Neural correlates of a decision in the dorsolateral prefrontal cortex of the macaque

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1 rticles Neurl correltes of decision in the dorsolterl prefrontl cortex of the mcque Jong-Nm Kim nd Michel N. Shdlen Deprtment of Physiology nd Biophysics nd Regionl Primte Reserch Center, University of Wshington Medicl School, Box , Settle, Wshington , USA Correspondence should be ddressed to M.N.S. To mke visul discrimintion, the brin must extrct relevnt informtion from the retin, represent pproprite vribles in the visul cortex nd red out this representtion to decide which of two or more lterntives is more likely. We recorded from neurons in the dorsolterl prefrontl cortex (res 8 nd 46) of the rhesus monkey while it performed motion discrimintion tsk. The monkey indicted its judgment of direction by mking pproprite eye movements. As the monkey viewed the motion stimulus, the neurl response predicted the monkey s subsequent gze shift, hence its judgment of direction. The response comprised mixture of high-level oculomotor signls nd weker visul sensory signls tht reflected the strength nd direction of motion. This combintion of sensory integrtion nd motor plnning could reflect the conversion of visul motion informtion into ctegoricl decision bout direction nd thus give insight into the neurl computtions behind simple cognitive ct. The brin uses sensory informtion to form interprettions nd decisions tht guide behvior. Such interprettions often outlst the fleeting sensory impressions on which they re bsed, so tht sensory input cn motivte subsequent behvior. To study this process, we trined rhesus monkeys to discriminte the direction of motion in dynmic rndom dot disply 1. The difficulty of the tsk ws controlled by vrying the frction of coherently moving dots. At high motion coherences, the niml cn commit to n ction the moment the stimulus is seen. In contrst, ner psychophysicl threshold, the monkey must bse its direction judgments on wek sensory signls perceived over hundreds of milliseconds 1. The extrstrite visul cortex (res MT nd MST) contins the neurl representtion of visul motion tht llows the monkey to perform this demnding tsk 1 4. The direction-selective neurons in these res represent the evidence fvoring one direction or nother, but this evidence must be interpreted to rech decision. This distinction between sensory evidence nd decision cn be pprecited by imposing dely between motion viewing nd behviorl response. Direction-selective neurons stop responding when the motion stimulus is bsent 5, wheres neurons tht encode decision must mintin their ctivity when the visul motion is no longer present, until the niml responds. The dorsolterl prefrontl cortex (PFC) is felt to be criticl for tsks with dely between instruction nd execution 6,7. During the dely, mny PFC neurons show sustined dischrge, which is often selective for prticulr object or loction We studied neurons with sustined ctivity through the memory/dely period before n eye movement to restricted region of the visul field, termed the neurl response field (RF). We hypothesized tht such neurons my be involved in linking the sensory evidence in visul cortex to behviorl pln to shift the gze. To test this, we rrnged the motion-discrimintion tsk so tht one of two response trgets ppered in the neuron s RF (Fig. 1). The monkey ws trined to mke delyed eye movement to one or the other response trget, depending on the direction of rndom dot motion. We found tht the ctivity of mny PFC neurons revels the monkey s intention to mke sccde to one or the other trget. The time course nd intensity of neurl ctivity seem to represent the formtion of decision bout motion direction. RESULTS We studied 88 neurons in the frontl eye field (FEF) nd the posterior third of the principl sulcus (PS) region (res 8Ar nd 46) tht responded selectively when the monkey plnned sccde to region of spce (the RF). For exmple, the PS neuron shown in Fig. 2 responded during the dely preceding sccdes to trgets tht ppered up nd to the right, but not down nd to the left of the fixtion point (Fig. 2 nd b). To determine this neuron s behvior during perceptul decision, we monitored its dischrge while the monkey judged the direction of rndom dot motion. The rndom dots ppered in five degree perture outside the neuron s RF (see Methods). Motion direction ws towrd or wy from the RF, nd motion strength ws vried to spn psychophysicl threshold. After dely, the monkey indicted its direction judgment by mking n eye movement to one of the two trgets. If the motion ws up-right, the monkey ws rewrded for choosing the trget inside the RF. Conversely, if the motion ws down-left, the monkey ws rewrded for choosing the other trget, outside of the RF. This neuron s response predicted the monkey s decision. The response ws lrger on trils in which the monkey s eyes moved towrd the RF (Fig. 2c, e nd g) nd ttenuted when they moved wy from the RF (Fig. 2d, f nd h). The spike dischrge from this 176 nture neuroscience volume 2 no 2 februry 1999

