sccde neurons in the FEF nd SC on the contrlterl (left) side of the rin, nd to phsic inhiition of sccde neurons on the ipsilterl (right) side (timepoint c in FIG. 2). On pro-sccde trils, sccde neurons on the left side lso dischrge sccdic urst commnd for the rightwrd pro-sccde tht follows immeditely from the phsic visul response. On ntisccde trils, the sccde neurons in the left FEF nd SC must e inhiited so tht sccde neurons in the NATURE REVIEWS NEUROSCIENCE VOLUME 5 FEBRUARY

5 Contrlterl c c d c SN FN SN FN Frontl eye fields Superior colliculus right FEF nd SC cn e ctivted to drive the leftwrd nti-sccde (timepoint d in the right pnel of FIG. 2). During the visul nd motor responses, fixtion neuron ctivity in oth the SC nd the FEF flls to minimum. Wht hppens in the SC nd FEF when direction error is triggered? Recll from FIG. 1c tht such errors occur only on nti-sccde trils nd most frequently in the gp condition. These direction errors re the result of insufficient inhiition of sccde neurons in the FEF nd SC efore the trget ppers (FIG. 3). Without sufficient inhiition, the incoming visul trnsient response tht is produced y the ppernce of the trget, sums with elevted pretrget ctivity nd n express sccde is triggered, driving the eyes towrds the stimulus insted of wy from it. Most importntly, these direction errors cn e predicted on the sis of the dischrge of sccde neurons in the FEF nd SC efore the trget ppers 18,28 : excessive pre-trget ctivity mong sccde neurons is correlted with incresed error rtes. So, correct performnce in the nti-sccde tsk requires top-down inhiition of sccde neurons in the SC nd FEF efore the trget ppers. This cn e represented in n ccumultor model s decrese in the pretrget level of neurl ctivtion, which moves the system further wy from the sccdic threshold (FIG. 4). This inhiition of the sccde neurons on nti-sccde FP T Ipsilterl c d 200 ms Figure 2 Dischrges recorded from fixtion neuron (FN) nd sccde neuron (SN) in frontl eye field nd superior colliculus when monkey performs the pro-sccde nd nti-sccde tsks in the gp condition. Blue trces, pro-sccde trils; red trces, nti-sccde trils. Trces re ligned on trget ppernce. Presenttion of the trget on the right side leds to direct ctivtion of sccde neurons tht re visully responsive on the left side of the rin. These cells must e inhiited nd sccde neurons on the right side ctivted to drive the leftwrd nti-sccde. Before trget ppernce, fixtion neurons re more ctive on nti-sccde trils, while sccde neurons re more ctive on pro-sccde trils. The neurons were recorded individully. FP, fixtion point; T, trget. 50 spikes s spikes s 1 trils ensures tht the phsic visul response tht is initited y the ppernce of the trget will not exceed sccdic threshold. The trget vector cn then e inverted into the sccdic vector, nd ctivity on the side of the rin ipsilterl to the trget (coding the contrversive nti-sccde) cn egin to uild towrds threshold s ctivity on the side contrlterl to the trget (coding the utomtic pro-sccde) dies wy. It is unlikely tht the ctivity of sccde neurons in the FEF nd SC lone cn ccount for the threshold crossing tht is required for the genertion of correct nti-sccdes. For mny sccde neurons, the mgnitude of the sccdic urst tht ccompnies nti-sccdes of the optiml vector is weker thn the mgnitude of the visul response tht ccompnies the presenttion of the trget into their response fields 27,28.Ifthe visul response of FEF nd SC sccde neurons does not trigger the sccde, then how does the sccde response do so, given tht it is weker in mgnitude? One possiility is tht the threshold is not constnt, ut rther increses trnsiently fter the sudden ppernce of visul stimulus. Omnipuse neurons in the rinstem reticulr formtion toniclly inhiit the sccde-generting circuit, nd these neurons must e silenced efore sccde cn e triggered 48,49. Omnipuse neurons dischrge t constnt tonic rte during fixtion nd puse for sccdes in ll directions. Their constnt tonic dischrge rte, even during the gp condition 50, indictes tht the threshold for sccde initition might e stle. However, the dischrge of these neurons trnsiently increses immeditely fter the sudden ppernce of visul stimuli So, it is possile tht the sccdic threshold increses immeditely fter trget ppernce so tht, in the nti-sccde tsk, it is hrder for the trnsient visul response to trigger the utomtic pro-sccde, ut the weker sccde urst cn trigger the correct nti-sccde. Another possiility is tht sccdic ctivity in other rin res contriutes to the ccumultion of ctivity towrds the threshold for sccde genertion. One re tht might provide such signl to supplement the motor commnd for nti-sccdes is the SEF 53,54. Neurons in the SEF hve oth visul nd motor responses, nd these responses re incresed on ntisccde trils 36,37.So, SEF motor commnds sent to the rinstem premotor circuit cn ugment motor commnds from the FEF nd SC for the successful production of volitionl nti-sccdes. This mens tht ction potentils from sccde neurons in the SC, FEF nd SEF together could contriute to the ccumultion of pre-sccdic ctivity tht is required to cross the threshold nd trigger the nti-sccde. However, projections from the SEF to the rinstem re elieved to terminte predominntly on omnipuse neurons 55.It therefore remins to e determined how the SEF cn influence rinstem urst neurons to ugment the input from the FEF nd the SC. Inhiition of sccde neurons in the FEF nd SC seems to e crucil for suppressing the utomtic prosccde on nti-sccde trils. Wht re the possile sources of this signl in the rin? One possiility is tht 222 FEBRUARY 2004 VOLUME 5

