The sensory nature of mnemonic representation in the primate prefrontal cortex

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1 rticles The sensory nture of mnemonic representtion in the primte prefrontl cortex Christos Constntinidis, Mtthew N. Frnowicz nd Ptrici S. Goldmn-Rkic Section of Neuroiology, Yle School of Medicine, New Hven, Connecticut 06510, USA Correspondence should e ddressed to P.S.G.-R. (ptrici.goldmn-rkic@yle.edu) A long-stnding issue concerning the function of the primte dorsolterl prefrontl cortex is whether the ctivity of prefrontl neurons reflects the perceived sensory ttriutes of rememered stimulus, or the decision to execute motor response. To distinguish etween these possiilities, we recorded neuronl ctivity from monkeys trined to mke sccde towrd the righter of two memornd, under conditions of vried luminnce. Our results indicted tht during the dely period when sensory informtion ws no longer ville, neuronl dischrge ws modulted y the luminnce of the stimulus ppering in the receptive field, nd ws directly correlted with psychophysicl performnce in the tsk. The findings suggest tht lthough prefrontl cortex codes for diversity of representtions, including the decision for n impending response, popultion of neurons mintins the dimensionl ttriutes of rememered stimuli throughout the dely period, which llows for flexiility in the outcome of mnemonic process. The primte prefrontl cortex (PFC) is criticl node of the network tht medites working memory, one component of which is the ility to retin nd mentlly mnipulte stimulus over the time scle of seconds 1,2. Prefrontl lesions in humns 3,4 nd monkeys 5,6 produce severe deficits in tsks tht require mnemonic representtions. Electrophysiologicl 7 10 nd imging experiments confirm prefrontl corticl ctivtion during working memory tsks. The nture of neuronl ctivity in PFC during working memory tsks, nd whether this ctivity represents rememered stimulus or preprtion for response hs een mtter of dete. Although neurons in the primte prefrontl cortex dischrge while stimulus is mintined in memory, it hs een rgued tht temporl correltion does not necessrily imply involvement of this ctivity in perceptul memory Indeed, evidence from recordings in posterior prietl nd dorsolterl prefrontl cortex using delyed discrimintion tsk rises the possiility tht neurons represent not the rememered stimulus itself ut the decision tht determines motor commnd 18,19. The dischrge rte of individul neurons in the primte visul cortex correltes well with psychophysicl performnce in ehviorl tsks 20,21, suggesting tht sensory representtions re medited y the ctivity of the neuronl popultion. No such link etween ehvior nd dischrge rte hs yet een estlished for neurons in res ctive during the mintennce of visul stimuli in memory. To explore the reltionship etween neuronl ctivity nd ehviorl performnce, we recorded from the dorsolterl prefrontl cortex of monkeys trined to perform delyed discrimintion tsk. Animls were riefly shown two stimuli of vried luminnce, nd fter dely period, they mde sccde to the rememered loction of the righter stimulus, which could pper inside or outside the neuron s receptive field. This protocol llowed us to determine whether ctivity in the dely period, fter ll sensory informtion for the formtion of perceptul decision hd een provided, ws modulted y the sensory ttriutes of the rememered stimulus, or represented the outcome of the nimls choice 19. If mnemonic ctivity represents sensory ttriutes, firing rtes in the dely period should reflect vritions in the luminnce of the stimulus to e reclled. Our results indicte tht mnemonic neuronl responses were not only grded y the sensory ttriutes of the stimulus, ut were lso directly correlted with psychophysicl performnce. RESULTS We nlyzed ctivity from 52 isolted neurons in the prefrontl cortex (res 8 nd 46) of two rhesus monkeys (Fig. 1). The nimls were trined to perform vrint of the oculomotor delyed response (ODR) tsk tht hs een used to chrcterize neuronl responses in the prefrontl cortex 9,22,23. The monkeys fixted on centrl spot on screen, nd were presented with two stimuli ppering simultneously, t dimetric positions (Fig. 1). The stimuli remined on the screen for 0.5 second nd were followed y dely period of 3 seconds. Susequently, the fixtion point turned off, nd the nimls were trined to mke sccde to the loction of the righter of the two stimuli, which could pper inside or outside the neuron s receptive field. The reltive contrst of the two stimuli differed rndomly in ech tril. The luminnce of one stimulus (trget) remined fixed in ll trils, wheres the luminnce of the second stimulus (distrctor) vried etween the ckground nd the luminnce of the trget. The nimls percentge of correct responses depended on the contrst rtio of the two stimuli (Fig. 1c nd d). They chieved 75% correct responses when the contrst rtio of the distrctor reltive to the trget ws 1 to 4%. We selected rnge of stimulus luminnce over which performnce vried in n essentilly liner fshion when plotted ginst the logrithm of the contrst rtio (liner regression, R 2 = 0.99, 0.97 for the two nimls respec- nture neuroscience volume 4 no 3 mrch