2 Although this pttern of response ws common in the FEF nd PS region, we lso encountered mny neurons tht modulted their ctivity only during the dely fter the rndom dot motion ws turned off, presumbly fter the monkey hd reched its decision. This ctivity (Fig. 3) clerly predicted the monkey s pln to look to the trget in the RF on the memory-sccde tsk. However, during the motion-discrimintion tsk, the response did not revel the monkey s decision until the dely (Fig. 3c nd d). During motion viewing, this neuron filed to signl the direction of the next eye movement. Such responses my reflect motor preprtion, but they provide little insight into the decirticles Fig. 1. Behviorl tsks nd neuron loctions. (, b) Direction-discrimintion tsk. The monkey gzed t the fixtion point for 350 ms. Then two trgets ppered, one of which ws in the neurl response field (RF, shded). After ms, the rndom dot kinemtogrm ppered between the trgets nd outside the RF. The direction of motion ws towrd one of the two trgets. Motion strength ws vried from tril to tril by djusting the percentge of coherently moving dots. After 1 s, the rndom dots were turned off, leving only the fixtion point nd trgets. After s, the fixtion point ws extinguished, signling the monkey to indicte its choice by shifting its gze to one of the trgets. The monkey ws rewrded for choosing the trget b motion dely sccde long the direction of rndom dot motion, or rndomly when there c ws no net motion (0% coherence). T 1 nd T 2, sccde trgets; d flsh dely sccde FP, fixtion point. (c) Averge psychometric function for 88 experiments. Error brs re stndrd devitions of the proportion of correct choices. (d) Memory-sccde tsk used to screen neurons. A trget ws flshed (100 ms) t rndom loction in the visul field. The monkey mintined fixtion through vrible dely until the Motion strength (% coherence) fixtion point ws extinguished. The monkey ws then required to shift its gze to the remembered loction of the flshed trget. (e) Loction of the recording cylinder in schemtic digrm of the rhesus monkey brin. (f) Mgnetic resonnce imging. Fst spin-echo, short-t1, inversion-recovery scn through the electrode grid of monkey S. This is one of series of imges obtined in the coronl plne (slice thickness 1.5 mm). The recording grid ws filled with sterile sline to revel the ngle nd e f loction of electrode guide tubes in the coronl plne. A second series ws obtined in the sgittl plne to determine the position nd ngle of guide tubes in the nterior posterior direction. The section shows the rcute sulcus nd prercute gyrus t the cudl end of the principl sulcus (ps, principl sulcus; s, rcute sulcus). Probbility correct (men ± stdev) Time neuron begn to revel the monkey s decision s erly s ms fter the onset of rndom dot motion nd remined informtive until the sccde. Moreover, the response ws modulted more strongly when the tsk ws esier: the neuron dischrged more intensely when the monkey viewed coherent motion towrd the RF (up-right) nd ttenuted more profoundly to coherent motion wy from the RF. Thus, the response reflected not only the monkey s impending eye movement, but lso the sensory input tht determined it. This mixture of visul-sensory nd visuomotor response properties is thought to occur t the nexus of sensory-tomotor conversion where the decision is computed. nture neuroscience volume 2 no 2 februry

3 rticles Fig. 2. Response of principlis neuron during the motion-discrimintion nd memory-sccde tsks. The response field of the neuron is shown in gry. The rrow indictes the direction of the monkey s sccde t the end of the tril. (, b) Response on memory sccdes to trgets in () nd out (b) of the RF. The time xis is broken to lign the response to two events: trget ppernce nd sccde initition. (c h) Response during the motion-discrimintion tsk. Responses re ligned to the onset of rndom dot motion nd to the time of the sccde. The left column (c, e, g) depicts trils in which the monkey decided the motion ws towrd the RF. The right column (d, f, h) shows trils in which the monkey decided tht the direction ws wy from the RF, leding to sccde to the trget outside the RF. Three motion strengths re shown (sub-, ner- nd supr-threshold). For the 0% coherence stimulus, there is no net direction of motion. Only correct discrimintion trils re shown for nonzero motion strengths. For clrity, only 10 trils re shown in the rsters. The response preceding the onset of motion ws ssocited with fixtion nd the ppernce of the sccde trgets. Spikes/s c b d f h sion-mking process. Unless the monkey mkes eye movements cpriciously possibility precluded by the well behved psy- e chometric function (Fig. 1c) the decision must form during motion viewing. For ech neuron, we computed n index of predictive ctivity using the responses mesured during motion viewing nd during the dely. The index mesures the g response distribution overlp from trils in which the monkey judged motion s towrd versus wy from the RF nd estimtes the probbility tht n idel observer could predict the monkey s decision bsed on the spike rte (Methods). For exmple, n index of 0.5 indictes chnce ssocition (complete overlp of response distributions ssocited with the two choices), wheres n index of 1 indictes perfect correspondence between predicted nd observed choices (no overlp). Most neurons (76/88, 86%) predicted the monkey s choice relibly during motion viewing or the dely or both (Fig. 4; predictive index > 0.5 nd p < 0.01 in t lest one epoch). Sixty percent (53/88) predicted the monkey s decision relibly during motion viewing (index > 0.5 nd p < 0.01) nd could reflect the ssocition between motion processing nd behviorl response. However, bout 1/4 of the neurons filed to indicte the monkeys choices until the dely (9/26 neurons in the FEF nd 10/62 in the posterior PS region), which is too lte for them to be involved in the decision process. Some neurons (11%, 1 FEF, 9 PS) filed to predict the monkey s response t ny time during the discrimintion tsk (vlues ner 0.5 on both xes, p > 0.01). Five neurons (1 FEF, 4 PS) relibly predicted the monkey s choices during motion viewing but in pttern opposite to their response on the memory-sccde tsk (predictive index < 0.5, p < 0.01). The ctivity of these five neurons diminished when the monkey chose the trget in the RF, but none retined this