6 Frontl eye field Superior colliculus 200 ms Figure 3 Activity of individul sccde neurons in the frontl eye field nd superior colliculus. Responses for correct nti-sccdes (red trces) re compred with responses for erroneous pro-sccdes (lue trces). The pre-trget ctivity of sccde neurons (light lue ox) cn e used to predict ehviour 18,28. FP, fixtion point; T, trget. suset of fixtion neurons in the FEF nd SC themselves inhiits the sccde neurons 41,56,57.Although fixtion neurons hve een identified s output neurons from the FEF nd SC, it is possile tht some insted re interneurons. Recll tht fixtion neurons hve greter ctivity t the time of trget ppernce in the nti-sccde condition, nd this signl could e used to inhiit the sccde neurons directly. Alterntively, fixtion neurons in the FEF might project to inhiitory interneurons in the SC to inhiit sccde neurons. However, the question remins, where does the signl come from to enhnce the ctivity of FEF nd SC fixtion neurons on nti-sccde trils? There re severl possiilities. One possile source of this signl is the SEF. As stted ove, the visul nd sccde-relted responses of mny neurons in the SEF re greter for nti-sccdes thn for pro-sccdes. Mny SEF neurons, especilly fixtion neurons, lso show incresed ctivtion on nti-sccde trils during the instruction period tht precedes trget presenttion, nd the ctivity of these neurons is lower on trils in which the monkey genertes direction error 36,37. The SEF projects directly to the FEF 58 nd SC 59, so SEF efferents could excite locl inhiitory interneurons to exert inhiition of sccde neurons in these structures. 50 spikes s spikes s 1 FP T Another possile source for the inhiition of sccde neurons in the FEF nd SC is the DLPFC. Neurons in the DLPFC project directly to the SC 60,61 nd the FEF 62, ut the function of these projections remins unknown. Funhshi nd collegues 29 recorded from neurons in the DLPFC when monkeys performed dely version of the pro- nd nti-sccde tsks. They found tht some neurons coded the stimulus loction wheres other neurons coded the required response direction during the dely period. Such role for the DLPFC in ritrry stimulus response mpping hs een confirmed in other studies 63,64.For exmple, lrge proportion of DLPFC neurons showed differences in their seline ctivity etween sptil, oject nd ssocition tsk while monkeys were looking t centrl fixtion mrker efore stimulus ws presented 65.These differences in ctivtion proly reflect differences in preprtory set nd could e involved in pre-setting the excitility of neurons in the SC nd FEF. Alterntively, other popultions of neurons in the DLPFC tht hve yet to e recorded in the nti-sccde tsk could provide inhiition to the sccde neurons in the FEF nd SC. A third source of inhiition of sccde neurons in the FEF nd SC could e the sustnti nigr prs reticult (SNpr) 66.A suset of neurons in the SNpr dischrges toniclly during fixtion nd puses for sccdes 67,68.Some of these neurons project directly to the SC 69 nd the thlmus, which in turn projects to the FEF. So, tonic neurons in the SNpr, which contin GABA (γ-minoutyric cid), could exert tonic inhiition over sccde neurons in oth the SC nd FEF, nd this inhiition could e enhnced on nti-sccde trils. The neurophysiologicl recording studies descried ove hve shown tht crucil step in the successful completion of the nti-sccde tsk is the inhiition of sccde neurons in the FEF nd SC to ensure tht the phsic visul response tht is generted y the ppernce of the trget cnnot trigger n utomtic prosccde. This inhiition must e present efore the trget ppers nd is represented in the ccumultor model s reduction in seline pre-trget ctivity of sccde neurons efore trget ppernce (solid line in FIG. 4). If this inhiition is sent or wek (FIG. 4, dshed line), then the incoming visul response will trigger direction error. Further work is required to ddress the precise role of the DLPFC, SEF nd SNpr s possile sources of the inhiition of sccde neurons in the FEF nd SC tht is required for the successful completion of the nti-sccde tsk. Vector inversion. How is the loction of the visul stimulus trnsformed into the pproprite motor commnd for the execution of sccdes? This prolem is reltively strightforwrd for pro-sccdes ecuse the visul response is mpped directly onto the sccde neurons in the FEF nd SC. However, this is not trivil prolem in the nti-sccde tsk ecuse the visul response is initilly mpped to the wrong popultion of sccde neurons in the SC nd FEF. This ctivity must e suppressed nd insted sccde response must e generted y sccde neurons on the opposite side of the NATURE REVIEWS NEUROSCIENCE VOLUME 5 FEBRUARY