2 rticles Fig. 1. Mcque rin nd ehviorl tsk. () Recordings were focused on the posterior third of the principle sulcus nd the nterior lip of the rcute sulcus. () Successive frmes represent ppernce of the fixtion point, presenttion of the two stimuli, dely period nd sccde. (c, d) Psychophysicl performnce of the two monkeys in the ehviorl tsk. Percentge of correct sccdes towrd the trget s function of contrst rtio etween trget nd distrctor. Conditions corresponding to 0% contrst rtio (no distrctor) nd 100% contrst rtio (equl luminnce of the two stimuli) re not shown. tively). This liner reltionship ws exploited to determine whether psychophysicl ehvior ws correlted with neuronl ctivity. Responses from one prefrontl neuron re shown in Fig. 2. The neuron exhiited phsic response during the cue presenttion followed y tonic response during the dely, when the trget ppered inside the receptive field (Fig. 2, c nd e). The neuron ws lso ctive when the distrctor ppered in the receptive field, nd moreover, its ctivity ws grded sed on the distrctor luminnce (Fig. 2d nd f). In ech cse, the neuron s ctivity in the dely period represented the stimulus tht ppered in its receptive field, regrdless of whether the niml mde sccde towrd it or wy from it. This ws representtive of our popultion, lthough we did oserve some neurons, prticulrly those with strong pre-sccdic responses, tht only reflected the niml s motor response. Most neurons in our smple mintined ctivity ove the seline during the dely period when distrctor ppered in the receptive field, lthough the c d c d niml mde sccde wy from the receptive field (Fig. 3). The effect ws sttisticlly significnt for 42% of the neurons (45% nd 25% for the two nimls respectively; t-test, p < 0.05). We tested the effect of stimulus luminnce on neuronl responses y performing regression nlysis (Fig. 4). The dely period ctivity of ech neuron ws normlized to the verge response to the trget in the receptive field, then responses from ll neurons were used for the regression. Dely period ctivity ws not significntly modulted y the presence of distrctor outside the receptive field, when the trget ppered inside (Fig. 4; regression nlysis, p > 0.3). However, dely period ctivity ws significntly dependent on contrst rtio when the distrctor ppered in the receptive field (regression nlysis, p <10 5 ). To ensure tht this effect ws not due to eye-movement prmeters, we repeted our nlysis fter including sccde metrics in the regression model. The effect of contrst rtio remined highly e f Fig. 2. Single neuron responses were modulted y stimulus contrst. ( f) Rsters nd PST histogrms represent responses of single prefrontl neuron to six stimulus conditions (right). Only correct trils re shown. Higher contrst rtios represent righter distrctors. The verge dischrge rte during the dely period is indicted ove ech histogrm. The neuron is ctive during the cue nd dely periods when stimulus ppers in its receptive field, whether the niml mkes sccde towrd it (, c, e) or not (d, f). Vlues of contrst rtios were rounded; ctul vlues, 0.13% nd 0.96%. 312 nture neuroscience volume 4 no 3 mrch 2001

3 rticles Fig. 3. Distrctors evoked dely-period responses for most neurons tested. Ech point represents responses of one neuron in the dely period. Asciss, ctivity recorded during the presenttion of sole trget stimulus outside the receptive field. Ordinte, ctivity recorded during the presenttion of the rightest distrctor in the receptive field. White circles, neurons with significntly different responses in the two conditions (t-test, p < 0.05). significnt (p <10 5 ), indicting tht the modultion ws independent of the motor response. This nlysis indicted tht the verge ctivity in the dely period ws modulted y the contrst rtio of rememered stimulus. It is possile, however, tht this sensory representtion is trnsient nd tht the outcome of the perceptul decision is reflected in neuronl ctivity lter in the dely period. To test this hypothesis, we quntified the proility tht neuronl responses cn distinguish etween trget nd distrctor y doing receiver-operting chrcteristic (ROC) nlysis in successive time windows. The re under the ROC curve ws clculted in 250-ms intervls for ech neuron nd then verged cross ll neurons. Our results indicted tht the ility to discriminte etween trget nd distrctor ws dependent on the contrst rtio throughout the dely period (Fig. 5). A grdul increse in predictive ctivity s function of time ws lso pprent. The effects of oth contrst nd time on the proility vlue were highly significnt (regression nlysis, p <10 5 ). The interction etween time nd contrst ws not significnt (two-wy ANOVA, F 66,4284 = 0.57, p > 0.9), lthough the ANOVA test confirmed tht the min effects of oth contrst nd time were significnt (contrst, F 6,4284 = 12.7, p <10 5 ; time, F 11,4284 = 5.1, p <10 5 ). This result suggests tht discrimintion proility cn e represented s liner function of contrst nd time. The results presented so fr were sed on the nlysis of trils with fixed dely intervl. It is possile tht the sensory ttriutes of rememered stimuli modulte responses in the dely period only under these conditions. Neurons my insted represent motor response if the dely vries rndomly, forcing the niml to form motor pln fter the offset of the cue. To test this hypothesis, we recorded ctivity from 24 dditionl neurons, tested with dely period tht could vry etween 0.15 nd 3 s in ech tril. The neuron depicted in Fig. 6 ws ctive during the dely period following presenttion of trget in the receptive field (Fig. 6) ut not if the trget ws outside the receptive field (Fig. 6). The sme neuron continued to dischrge in the dely period following presenttion of distrctor in the receptive field (Fig. 6c) even though the durtion of the dely vried rndomly from tril to tril. The effect of stimulus contrst cross the popultion ws sttisticlly significnt when the distrctor ppered inside the receptive field (two-wy ANOVA, p <10 5 ) ut not significnt when the trget ppered in the receptive field (p > 0.3) s ws the cse when using fixed dely intervl (Fig. 7). DISCUSSION Activity of neurons in the dorsolterl prefrontl cortex during the dely period of mnemonic tsk ws modulted y the perceived sensory ttriutes of rememered stimuli, nd correlted directly with psychophysicl performnce in the tsk. This response pttern cnnot e ccounted for y fctors such s tsk difficulty or rewrd expecttion, which modulte the firing rte of prefrontl neurons The verge popultion response ws not significntly modulted y the difficulty of the discrimintion when the trget ppered inside the receptive field (Fig. 4). Indeed, neurons dischrged more vigorously when the distrctor ppering in their receptive field ws identicl to the trget, the condition tht represented the minimum rewrd expecttion (Fig. 4). Our experiments ddressed whether prefrontl corticl ctivity represents the formtion of decision to execute prticulr response. If tht were the cse, neurl ctivity should reflect sensory ttriutes erly in the decision process, ut only stereotyped outcome of the niml s choice fter ll sensory informtion hd een ccumulted 19,27. Responses to ll contrst levels should therefore e identicl nd not differentile during the dely period (Fig. 8, top). Contrry to tht prediction, our results indicted grded pttern of responses relted to luminnce throughout the dely. The present findings re in greement with previous experiments in the dorsolterl prefrontl cortex suggesting tht neuronl ctivity in mnemonic tsk represents the rememered visul stimulus, s demonstrted y the nti-sccde prdigm, sptil mtch-to-smple nd conditionl response tsks 10,28,29. Fig. 4. Popultion responses were modulted y the luminnce of the stimulus in the receptive field. Averge normlized responses for neurons tested with the rnge of contrsts shown in Fig. 1c (n = 39, from one monkey). Line, regression of dischrge rtes on the logrithm of contrst rtio. () Trils with the trget ppering inside the receptive field. Regression slope ws not significntly different from zero ( 0.004, p > 0.3). () Trils with the distrctor ppering in the receptive field. The regression slope ws significntly different from zero ( 0.037, p < 10 5 ). Squres, responses to the trget lone (not included in the regression nlysis). nture neuroscience volume 4 no 3 mrch

4 rticles Fig. 5. Proility of discrimintion etween trget nd distrctor ws grded s function of their contrst rtio. Proility vlues were computed s the re under the ROC curve in 250-ms windows, then verged cross ll neurons. The three curves represent stimulus presenttions with no distrctor (0% contrst rtio), distrctor equl in luminnce to the trget (100% contrst rtio) nd distrctor of ner-threshold luminnce (1 4% contrst rtio). In ech cse, most neurons reflect the position of the rememered stimulus rther thn the direction of response. Similr conclusions re drwn from experiments in the posterior prietl cortex 30,31, n re tht provides direct ntomicl input to dorsolterl PFC (ut see refs. 32, 33). Studies in the inferior convexity of the PFC lso indicte tht neurons respond sed on the identity of rememered visul stimulus 34 37, lthough tsk demnds my modulte the level of ctivity evoked y the stimulus 38,39. Experiments using tctile tsk further indicte tht sensory informtion is represented in prmetric fshion in the PFC, reflecting the frequency of rememered virtory stimulus 40. A direct link etween the sensory ttriutes of stimuli, dely-period ctivity of prefrontl neurons, nd ehviorl performnce in mnemonic tsk, s estlished here, provides compelling evidence tht dorsolterl prefrontl neurons cn medite the mentl representtion of sensory informtion in working memory. In contrst to these results, previous studies nlyzing ctivity in the dely period of discrimintion tsk concluded tht neuronl responses est correlte with the outcome of perceptul