reversed ctivity pttern during the dely. We tended to encounter similr ptterns of predictive ctivity in the FEF nd PS region (Fig. 4, p > 0.08, two-dimensionl Kolmogorov- Smirnov test 15 ), which my result from our strtegy of smpling neurons of similr type in both res. Time course of predictive ctivity To perform bove chnce on this tsk, the monkey must decide bout the motion direction bsed on the evidence cquired during motion viewing. Those neurons tht predicted the monkey s subsequent eye movement during motion viewing my therefore divulge properties of the decision process itself, the linkge between sensory processing nd sccde plnning. A neurl correlte of the decision process is likely to reflect both the outcome of the decision nd the qulity of the evidence upon which it is founded. Moreover, neurons linking sensory evidence to behviorl response should undergo temporl trnsformtion in their ctivity s the evidence produces ctegoricl nswer. Erly responses might reflect properties of the sensory stimulus (the strength of the evidence). Responses lter in the decision process should reflect stereotyped outcome, 178 nture neuroscience volume 2 no 2 februry 1999

4 rticles Spikes/s c Movement/memory response field regrdless of whether the evidence ws strong or wek, nd whether it ws interpreted correctly or incorrectly. These properties re evident in the PFC response. Motion strength ffected the response of mny PFC neurons (Fig. 5 nd b). For this nlysis, we selected neurons tht predicted the monkey s subsequent choice during motion viewing (n = 53 neurons with predictive index > 0.5 nd significnt permuttion test, p < 0.01). For ech neuron, we computed the verge spike rte during motion viewing (from ms fter the onset of dot motion) nd normlized the spike rte to the men. We pplied this procedure seprtely for the two directions of motion nd restricted the nlysis to correct choices. For motion towrd the RF, the degree of response enhncement vried by 12.5% cross the rnge of motion strengths (~3.2 spikes/s; Fig. 5). For motion wy from the RF, the degree of suppression vried by 22% cross the rnge of motion strengths (~4.3 spikes/s; Fig. 5b). This normliztion procedure removes the min determinnt of the response mgnitude for these neurons: whether n eye movement is ultimtely mde to the RF or wy from it. The effect of motion strength is therefore reltively subtle. The regression nlysis ws sttisticlly significnt (p = nd p < for Fig. 5 nd b, respectively) nd ws unffected by the incorportion of eye movement descriptors such s sccdic ltency, mplitude, durtion nd velocity (see Methods). This lst point implies tht subtle vritions in the ctul sccde produced in ech tril of the experiment does not explin the vrition in neurl response found s function of tsk difficulty. We represented the evolution of predictive ctivity during motion discrimintion by clculting the predictive index in 250- ms epochs beginning 500 ms before the onset of rndom dot motion nd ending just fter the sccde (Fig. 5c). We computed the index seprtely for ech of the 53 neurons tht predicted the monkey s behvior during motion viewing (s bove), using only b d Fig. 3. Response of frontl eye field neuron during the motion-discrimintion nd memory-sccde tsks. (, b) Response on memory-guided sccdes to trgets flshed briefly inside or outside the response field. This neuron hd prominent visul response t the onset of the trget nd sustined response when the monkey plnned n eye movement up-leftwrd. (c, d) Response on the motion-discrimintion tsk. The poststimulus time histogrm includes ll trils in which the monkey chose the correct direction. The response ws stronger when the monkey judged the motion to be towrd the RF, but the effect ws not pprent until the dely (lower rrows). Responses re ligned to the onset of rndom dot motion nd to the sccde initition. The trnsient response t the time of motion onset ws cused by the ppernce of sccde trgets. correct choices t ech of six motion strengths. On verge, the response begn to predict the monkey s decision ms fter onset of the rndom dot motion. Lter in the tril, the response predicted the monkey s choice with greter fidelity, reching mximum during the dely, just before the eye movement. Although ech point represents the predictive ctivity from just 250 ms of spike dischrge, the curves look like cumultive functions. Predictive index dely period Predictive index motion viewing period Fig. 4. Predictive ctivity for 88 neurons during motion viewing nd the dely. The predictive index pproximtes the ccurcy with which one could guess monkey s decision bsed on the spike dischrge mesured during motion viewing or the dely (Methods). Vlues lrger thn 0.5 imply greter ccurcy in predicting the monkey s decision from the neurl response. The histogrms summrize the distribution of these indices; shding indictes significnt deprture from 0.5 (p < 0.01 by permuttion test; Methods). Blue circles, FEF; red circles, PS (re 8Ar nd Wlker re 46). The open symbols indicte the neurons shown in Figs. 2 (red) nd 3 (blue). nture neuroscience volume 2 no 2 februry