7 Neuronl ctivtion c Neuronl ctivtion d Neuronl ctivtion Eye Trget Contr to trget Control DLPFC lesion FEF lesion Control ADHD Tourette Schizophreni/Prkinson's disese Ipsi to trget Figure 4 An ccumultor model cn e used to represent the ccumultion of sccde ctivity in the rin on nti-sccde trils. Schemtized correct (solid trces) nd error (dshed trces) responses. Hypothesized neurl ctivtion for correct nd error responses. Activity contrlterl to the trget (left pnel) must e suppressed nd ctivity ipsilterl to the trget (right pnel) must grow to trigger the nti-sccde. c Hypothesized ctivtion for control sujects (grey trces) contrsted with ptients with lesions of the frontl eye field (FEF; lue trces) nd dorsolterl prefrontl cortex (DLPFC; red trces). d Hypothesized ctivtion for control sujects (grey trces) contrsted with ptients dignosed with ttention-deficit hyperctivity disorder (ADHD; red trces), Tourette s syndrome (lue trces), Prkinson s disese nd schizophreni (pink trces). Dshed trces refer to error trils. rin. Somewhere etween the initil registrtion of trget ppernce nd the genertion of the sccdic urst in the FEF nd SC, the trget vector must e trnsformed (inverted) into the movement vector. One re tht might hve crucil role in vector inversion is the lterl intrprietl re (LIP). This re is locted t the interfce etween sensory nd motor processing Gottlie nd Golderg 31 recorded from neurons in re LIP while monkeys performed prond nti-sccdes. Most of the recorded neurons in LIP represented the trget vector. Few neurons represented the direction of movement, nd their ctivity occurred lte. More recently, Zhng nd Brsh 32,33 employed memory-delyed version of the nti-sccde tsk nd identified prdoxicl type of response mong visul neurons in LIP. On nti-sccde trils, when the sccde vector ut not the trget vector ws ligned with the response field of the neuron, these neurons were ctivted out 50 ms fter the visul neurons on the opposite side of the rin. Although the dischrge ws not visul, it seemed to e visul in tht it ws oserved t fixed ltency fter trget ppernce, well within the rnge of visul responses in LIP, nd it declined to seline during the memory period, long efore movement initition. Zhng nd Brsh 32,33 concluded tht the presence of the prdoxicl ctivity in suset of visul neurons in LIP might represent rempped visul response. They rgued tht in the time immeditely fter trget presenttion, some context-ctegoriztion process switched on non-stndrd input pthwy. This inverted signl is pproprite to feed to frontocolliculr regions to initite the correct nti-sccde. Whether this prdoxicl signl ctully prticiptes in vector inversion remins to e determined. The FEF might lso e importnt in vector inversion. Sto nd Schll 38 used singleton serch tsk with mnipultion of pro- nd nti-sccde responses to dissocite trget selection from sccde selection. In most singleton serch tsks, the suject must identify n oddll stimulus mong severl uniform distrctors. Sto nd Schll used colour to identify the singleton nd the shpe of the singleton to instruct the type of response. When the singleton ws verticl r, the monkey ws required to initite pro-sccde to the singleton. When the singleton ws horizontl r, the monkey ws required to initite sccde wy from the singleton. Sto nd Schll 38 identified two types of neuron in the FEF. Type I neurons selected the singleton nd the endpoint of the sccde (sccde vector). The time of singleton selection mong type I neurons did not vry with sccdic rection time. Type II neurons, on the other hnd, selected only the endpoint of the sccde, nd their selection times vried with sccdic rection times. Sto nd Schll 38 concluded tht visul selection nd sccde selection re different processes. Future experiments re required to elucidte the exct mechnisms for the implementtion of vector inversion. Nonetheless, evidence hs ccumulted to indicte tht neurons in oth the LIP 32,33 nd the FEF 38 prticipte in the process. Imging nd ERP studies in humns There is now experimentl evidence showing tht the setting of pre-trget excitility of sccde neurons is lso crucil if humns re to perform the nti-sccde tsk correctly. This evidence hs come from eventrelted potentil (ERP) nd functionl imging studies. ERP studies hve found tht the pre-sccdic negtivity tht cn e recorded over frontl nd centrl corticl sites is lrger for nti-sccdes thn for pro-sccdes Furthermore, trils with direction errors re ssocited with reduced negtivity immeditely efore trget presenttion, compred with correct nti-sccde trils 76. Although the low sptil resolution of ERPs is insufficient to identify where these differences originte, these studies show importnt differences etween prond nti-sccde trils tht re present efore trget presenttion. A role for prietl res in vector inversion is supported y the nlysis of post-stimulus ERPs 76. These show tht negtive potentil shifts from the hemisphere contrlterl to the stimulus to the hemisphere ipsilterl to the stimulus (contrlterl to the movement), which is consistent with the time course of prdoxicl visul responses in LIP neurons 32,33. Erly imging studies using functionl mgnetic resonnce imging (fmri) nd positron emission tomogrphy (PET) identified corticl res tht re ctivted differentilly during nti- nd pro-sccde tsks Specificlly, prietl nd frontl res hve n incresed lood-oxygen-level-dependent (BOLD) signl nd cererl lood flow on nti-sccde trils. However, 224 FEBRUARY 2004 VOLUME 5

8 these erly studies used lock designs in which sujects typiclly performed lternting locks of pro- nd nti-sccdes. With this lock design it is not possile to determine when these res re ctivted during the tsk. Event-relted imging provides mens to dissocite preprtory from sccde-relted BOLD ctivity. Recent studies hve used event-relted designs nd found tht, during the instruction period efore trget ppernce nd movement initition, the BOLD signl in frontl res (SEF, FEF nd DLPFC) is greter on nti-sccde trils thn on pro-sccde trils. It will e interesting to test whether the BOLD signl differs in these res etween correct nti-sccde trils nd trils with direction errors. There is now converging evidence from primte electrophysiology, humn ERP nd event-relted fmri studies tht top-down inhiition of sccde neurons is crucil to ensure the suppression of the utomtic pro-sccde on nti-sccde trils. Severl res of the frontl cortex nd sl gngli might e involved in this top-down control of the sccde-generting circuit. Clinicl studies Becuse of the dependency on frontl nd sl gngli structures, the nti-sccde tsk hs emerged s n importnt clinicl tool for investigting development nd dysfunction in vrious neurologicl nd psychitric disorders 85,86.A quick test of nti-sccde function is often included in edside neurologicl exm. Ptients cn e instructed to look either towrds or wy from the wiggling fingers of the physicin to ssess sccdic suppression ility. Mny ptient groups hve now een studied with the nti-sccde tsk nd some of the key findings cn e interpreted in the context of the neurophysiologicl findings tht re descried ove to mke specific predictions out how pthophysiology cn influence top-down inhiitory control of sccde neurons nd ccumultion of ctivity towrd sccdic threshold. We now review only smll prt of this literture to illustrte how the ccumultor model cn e used to interpret the clinicl findings. Importnt developmentl chnges hve een identified in the ility of norml children nd dults to perform the nti-sccde tsk 5,87 90.Young children (<8 yers of ge) hve difficulty in suppressing the utomtic pro-sccde in the nti-sccde tsk. Mny of the direction errors tht re triggered y children re corrected quickly, reveling tht these young sujects hve no difficulty in understnding the tsk. Rther, their difficulty is in suppressing the utomtic pro-sccde to the trget. This suppression ility develops grdully in school-ge children, nd dult levels of performnce re chieved only t out 18 yers of ge. These developmentl chnges hve een ttriuted to protrcted mturtion of the frontl loes well into the second decde 91. This grdul improvement in the ility to suppress the utomtic pro-sccde is presumly the result of improved inhiitory control over the sccde-generting circuitry. Becuse young children hve reduced inhiitory control, they will hve difficulty in pre-setting the excitility of sccde neurons in the FEF nd SC efore the trget ppers (FIG. 4; dshed trces). On the other hnd, norml dults cn selectively inhiit pretrget ctivity in sccde neurons (FIG. 4; solid trces) so tht it is esier to suppress utomtic pro-sccdes in the nti-sccde tsk. Anlysis of ptients with discrete corticl lesions hs provided importnt insight into how the rin solves the nti-sccde tsk. Ptients with discrete lesions of the DLPFC hve difficulty in suppressing the utomtic pro-sccde in the nti-sccde tsk It is elieved tht the DLPFC provides importnt top-down signls to the FEF nd perhps the SC to inhiit the utomtic pro-sccde 96,97.Removl of the DLPFC presumly reduces the ility of sujects to inhiit sccde neurons in the FEF nd SC selectively on nti-sccde trils, resulting in too much pretrget ctivity tht will sum with the incoming visul response to trigger direction errors (FIG. 4c; red dshed trces). Lesions of the FEF, on the other hnd, do not reduce the ility to suppress the utomtic pro-sccde, ut insted impir the ility to generte the voluntry nti-sccde 98,99.The loss of sccde neurons in the FEF will reduce input to the SC nd the sccde premotor circuitry, therey incresing the time tht is required to ccumulte ctivity to threshold so s to trigger the voluntry nti-sccde (FIG. 4c; lue solid trces). A numer of studies hve shown tht ptients with schizophreni perform poorly on nti-sccde tsks 100. Two common findings re incresed error rtes nd prolonged rection times for correct nti-sccdes. This ehviour shows striking similrity to tht of ptients with prefrontl lesions, nd mny studies hve confirmed correltion etween the frequency of direction errors nd performnce on the Wisconsin Crd Sorting Test , n estlished test of prefrontl function. Consistent with the ehviourl similrities etween ptients with schizophreni nd ptients with frontl loe lesions is recent fmri study tht compred the BOLD signl ssocited with nti-sccdes etween ptients with schizophreni nd control sujects nd found differences in the right DLPFC 104.Similr to ptients with DLPFC lesions, ptients with schizophreni might hve reduced ility to suppress the ctivity of sccde neurons in the FEF nd SC on