5 rticles Fig. 5. Effect of motion strength on the mgnitude nd time of the prefrontl response. (, b) Effect of stimulus strength on verge response during motion viewing for 53 neurons with sttisticlly significnt predictive indices. () For decisions fvoring motion towrd the RF, the response ws lrger to stronger rndom dot motion. The ordinte represents the response strength reltive to the men for ll decisions towrd the RF. Filled points represent the men ± stndrd error of the normlized response. (b) For decisions fvoring motion wy from the RF, the response ws more suppressed to stronger motion stimuli. Conventions re the sme s in () except tht the response is normlized to the men of ech neuron s response ssocited with choices outside the RF. (c) The predictive power of the response ws computed in 250-ms epochs whose midpoint is plotted on the time xis. Ech point represents the probbility of correctly predicting the monkey s choice from 250 ms of spike dischrge. Curves represent the verged probbilities from 53 neurons with predictive ctivity during motion viewing. The neurons predicted the monkey s choice sooner nd more relibly when the motion ws stronger. The emergence of predictive ctivity on the most difficult motion condition (no coherent motion) indictes tht the neurons primrily encode vribles tht pertin to the monkey s behviorl response. On the other hnd, when the motion ws stronger (tht is, esier), the response predicted the monkey s choice sooner nd better thn when the motion ws weker. This effect ws subtle for individul neurons but highly relible cross the popultion (p < , likelihood rtio test using modified probit nlysis; Eq. 3 in Methods). It reflects stronger nd more consistent rise in the response when motion ws towrd the RF nd more profound ttenution of the dischrge when motion ws towrd the trget outside the neuron s RF (Fig. 2). This response pttern could represent the ccumultion of motion informtion from the extrstrite cortex towrd plteu. Indeed, some neurons responded to the direction of rndom dot motion during pssive viewing, when the monkey ws not engged in the discrimintion tsk (Fig. 6). The wek direction bis observed in this control experiment fvored motion towrd the RF, suggesting tht instructive visul signls rech the PFC even without tsk. Errors Could pssive visul responses explin our finding of predictive responses during motion viewing of the discrimintion tsk? This seems unlikely becuse the neurons were predictive when the motion strength ws negligible, s in the 0% coherent motion condition (Figs. 2c nd d nd 5). The neurl response is dominted by the direction tht the monkey judges, nd hence the direction of the plnned sccde. This point is further supported by exmining error trils, in which the motion direction nd the sccde choice re opposed. The response ws lrger when the monkey chose the trget in the RF, whether or not this ws bsed on proper interprettion of the rndom dot motion (Fig. 7). Thus, the response ws dominted by wht the monkey plnned to do, rther thn by wht the monkey sw. There ws, however, subtle difference between correct nd erroneous decisions. On verge, neurons modulted their response less strongly on the error trils. During motion viewing, the response ws weker when the monkey s choice of the trget in Normlized response c Probbility (men) b Motion strength (% coherence) Time (s) Sccde the RF ws erroneous s compred to correct (p = 0.001; t-test of men normlized response), nd the response ws less ttenuted on erroneous decisions fvoring motion wy from the RF (p < ). Thus, the response cnnot be explined solely by the behviorl outcome. The observtion is consistent with the ide tht the neurl response reflects the ccumultion of sensory evidence towrd decision. As shown in the next section, this is becuse the strength of neurl signls fvoring the wrong direction (for exmple, the responses of rightwrd motion sensors when the direction is ctully leftwrd) re unlikely to exceed by much the neurl signls tht would fvor the correct direction. Theory Our results re consistent with the ide tht neurons in the dorsolterl PFC compre sensory signls from the extrstrite cortex tht fvor motion towrd or wy from the response field. Accumulted spike counts from pools of neurons in res MT nd MST cn ccount for the monkey s sensitivity nd tril-totril choices on the rndom dot motion tsk 16. We therefore expect tht neurons involved in the decision process must ccumulte spikes from groups of sensory neurons nd mke the pproprite comprison, nd tht the neurl computtions underlying decision probbly involve integrtion in time. The sensory signls tht inform the monkey s choices on ner-threshold discrimintion (Fig. 8) re presumed to be the ccumulted spike counts from pools of noisy nd wekly correlted direction sensors in the extrstrite visul cortex 16. These 180 nture neuroscience volume 2 no 2 februry 1999

6 rticles b Direction wy from response field Direction towrd response field Fig. 6. Response to rndom dot motion during pssive viewing. () Direction-tuning function for one neuron. This neuron s RF ws ner the upper verticl meridin t n eccentricity of 10 degrees. The rndom dots were shown in five-degree perture centered on the fixtion point, outside the RF of the neuron. The response histogrms re displyed to indicte the direction of rndom dot motion. Responses re ligned to motion onset. The polr plot shows the men response clculted during viewing. The response ws lrgest when motion ws towrd the RF. (b) Summry dt from 10 neurons tested during pssive fixtion, compring responses to pssively viewed motion towrd or wy from the RF. Filled symbols denote neurons with significnt predictive ctivity during motion viewing on discrimintion trils (done in seprte block). These neurons hd stronger direction bis (points frther from digonl; p < 0.001, ROC re comprison nd permuttion test; see Methods). Error brs represent stndrd error. ccumultions constitute the evidence for rightwrd or leftwrd choice. Imgine PFC neuron whose RF is situted so tht rightwrd decision increses its response. According to our scheme, this neuron compres the rightwrd cumulnt to the leftwrd cumulnt. The monkey chooses right when this difference is positive nd left when it is negtive. The mgnitude of the difference