nti-sccde trils (FIG. 4d; dshed pink trce) nd reduction in the rte of ccumultion of ctivity for the correct nti-sccde (FIG. 4d; solid pink trce). Attention-deficit hyperctivity disorder (ADHD) is chrcterized s deficit in response inhiition 105. Children nd dults dignosed with ADHD hve mrked difficulties in suppressing the utomtic pro-sccde on nti-sccde trils 106.Despite the increse in direction errors, there is no chnge in the men rection time of correct nti-sccdes, implying no deficit in the ility to initite voluntry response. We hve hypothesized tht the incresed occurrence of direction errors in ADHD is the result of compromised top-down control of sccde neurons in the FEF nd SC. This results in excessive pretrget ctivity in the FEF nd SC so tht direction errors re esily triggered fter ppernce of the visul stimulus (FIG. 4d; red dshed trce). NATURE REVIEWS NEUROSCIENCE VOLUME 5 FEBRUARY

9 A hllmrk of Prkinson s disese (PD) is tht ptients hve difficulty in generting voluntry responses 107.Rection times for correct nti-sccdes re significntly incresed in ptients with PD , indicting tht the ctivity required to trigger correct nti-sccdes might ccumulte more slowly in these ptients (FIG. 4d; compre solid pink nd lck trces). Prdoxiclly, ptients with PD re fster thn control sujects t generting the utomtic responses in the pro-sccde tsk, mking more express sccdes thn ge-mtched control sujects 108.As consequence, significntly more direction errors re triggered on ntisccde trils 110 (ut see REFS 111,112). As result of this reduced inhiitory control in PD, inpproprite top-down sccdic suppression might e present t stimulus onset, resulting in excessive ctivity in sccde neurons. This reduced inhiitory control is illustrted in the ccumultor model s elevtion of the pre-trget seline (FIG. 4d; dshed pink line). Ptients dignosed with Tourette s syndrome produce different pttern of results in the nti-sccde tsk 113.Rther thn generting more direction errors, these ptients insted hve incresed rection times in oth pro- nd nti-sccde tsks nd, like control sujects, they generte few direction errors. At first this seems counterintuitive, ecuse hllmrk of ptients with Tourette s is their inility to suppress inpproprite ctions. Perhps s consequence of dpting to the symptoms of the disorder, the ptients hve incresed top-down inhiition cting on the sccde-generting system, therey mking it hrder for ctivity to ccumulte to trigger sccdes in either pro- or nti-sccde conditions (FIG. 4d; solid lue trces). The ove review of clinicl studies is y no mens exhustive (see REF. 86 for more thorough review). Nonetheless, it shows how recent neurophysiologicl findings cn e used to interpret the ehviour of clinicl groups in the context of the ccumultor model. Most importntly, there re specific predictions of how control signls might e impired in these clinicl groups. Specificlly, the nti-sccde tsk is good test of inhiitory control nd the ility to generte voluntry ctions. Top-down inhiitory control is required to reduce pre-trget seline ctivity mong sccde neurons efore trget ppernce, nd insufficient inhiition will led to incresed direction errors. In ddition, the nti-sccde tsk is lso sensitive to deficits in initition of movement tht cn lter the rte of ccumultion of ctivity towrd threshold. These predictions cn now e tested y comining fmri, ERP nd ehviourl investigtions in the sme ptient groups. Conclusions Neurl circuits hve evolved to give us voluntry, flexile control over ehviour. Mny lively nd colourful detes etween prtners cn e voided when glnces to ttrctive individuls re suppressed nd gze is insted diverted in the opposite direction. This flexile control over voluntry ehviour is hllmrk of executive control. In the cse of the nti-sccde tsk, it requires the top-down inhiition of utomtic pro-sccde responses nd the genertion of voluntry nti-sccdes. Future work should e directed t identifying the precise neurl sustrte required for sccdic suppression nd vector inversion. Here,we hve reviewed recent neurophysiologicl, imging nd ehviourl performnce dt collected from the nti-sccde tsk. Monkey neurophysiologicl dt cn e comined with humn neuroimging dt to identify the neurl sustrtes tht re required for sccdic suppression nd vector inversion in humns. These results, when comined with ehviourl performnce dt, cn e used to mke specific predictions of signl normlities in vrious ptient groups tht cn e tested directly in the lortory. So, the nti-sccde tsk is emerging s n importnt tool to investigte not only norml rin function, ut lso dysfunction in vrious neurologicl nd psychitric disese conditions. In the future, this tsk might e importnt to evlute future tretment protocols tht re designed to meliorte deficits in response inhiition nd movement initition. 1. Hllett, P. E. Primry nd secondry sccdes to gols defined y instructions. Vision Res. 18, (1978). This study introduced the nti-sccde tsk. 2. Amdor, N., Schlg-Rey, M. & Schlg, J. Primte ntisccdes. I. Behviorl chrcteristics. J. Neurophysiol. 80, (1998). 3. Bell, A. H., Everling, S. & Munoz, D. P. Influence of stimulus eccentricity nd direction on chrcteristics of pro- nd ntisccdes in non-humn primtes. J. Neurophysiol. 84, (2000). 4. Fischer, B. & Weer, H. Effects of stimulus conditions on the performnce of ntisccdes in mn. Exp. Brin Res. 116, (1997). 5. Munoz, D. P., Broughton, J. R., Goldring, J. E. & Armstrong, I. T. Age-relted performnce of humn sujects on sccdic eye movement tsks. Exp. Brin Res. 121, (1998). 6. Hllett, P. E. & Adms, B. D. The predictility of sccdic ltency in novel voluntry oculomotor tsk. Vision Res. 20, (1980). 7. Dorris, M. C. & Munoz, D. P. A neurl correlte for the gp effect on sccdic rection times in monkey. J. Neurophysiol. 73, (1995). 8. Fores, K. & Klein, R. M. The mgnitude of the fixtion offset effect with endogenously nd exogenously controlled sccdes. J. Cogn. Neurosci. 8, (1996). 9. Fischer, B. & Weer, H. Express sccdes nd visul ttention. Behv. Brin Sci. 16, (1993). 10. Fischer, B. & Boch, R. Sccdic eye movements fter extremely short rection times in the monkey. Brin Res. 260, (1983). 11. Pre, M. & Munoz, D. P. Sccdic rection time in the monkey: dvnced preprtion of oculomotor progrms is primrily responsile for express sccde occurrence. J. Neurophysiol. 76, (1996). 12. Hess, W. R., Burgi, S. & Bucher, V. Motor function of tectl nd tegmentl re. Montsschr. Psychitr. Neurol. 112, 1 52 (1946). 13. Crpenter, R. H. S. in Eye Movements: Cognition nd Visul Perception (eds Fischer, D. F. & Monty, R. A.) (Erlum, Hillsdle, New Jersey, 1981). 14. Edelmn, J. A. & Keller, E. L. Activity of visuomotor urst neurons in the superior colliculus ccompnying express sccdes. J. Neurophysiol. 76, (1996). 15. Dorris, M. C., Pre, M. & Munoz, D. P. Neuronl ctivity in monkey superior colliculus relted to the initition of sccdic eye movements. J. Neurosci. 17, (1997). This pper shows tht the level of pretrget ctivtion of sccde neurons in the superior colliculus is negtively correlted with sccdic rection times. 16. Sprks, D., Rohrer, W. H. & Zhng, Y. The role of the superior colliculus in sccde initition: study of express sccdes nd the gp effect. Vision Res. 40, (2000). 17. Fischer, B., Gezeck, S. & Hrtnegg, K. On the production nd correction of involuntry prosccdes in gp ntisccde tsk. Vision Res. 40, (2000). 18. Everling, S., Dorris, M. C. & Munoz, D. P. Reflex suppression in the nti-sccde tsk is dependent on prestimulus neurl processes. J. Neurophysiol. 80, (1998). This study demonstrtes tht errors in the ntisccde tsk re ssocited with high level of pretrget excittion of sccde neurons in the primte superior colliculus. 19. Luce, R. D. Response Times: Their Role in Inferring Elementry Mentl Orgniztion (Oxford Univ. Press, Oxford, 1986). 20. Crpenter, R. H. & Willims, M. L. Neurl computtion of log likelihood in control of sccdic eye movements. Nture 377, (1995). An experimentl study tht supports the ccumultor model of sccde initition. 21. Rtcliff, R. A diffusion model ccount of response time nd ccurcy in rightness discrimintion tsk: fitting rel dt nd filing to fit fke ut plusile dt. Psychon. Bull. Rev. 9, (2002). 226 FEBRUARY 2004 VOLUME 5

10 22. Trppenerg, T. P., Dorris, M. C., Munoz, D. P. & Klein, R. M. A model of sccde initition sed on the competitive integrtion of exogenous nd endogenous signls in the superior colliculus. J. Cogn. Neurosci. 13, (2001). 23. Hnes, D. P. & Schll, J. D. Neurl control of voluntry movement initition. Science 274, (1996). 24. Gold, J. I. & Shdlen, M. N. Representtion of perceptul decision in developing oculomotor commnds. Nture 404, (2000). 25. Rtcliff, R., Cherin, A. & Segrves, M. A comprison of mcque ehvior nd superior colliculus neuronl ctivity to predictions from models of two-choice decisions. J. Neurophysiol. 90, (2003). 26. Pre, M. & Hnes, D. P. Controlled movement processing: superior colliculus ctivity ssocited with countermnded sccdes. J. Neurosci. 23, (2003). 27. Everling, S., Dorris, M. C., Klein, R. M. & Munoz, D. P. Role of primte superior colliculus in preprtion nd execution of nti-sccdes nd pro-sccdes. J. Neurosci. 19, (1999). 28. Everling, S. & Munoz, D. P. Neuronl correltes for preprtory set ssocited with pro-sccdes nd ntisccdes in the primte frontl eye field. J. Neurosci. 20, (2000). References 27 nd 28 show differences in the ctivity of neurons in the superior colliculus nd FEF etween pro-sccdes nd nti-sccdes. 29. Funhshi, S., Chfee, M. V. & Goldmn-Rkic, P. S. Prefrontl neuronl ctivity in rhesus monkeys performing delyed nti-sccde tsk. Nture 365, (1993). 30. Desouz, J. F., Iversen, S. D. & Everling, S. Preprtory set ctivity ssocited with pro-sccdes nd nti-sccdes within the primte prefrontl cortex. Soc. Neurosci. Astr. 33, (2003). 31. Gottlie, J. & Golderg, M. E. Activity of neurons in the lterl intrprietl re of the monkey during n ntisccde tsk. Nture Neurosci. 2, (1999). 32. Zhng, M. & Brsh, S. Neuronl switching of sensorimotor trnsformtions for ntisccdes. Nture 408, (2000). 33. Zhng, M. & Brsh, S. Persistent LIP ctivity in memoryntisccdes: working memory for sensorimotor trnsformtion. J. Neurophysiol. 91, , (2004). References 32 nd 33 descrie prdoxicl visul responses in LIP neurons in n nti-sccde tsk. 34. Toth, L. J. & Assd, J. A. Dynmic coding of ehviourlly relevnt stimuli in prietl cortex. Nture 415, (2002). 