represents the strength of the evidence fvoring decision. Figure 8 shows idelized distributions of pooled responses from leftwrd nd rightwrd sensors to ner-threshold rightwrd motion stimulus. The size of the responses is expressed in units of stndrd devition (σ). Notice tht the distribution of pooled rightwrd signls exceeds tht of the leftwrd signls by 1 σ on verge (tht is, the index of discriminbility, d, equls 1), consistent with motion strength tht would support 76% correct choices. When the stimulus direction is leftwrd, the leftwrd signls re lrger on verge (Fig. 8b). This nlysis permits us to ssess the strength of the evidence ssocited with ech of four types of decisions s seen from the point of view of choose right neuron in the PFC (Fig. 8c f). When motion is rightwrd nd the correct choice follows (Fig. 8d), the strength of the evidence fvoring rightwrd is positive nd lrge on verge. The expected men difference between rightwrd nd leftwrd sensory signls is 1.6 units of signl stndrd devition. When motion is leftwrd nd the correct choice follows, the evidence fvoring rightwrd choice is negtive nd lrge (Fig. 8e; expected men, 1.6 σ). The error trils re ssocited Response (men normlized) Time from motion onset with weker evidence. At the ner-threshold motion strength in this exmple, pproximtely 24% of the trils would result in errors. For erroneous rightwrd choices (Fig. 8f), the difference signls on error trils tend to be smll (compre Fig. 8d nd f). The expected men is 0.84 units of signl stndrd devition. This nlysis could explin the subtle difference in the neurl response tht we observed on correct versus error trils (Fig. 7). This sme nlysis cn be extended cross the rnge of stimulus strengths (Fig. 8g). At ech motion strength, there re four possible outcomes: two directions times two choices. At ll motion strengths, whenever the monkey chooses rightwrd correct or not the evidence for rightwrd motion (Fig. 8g) exceeds the evidence for leftwrd. However, the strength of the evidence increses with stronger motion (lrger vlues of d ), leding to Fig. 7. Comprison of the responses on error nd correct trils. The responses from 53 neurons with predictive ctivity during motion viewing were used to construct these curves, using ll non-zero motion strengths. Responses were normlized to the men of ech neuron s response over the 600-ms epoch indicted by the gry br. The blck curves depict trils in which the monkey judged the direction s towrd the RF, culminting in sccde to the trget in the RF (T1); the gry curves indicte decisions resulting in sccdic eye movement to the trget outside the RF (T2). Error trils re indicted by the dshed curves. The prominent response tht begins before the onset of motion ws cused by the presenttion of the sccde trgets. nture neuroscience volume 2 no 2 februry

7 rticles Distribution of signls from rightwrd nd leftwrd sensors Motion is rightwrd (d = 1) b Motion is leftwrd (d = 1) c Distribution of difference signls received by choose right neuron d e Wrong left choice Correct right choice Correct left choice Wrong right choice S Right S Left (σ) S Right S Left (σ) S Right S Left (σ) S Right S Left (σ) Fig. 8. Theoreticl bsis for vrition in the strength of evidence ssocited with direction judgments. The grphs trce the flow of informtion from popultions of opponent direction sensors to neuron in the PFC tht would increse its response in ssocition with rightwrd decision. The input to the PFC neuron represents the evidence tht motion is rightwrd, in the form of the difference between rightwrd nd leftwrd sensory signls. Four scenrios re depicted: motion is either leftwrd or rightwrd, nd the choice is either correct or erroneous. () Activity of the leftwrd nd rightwrd motion sensors when the true direction is rightwrd. The surfce shows the joint probbility distribution of pir of signls from rightwrd nd leftwrd sensors. The two signls should be interpreted s the popultion verge responses from mny neurons. The grph depicts the sitution t psychophysicl threshold when the rightwrd signl is one stndrd devition lrger thn the leftwrd signl, on verge (projected bell-shped curves). The points below the surfce re 100 rndom smples from the overlying distribution. Ech point is lbeled ccording to the resulting Stimulus strength (d ) decision (blue, rightwrd decision; red, leftwrd decision). The mjority of smples fll on the side of the min digonl tht indictes tht the rightwrd signl exceeds the leftwrd signl. In this plot, the rightwrd choices re correct. (b) Activity of the motion sensors when the true direction is leftwrd. Sme conventions s in (). The leftwrd sensors produce the lrger signl, on verge. In this plot, the leftwrd choices (red) re correct. (c f) Frequency histogrms of the difference in sensory signls between rightwrd nd leftwrd sensors. The differences re tbulted seprtely for the two directions of motion nd the two decisions. The histogrms re shown under the simulted points from which they were obtined in () nd (b). The difference, S Right S Left, is positive when the decision is rightwrd (blue) nd negtive when the decision is leftwrd (red). Notice tht there re more smples corresponding to correct choices (d nd e), nd the difference signls tend to be lrger positive nd negtive vlues. (g) Averge difference signl, S Right S Left, ccompnying correct nd incorrect choices for rnge of motion strengths spnning the psychometric function. The d = 1 cse corresponds to motion strength supporting 76% correct choices (~10% coherence), s illustrted in ( f). The theoreticl mens for (c f) re shown. When d = 0, there is no net motion direction (0% coherence), nd there is no distinction between correct