35. Olson, C. R. & Gettner, S. N. Neuronl ctivity relted to rule nd conflict in mcque supplementry eye field. Physiol. Behv. 77, (2002). 36. Schlg-Rey, M., Amdor, N., Snchez, H. & Schlg, J. Antisccde performnce predicted y neuronl ctivity in the supplementry eye field. Nture 390, (1997). The first study to contrst the ctivity of SEF neurons etween pro-sccde nd nti-sccde trils. 37. Amdor, N., Schlg-Rey, M. & Schlg, J. Primte ntisccde II. Supplementry eye field neuronl ctivity predicts correct performnce. J. Neurophysiol. 26 Nov 2003 [epu hed of print]. 38. Sto, T. R. & Schll, J. D. Effects of stimulus-response comptiility on neurl selection in frontl eye field. Neuron 38, (2003). This study demonstrtes tht visul selection nd sccde selection re different processes in the FEF. 39. Schiller, P. H., True, S. D. & Conwy, J. L. Deficits in eye movements following frontl eye-field nd superior colliculus ltions. J. Neurophysiol. 44, (1980). 40. Munoz, D. P. & Schll, J. D. in The Superior Colliculus: New Approches for Studying Sensorimotor Integrtion (eds Hll, W. C. & Moschovkis, A.) (CRC, Boc Rton, Florid, 2003) 41. Munoz, D. P. & Istvn, P. J. Lterl inhiitory interctions in the intermedite lyers of the monkey superior colliculus. J. Neurophysiol. 79, (1998). 42. Munoz, D. P. & Wurtz, R. H. Sccde-relted ctivity in monkey superior colliculus. I. Chrcteristics of urst nd uildup cells. J. Neurophysiol. 73, (1995). 43. Dis, E. C. & Bruce, C. J. Physiologicl correlte of fixtion disenggement in the primte s frontl eye field. J. Neurophysiol. 72, (1994). 44. Sslow, M. G. Effects of components of displcement-step stimuli upon ltency of sccdic eye movements. J. Opt. Soc. Am. 57, (1967). 45. Myfrnk, L., Moshery, M., Kimmig, H. & Fischer, B. The role of fixtion nd visul ttention in the occurrence of express sccdes in mn. Eur. Arch. Psychitry Neurol. Sci. 235, (1986). 46. Munoz, D. P. & Corneil, B. D. Evidence for interctions etween trget selection nd visul fixtion for sccde genertion in humns. Exp. Brin Res. 103, (1995). 47. Weer, H. & Fischer, B. Gp durtion nd loction of ttention focus modulte the occurrence of left/right symmetries in the sccdic rection times of humn sujects. Vision Res. 35, (1995). 48. Scudder, C. A., Kneko, C. S. & Fuchs, A. F. The rinstem urst genertor for sccdic eye movements: modern synthesis. Exp. Brin Res. 142, (2002). 49. Moschovkis, A. K., Scudder, C. A. & Highstein, S. M. The microscopic ntomy nd physiology of the mmmlin sccdic system. Prog. Neuroiol. 50, (1996). An uthortive review of the neurophysiology nd ntomy of the sccdic eye movement system. 50. Everling, S., Pre, M., Dorris, M. C. & Munoz, D. P. Comprison of the dischrge chrcteristics of rin stem omnipuse neurons nd superior colliculus fixtion neurons in monkey: implictions for control of fixtion nd sccde ehvior. J. Neurophysiol. 79, (1998). 51. Evinger, C., Kneko, C. R. & Fuchs, A. F. Activity of omnipuse neurons in lert cts during sccdic eye movements nd visul stimuli. J. Neurophysiol. 47, (1982). 52. King, W. M., Precht, W. & Dieringer, N. Afferent nd efferent connections of ct omnipuse neurons. Exp. Brin Res. 38, (1980). 53. Schlg, J. & Schlg-Rey, M. Unit ctivity relted to spontneous sccdes in frontl dorsomedil cortex of monkey. Exp. Brin Res. 58, (1985). 54. Schlg, J. & Schlg-Rey, M. Evidence for supplementry eye field. J. Neurophysiol. 57, (1987). 55. Shook, B. L., Schlg-Rey, M. & Schlg, J. Direct projection from the supplementry eye field to the nucleus rphe interpositus. Exp. Brin Res. 73, (1988). 56. Munoz, D. P. & Fecteu, J. H. Vying for dominnce: dynmic interctions control visul fixtion nd sccdic initition in the superior colliculus. Prog. Brin Res. 140, 3 19 (2002). 57. Meredith, M. A. & Rmo, A. S. Intrinsic circuitry of the superior colliculus: phrmcophysiologicl identifiction of horizontlly oriented inhiitory interneurons. J. Neurophysiol. 79, (1998). 58. Huert, M. F., Kruitzer, L. A. & Ks, J. H. Frontl eye field s defined y intrcorticl microstimultion in squirrel monkeys, owl monkeys, nd mcque monkeys. II. Corticl connections. J. Comp. Neurol. 265, (1987). 59. Shook, B. L., Schlg-Rey, M. & Schlg, J. Primte supplementry eye field: I. Comprtive spects of mesencephlic nd pontine connections. J. Comp. Neurol. 301, (1990). 60. Goldmn, P. S. & Nut, W. J. Autordiogrphic demonstrtion of projection from prefrontl ssocition cortex to the superior colliculus in the rhesus monkey. Brin Res. 116, (1976). 61. Leichnetz, G. R., Spencer, R. F., Hrdy, S. G. & Astruc, J. The prefrontl corticotectl projection in the monkey; n nterogrde nd retrogrde horserdish peroxidse study. Neuroscience 6, (1981). 62. Selemon, L. D. & Goldmn-Rkic, P. S. Common corticl nd sucorticl trgets of the dorsolterl prefrontl nd posterior prietl cortices in the rhesus monkey: evidence for distriuted neurl network suserving sptilly guided ehvior. J. Neurosci. 8, (1988). 63. Asd, W. F., Riner, G. & Miller, E. K. Neurl ctivity in the primte prefrontl cortex during ssocitive lerning. Neuron 21, (1998). 64. White, I. M. & Wise, S. P. Rule-dependent neuronl ctivity in the prefrontl cortex. Exp. Brin Res. 126, (1999). 65. Asd, W. F., Riner, G. & Miller, E. K. Tsk-specific neurl ctivity in the primte prefrontl cortex. J. Neurophysiol. 