nd error trils. When d = 2, there re very few errors ( 25% coherence). The difference signls ssocited with correct choices ttin greter positive nd negtive vlues when the motion is stronger. The opposite trend is predicted for error trils. f g Evidence for rightwrd (σ) lrger responses when the decision is rightwrd nd greter suppression when the decision is leftwrd. The incresing seprtion of the solid curves in Fig. 8g helps explin the increse in predictive index s function of motion strength (see Fig. 5). The nlysis lso predicts tht the responses ssocited with errors should diminish t higher motion strengths. We cnnot evlute this prediction becuse errors occur rrely for strong motion. Finlly, this nlysis helps to explin the reltively subtle vrition in response tht we observed in the PFC s function of motion strength. Across the entire psychometric function, the evidence for rightwrd chnges by only one unit of signl stndrd devition for correct choices tht led to the sme behviorl response (Fig. 8g). The unit, σ, cn be relted to the responses of MT neurons. At d vlue of 1, the response of pooled rightwrd-preferring MT neurons exceeds the response of pooled leftwrd-preferring MT neurons by one stndrd devition of the pooled vlues. Recordings from re MT show tht t motion strength of 10% (corresponding to d ~1), rightwrd- nd leftwrd-preferring neurons differ in their responses by ~5 spikes/s 1,17. According to the nlysis (Fig. 8g), 182 nture neuroscience volume 2 no 2 februry 1999

8 rticles the monkey s judgments t the wekest motion strength (0% coherence) re bsed on evidence of ± 1.13 σ, or ~5 spikes/s from the verge MT neuron. We do not know how to convert this vlue to spike rte in the PFC; in the exmple we re pursuing, ll rightwrd choices re ssocited with high spike rte. However, s the motion strength increses to spn the monkey s psychometric function, the strength of the evidence increses (or decreses) by only nother unit of σ or ~5 spikes/s. This vlue is comprble to the chnge in PFC response tht we observed cross the rnge of motion strengths used in our experiments (see Fig. 5, b nd legend). DISCUSSION The dorsolterl prefrontl cortex is importnt in linking senstion to ction, especilly when the linkge involves dely 6,7. Our study provides glimpse of this linkge in the ctivity of individul PFC neurons. We used tsk in which delyed sccdes were instructed by direction judgment. By requiring the niml to mke difficult judgments ner psychophysicl threshold, we were ble to chrcterize neurl ctivity during period in which sensory processing grdully gve wy to ctegoricl choice, wht we hve termed decision process. Our results demonstrte grdul unfolding of neurl ctivity, which we interpret s correlte of the monkey s decision. To find neurl correlte of the monkey s decision bout the direction of motion, we serched for neurons tht signled the monkey s commitment to prticulr behviorl option. We therefore studied neurons in the FEF nd principlis region tht showed sustined ctivity during n oculomotor delyedresponse tsk. These neurons could be sid to lie towrd the motor side of senstion ction continuum 14, linking the visul cortex with the motor system 18. The sustined response of PFC neurons hs been interpreted s neurl correlte of short-term memory for sptil loction 19,20, but we do not know if such neurl ctivity represents the instruction (for exmple, loction of sptil cue) or the behviorl pln to move the eyes to tht loction. Our results suggest tht the response my conflte these representtions. Most neurons modulted their response in ssocition with ll the key ingredients of the discrimintion tsk: the ppernce of trget within the response field, the direction nd strength of rndom dot motion nd the direction of plnned sccde. Our nlysis showed tht erly in the tsk, during formtion of the decision, the modultion in neurl response vries prmetriclly with the strength of visul motion (Fig. 5). By the end of this process, mny neurons in the PFC reflect the monkey s choice. These observtions suggest tht the PFC represents not simply the finl outcome of sensory processing but the conversion of n nlog motion representtion to binry decision vrible. This conclusion must be viewed cutiously becuse we do not know the moment tht the monkey decides the direction of motion, or indeed if there is such discrete moment. It is possible tht on different trils, the monkey reches its decisions t different times nd the neurl responses chnge shortly therefter to revel the intended ction. The verge response from mny trils might give the ppernce of grdul evolution of the monkey s pln (Fig. 5c). If the decision were to occur sooner, on verge, for esier discrimintions, then this could explin the prmetric vrition in response mgnitude tht we observed with different motion strengths (Fig. 5 nd b). We hve looked for discrete chnges in the firing ptterns of our neurons using previously described lgorithm 21, but we hve filed to find evidence for such brupt trnsitions. Simultneous recordings from two or more neurons could, in principle, fcilitte detection of such brupt chnges in firing pttern. Our observtions support n emerging view tht the distinction between sensory nd motor systems my be blurred within the ssocition res of the cerebrl cortex 18,22,23. In mny ssocition res, neurl responses re predicted by stimulus qulities s well s motor preprtion. It is tempting to regrd the former s instructing the ltter. For exmple, FEF neurons represent fetures of visul stimuli tht instruct n eye movement in visul serch tsk 24. Neurons in re 46 respond t the moment n instruction is given to guide future eye movement 11. Even neurl responses in the primry nd supplementry motor cortex reflect not only the plnned behvior but the sensory cue tht instructs tht ction 12, Any brin region contining signls relted to both sensory processing nd motor preprtion my be involved in the conversion of the former to the ltter. For most tsks, however, there is insufficient time to study the process of conversion: the moment the instruction is received, the niml cn prepre n ction. In the threshold discrimintion tsk tht we used, the monkey cnnot process the instruction instntly. The monkey, like humn subjects, benefits from the temporl ccumultion of informtion 1,32 (J.D. Roitmn & M.N.S., Soc. Neurosci. Abstr. 24, 262, 1998). Our results suggest tht prefrontl neurons my do more thn hold informtion in short-term memory. They seem to be involved in the ccumultion (tht is, integrtion) nd comprison of sensory strems towrd ctegoricl outcome or behviorl pln. This does not imply tht the neurons we recorded re directly responsible for deciding direction. They my reflect the computtion mde t nother site in the brin. In fct, the neurons described here respond similrly to neurons in the lterl intrprietl re (LIP) nd the superior colliculus 33,34 during the sme motion discrimintion tsk. This is not surprising becuse re LIP, the FEF nd the posterior principlis region re strongly connected with ech other Both LIP nd the dorsolterl PFC seem to be ctivted during similr delyed eye movement tsks 39, nd both res project to the superior colliculus 36, The reltive importnce of these brin regions will need to be ddressed with reversible inctivtion or simultneous recording. Menwhile, the ctivity in the prefrontl nd inferior prietl cortex revels something bout the computtions tht my underlie the linkge between sensory dt, interprettion nd behviorl plnning. We propose tht such neurons compute the time integrl of sensory evidence towrd plteu stte. Neurons whose dominnt mode of response signls the pln to enct behvior must be influenced by sensory signls. The existence of such link comes s no surprise, but the mixture of signls on single neurons, reflecting motor plnning nd sensory strength, constrins view of the brin s logicl rchitecture. It seems inconsistent with centrl executive function tht interprets the sensory dt, declres n interprettion nd recruits circuitry to enct response. Insted, it supports view of brin orgniztion tht would recruit premotor circuitry in the interest of severl potentil ctions while querying sensory strems for evidence to select the pproprite one. METHODS Electrophysiology. We recorded from 88 neurons in the frontl eye field (FEF, res 8Ac nd 45) nd posterior principlis region (res 8Ar nd Wlker re 46) of two rhesus monkeys trined on rndom nture neuroscience volume 2 no 2 februry

9 rticles dot motion discrimintion tsk 1. Monkeys were implnted with n eye coil, hed-holding device nd recording cylinder suitble for mgnetic resonnce imging (MRI; Crist Instrument Co., Dmscus, Mrylnd). The recording cylinder ws plced over the rcute sulcus nd the posterior third of the principl sulcus (PS; Fig. 1e). Sterile guide tubes were plced through plstic grid (Crist Instruments) to introduce tungsten/glss microelectrodes to the surfce of the dur mter. The grid rry ws visulized in situ by MRI nd registered with the ntomy (Fig. 1f). We used the MRI to identify the FEF in the nterior bnk of the rcute sulcus nd to distinguish the re principlis from more cudl portions of the prercute gyrus. Action potentils were identified using dul-voltge, time-window discrimintor (Bk Electronics, Germntown, Mrylnd) nd stored on computer with 1- ms precision 43. All trining, surgery nd experimentl procedures complied with the Ntionl Institutes of Helth Guide for the Cre nd Use of Lbortory Animls nd were pproved by the University of Wshington Animl Cre Committee. Electricl stimultion. To id in identifying recording sites within the frontl eye field, we ttempted to elicit sccdes using the electricl microstimultion protocol described 44. We clssified sites s low threshold if we could elicit fixed-vector sccde with stimulting current less thn 50 µa. We clssified cells s in or out of the FEF bsed on their loction in the nterior bnk of the rcute sulcus nd their proximity to low-threshold stimultion sites. This procedure unequivoclly clssified most neurons. Behviorl tsks. Neurons were selected using delyed-sccde tsk tht relies on working memory (Fig. 1d) 8,45,46. We studied neurons tht responded during the dely (memory) period preceding sccdes to restricted region of the visul field. We refer to this region s the neurl response field (RF) to remin gnostic s to function. Mny neurons lso responded trnsiently t the onset of movement or to the onset of sccde trgets, but this ws not criterion in their selection. Similr selection criteri were used in relted study of re LIP 33. In the motion-discrimintion tsk (Fig. 1 nd b), two response trgets ppered. One trget ws in the RF of the neuron; the rndom dot kinemtogrm nd the second response trget ppered outside the RF. After brief puse ( ms), the rndom dot motion ws displyed for 1 s. The direction of motion ws towrd one or the other trget. Both the direction of motion nd the frction of coherently moving dots were rndomized. After dely, the monkey indicted its direction judgment by mking n eye movement to one of the two response trgets. The monkey ws trined to ssocite rightwrd motion with the trget to the right of the dots perture, upwrd motion with trget bove the perture, nd so forth. The monkey received liquid rewrd for correct responses (nd on hlf of the trils in which the 0% coherent motion ws shown). In ll experiments, the monkeys showed smooth improvement in performnce s function