84, (2000). 66. Hikosk, O., Tkikw, Y. & Kwgoe, R. Role of the sl gngli in the control of purposive sccdic eye movements. Physiol. Rev. 80, (2000). 67. Hikosk, O. & Wurtz, R. H. Visul nd oculomotor functions of monkey sustnti nigr prs reticult. II. Visul responses relted to fixtion of gze. J. Neurophysiol. 49, (1983). 68. Hndel, A. & Glimcher, P. W. Quntittive nlysis of sustnti nigr prs reticult ctivity during visully guided sccde tsk. J. Neurophysiol. 82, (1999). 69. Hikosk, O. & Wurtz, R. H. Visul nd oculomotor functions of monkey sustnti nigr prs reticult. IV. Reltion of sustnti nigr to superior colliculus. J. Neurophysiol. 49, (1983). 70. Lynch, J. C., Gryiel, A. M. & Loeck, L. J. The differentil projection of two cytorchitectonic suregions of the inferior prietl loule of mcque upon the deep lyers of the superior colliculus. J. Comp. Neurol. 235, (1985). 71. Coly, C. L., Duhmel, J. R. & Golderg, M. E. Visul, presccdic, nd cognitive ctivtion of single neurons in monkey lterl intrprietl re. J. Neurophysiol. 76, (1996). 72. Gndt, J. W. & Andersen, R. A. Memory relted motor plnning ctivity in posterior prietl cortex of mcque. Exp. Brin Res. 70, (1988). 73. Everling, S., Krppmnn, P. & Flohr, H. Corticl potentils preceding pro- nd ntisccdes in mn. Electroencephlogr. Clin. Neurophysiol. 102, (1997). 74. Evdokimidis, I., Likopoulos, D., Constntinidis, T. S. & Ppgeorgiou, C. Corticl potentils with ntisccdes. Electroencephlogr. Clin. Neurophysiol. 98, (1996). 75. Klein, C., Heinks, T., Andresen, B., Berg, P. & Moritz, S. Impired modultion of the sccdic contingent negtive vrition preceding ntisccdes in schizophreni. Biol. Psychitry 47, (2000). 76. Everling, S., Spntekow, A., Krppmnn, P. & Flohr, H. Event-relted potentils ssocited with correct nd incorrect responses in cued ntisccde tsk. Exp. Brin Res. 118, (1998). 77. O Driscoll, G. A. et l. Functionl neurontomy of ntisccde eye movements investigted with positron emission tomogrphy. Proc. Ntl Acd. Sci. USA 92, (1995). 78. Pus, T., Petrides, M., Evns, A. C. & Meyer, E. Role of the humn nterior cingulte cortex in the control of oculomotor, mnul, nd speech responses: positron emission tomogrphy study. J. Neurophysiol. 70, (1993). 79. Sweeney, J. A. et l. Positron emission tomogrphy study of voluntry sccdic eye movements nd sptil working memory. J. Neurophysiol. 75, (1996). 80. Doricchi, F. et l.neurl control of fst-regulr sccdes nd ntisccdes: n investigtion using positron emission tomogrphy. Exp. Brin Res. 116, (1997). 81. Connolly, J. D., Goodle, M. A., Desouz, J. F., Menon, R. S. & Vilis, T. A comprison of frontoprietl fmri ctivtion during nti-sccdes nd nti-pointing. J. Neurophysiol. 84, (2000). 82. Connolly, J. D., Goodle, M. A., Menon, R. S. & Munoz, D. P. Humn fmri evidence for the neurl correltes of preprtory set. Nture Neurosci. 5, (2002). An importnt demonstrtion tht frontl res nd not prietl res crry preprtory signls for ntisccdes. 83. Desouz, J. F., Menon, R. S. & Everling, S. Preprtory set ssocited with pro-sccdes nd nti-sccdes in humns investigted with event-relted FMRI. J. Neurophysiol. 89, (2003). Strong fmri evidence tht differences etween prosccdes nd nti-sccdes originte from differences in preprtory ctivity nd not motor ctivity. 84. Curtis, C. E. & D Esposito, M. Success nd filure suppressing reflexive ehvior. J. Cogn. Neurosci. 15, (2003). 85. Leigh, R. J. & Kennrd, C. Using sccdes s reserch tool in the clinicl neurosciences. Brin 7 Nov 2003 (doi /rin/wh035). A recent review covering the usefulness of sccdic motor tsks in clinicl studies. 86. Everling, S. & Fischer, B. The ntisccde: review of sic reserch nd clinicl studies. Neuropsychologi 36, (1998). 87. Fischer, B., Biscldi, M. & Gezeck, S. On the development of voluntry nd reflexive components in humn sccde genertion. Brin Res. 754, (1997). 88. Lun, B. et l.mturtion of widely distriuted rin function suserves cognitive development. Neuroimge 13, (2001). 89. Klein, C. & Foerster, F. Development of prosccde nd ntisccde tsk performnce in prticipnts ged 6 to 26 yers. Psychophysiology 38, (2001). 90. Fukushim, J., Htt, T. & Fukushim, K. Development of voluntry control of sccdic eye movements. I. Age-relted chnges in norml children. Brin Dev. 22, (2000). 91. Fuster, J. M. The Prefrontl Cortex: Antomy, Physiology, nd Neuropsychology of the Frontl Loe (Rven, New York, 1997). 92. Guitton, D., Buchtel, H. A. & Dougls, R. M. Frontl loe lesions in mn cuse difficulties in suppressing reflexive glnces nd in generting gol-directed sccdes. Exp. Brin Res. 58, (1985). A seminl study showing tht ptients with frontl loe lesions hve high error rtes in n nti-sccde tsk. 93. Pierrot-Deseilligny, C., Rivud, S., Gymrd, B. & Agid, Y. Corticl control of reflexive visully-guided sccdes. Brin 114, (1991). 94. Pierrot-Deseilligny, C. et l. Decisionl role of the dorsolterl prefrontl cortex in oculr motor ehviour. Brin 126, (2003). 95. Wlker, R., Husin, M., Hodgson, T. L., Hrrison, J. & Kennrd, C. Sccdic eye movement nd working memory deficits following dmge to humn prefrontl cortex. Neuropsychologi 36, (1998). NATURE REVIEWS NEUROSCIENCE VOLUME 5 FEBRUARY