of motion strength (Fig. 1c). The verge threshold motion strength supporting 81% correct choices ws 12.9% (rnge 1.5 to 34.1%; stndrd devition, 5.2%), which is typicl of highly trined rhesus monkeys in similr studies 1,16. We occsionlly held neurons long enough to do pssive-fixtion control experiment (Fig. 6). No sccde trgets ppered on this block of trils, nd the monkey ws rewrded simply for mintining fixtion. Rndom dot motion (51.2% coherence) ppered in the sme loction s in the discrimintion block nd moved towrd the RF or in one to seven directions wy from the RF. Dt nlysis. Responses were nlyzed off-line using custom softwre. To combine dt from severl neurons, we first normlized ech neuron s response using the men spike rte in n epoch from ms fter the onset of rndom dot motion. This epoch corresponds to motion viewing, when the monkey decides the direction of motion nd fter the prominent trnsient response to the onset of sccde trgets. The effect of motion strength on the neurl response ws estimted using liner regression model, Y = β 0 + β 1 C + ε where Y is the normlized spike rte nd C is the rnk motion strength (0 to 5). For ech tril, we lso extrcted five descriptors of the sccde: its ltency, mplitude, ccurcy, mximl speed nd durtion. We included these fctors long with motion strength in multivrite regression nlysis, fitting the model, Y = β 0 + β 1 C + β 2 LAT + β 3 AMP + β 4 ACC + β 5 VMAX + β 6 DUR + ε (1) The fit to eqution 1 llowed us to test whether motion strength ffects the neurl response in mnner tht cnnot be ttributed to vrition in sccdic eye movements. This is test of the null hypothesis, β1 = 0, which is done by compring the extr sum of squres with nd without this regressor nd computing n F rtio 47. Anlysis of predictive ctivity. For severl nlyses, we computed n index tht describes the ssocition between neurl response nd the monkey s decision. This index, the probbility tht the neurl response ssocited with one behviorl choice exceeds the neurl response ssocited with the other behviorl choice, pproximtes the bility of the experimenter to predict the monkey s behvior from the neurl response. Denoting the responses ssocited with the two choices by {r 1 } nd {r 2 }, this is the joint probbility of observing r 1 =k nd r 2 < k, over ll possible vlues of k: Predictive index = Pr(r 1 = k)pr(r 2 <k)dk (2) - k = Pr(r 1 = k) [ Pr(r 2 =µ)dµ ] dk - - Eqution 2 cn be estimted by computing the re under receiver-opertor-chrcteristic (ROC) curve obtined from the two response distributions 1,48. The distribution of the predictive index under the null hypothesis is typiclly not norml. We used permuttion test to estimte the probbility tht the mesured index would be observed under the null hypothesis of rndom ssocition between neurl nd behviorl response (tht is, the true index is 0.5). Ech neurl response nd ech behviorl response were rndomly ssocited to construct the two distributions, {r 1 } nd {r 2 }, which therefore contin the sme number of observtions s the originl {r 1 } nd {r 2 }. The predictive index ws computed using Eqution 2, nd the distribution of its bsolute difference from 0.5 ws estimted using 1000 permuttions of the dt. The probbility of obtining the mesured index under the null hupothesis is the frction of this distribution exceeding the bsolute vlue of the mesured index s difference from 0.5. The sme procedure ws used to mesure of the time course of predictive ctivity (Fig. 5c) by computing the predictive index from spike counts obtined from 250-ms epochs t intervls designted with respect to the onset rndom dot motion or the monkey s sccdic eye movement. The resulting sigmoid functions re well fit by the scled integrl of Gussin function of time: p(t) = C + (b 0 + b 1 C)Φ(t), where (3) t [τ (µ 0 + µ 1 C] Φ(t) = 1 2 e 2[σ 0 + σ 1 C] 2 dτ 2 π (σ 0 + σ 1 C) - Notice tht Φ(t) is cumultive Gussin function of time, prmeterized by its men nd stndrd devition: the men determines the position of the sigmoid from left to right, nd the stndrd devition determines its slope. We modeled the bseline vlues, ; the scling terms, b; nd the sigmoid prmeters, µ nd σ, s liner functions of the motion strength, C. We fit eqution 3 to the mesured predictive indices using simplex lgorithm to find the mximum likelihood solution (ssuming binomilly distributed error). The null hypothesis tht motion strength does not ffect the shpe of these sigmoid functions ws tested by fitting the model with 1 = b 1 = µ 1 = σ 1 = 0 nd compring likelihoods under the full nd reduced models (likelihood rtio test, df = 4) 49. We refer to this method s modified probit nlysis. 184 nture neuroscience volume 2 no 2 februry 1999

10 rticles ACKNOWLEDGEMENTS We thnk Meliss Mihli for niml trining nd technicl support. We lso thnk Joshu Gold, Greg Horwitz, Mrk Mzurek, Bill Newsome, Jeff Schll nd Kirk Thompson for helpful suggestions on the mnuscript. This reserch ws supported by RR00166, EY11378 nd the McKnight Foundtion. RECEIVED 24 AUGUST: ACCEPTED 23 DECEMBER Britten, K. H., Shdlen, M. N., Newsome, W. T. & Movshon, J. A. The nlysis of visul motion: comprison of neuronl nd psychophysicl performnce. J. Neurosci. 12, (1992). 2. Newsome, W. & Pre, E. A selective impirment of motion perception following lesions of the middle temporl visul re (MT). J. Neurosci. 8, (1988). 3. Slzmn, C. D., Mursugi, C. M., Britten, K. H. & Newsome, W. T. Microstimultion in visul re MT: Effects on direction discrimintion performnce. J. Neurosci. 12, (1992). 4. Celebrini, S. & Newsome, W. T. Neuronl nd psychophysicl sensitivity to motion signls in extrstrite re MST of the mcque monkey. J. Neurosci. 14, (1994). 5. 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