decision 18,19. An importnt cvet in these experiments is tht, in n ttempt to seprte sensory nd motor responses, stimuli were lwys plced outside the neuron s receptive field nd instructed sccde towrd or wy from it. Therefore, it is possile tht the potentil of prefrontl neurons to represent the rememered visul stimulus ws not ssessed in these studies. Neurons presented with stimuli outside their receptive fields my e ctive in the dely period if the niml is plnning response towrd the neuron s receptive field 41. However, it is questionle whether the ctivity of neurons with no ccess to the relevnt sensory informtion is pooled towrd the formtion of decision. How cn the results of these discrimintion experiments e reconciled with our own? It is likely tht the erlier studies recorded from the popultion of neurons tht reflected motor response 10,29. We oserved such neurons in our own smple, nd their ctivity is reflected in the popultion verge (Figs. 4 nd 5). Motor-relted neu- rons represent the impending response s well s the perceptul decision out the rightness of the two stimuli. These neurons tend to dischrge in n ccelerted fshion efore the onset of movement 42, which could ccount for the fct tht the popultion of PFC neurons est discriminted etween the trget nd distrctor t the time intervl immeditely preceding the eye movement, for ech contrst level (Fig. 5). Bsed on these considertions, we propose tht dorsolterl PFC encompsses neurons engged in t lest two seprte processes: sensory representtion tht remins firly constnt or slowly decys during the dely period, nd response preprtion tht increses towrd the onset of the sccde (Fig. 8). Our present findings fvor the view tht motor pln is n emergent property of network composed in prt y neurons sustining sensory informtion, rther thn involving discrete decision stge in which sensory prmeters re trnsformed into motor vriles y single neurons 43,44. Our tsk did not explicitly require the nimls to rememer the luminnce of the stimuli; the suject needed only to discriminte etween their reltive difference. However, dely period ctivity did mintin fithful representtion of the perceived sensory ttriutes of the stimuli, evidenced y its strong correltion with the nimls performnce. In this context, dely-period responses to distrctor cn e thought of s short-term memory trces for n unttended stimulus. This point is importnt in interpreting the results of imging studies tht often rely on the comprison of Fig. 6. Individul neuronl responses were dependent on contrst in vrile dely experiment. PST histogrms represent responses of single PFC neuron. () The neuron ws ctive during the dely period of 1 s (left) or 3 s (right) when the trget ppered in the receptive field. () The sme neuron did not respond during presenttion of the trget outside the receptive field. (c) The neuron displyed significnt dely period ctivity following presenttion of distrctor (contrst rtio, 4%) in the receptive field. c 314 nture neuroscience volume 4 no 3 mrch 2001

5 rticles Fig. 7. Popultion responses for ech contrst level in vrile dely period experiment. Points, verge normlized responses of ll neurons tested with the vrile dely tsk (n = 24). Blck circles, 1-s dely period; gry circles, 2-s dely period; white circles, 3-s dely period. The effect of distrctor contrst ws significnt only when the distrctor ppered in the receptive field. The effect of dely durtion ws not sttisticlly significnt. pssive versus ctive memory tsks to identify rin res involved in working memory 17,45,46. Our results demonstrte the functionl cpcity of PFC neurons to sustin representtion of the perceived sensory spects of stimuli in working memory tht could e potentilly used or mnipulted flexily, nd tht could serve mny options. This nture of neuronl representtion in prefrontl cortex is comptile with role for PFC in executive processes. A response code, in contrst, would limit neuronl ctivity to corticl reflex, tht is, the oligtory outcome of sensory motor ssocition. METHODS Behviorl tsk. All neurons were initilly tested with the oculomotordelyed response (ODR) tsk 9. Eye position ws monitored with sclerl eye-coil 47. Neurons exhiiting significntly elevted firing rte in the ODR tsk were further tested with discrimintion tsk, s follows. Trils egn with the ppernce of point on tngent screen tht the nimls were required to fixte on throughout the tril. Two stimuli were susequently presented for 0.5 s t dimetric positions round the fixtion trget. The stimuli were 1 in size, nd they ppered t n eccentricity of 14, mking the discrimintion very difficult unless the two stimuli differed considerly in luminnce. After dely period of 3 s, the fixtion point turned off nd the monkeys were trined to mke sccde to the loction of the righter stimulus (trget). The trget hd luminnce of 110 or 150 cd/m 2 (Michelson contrst, 99%) nd it could pper rndomly on either sptil loction. The luminnce of the finter stimulus (distrctor) vried etween the ckground (no visile distrctor) nd the luminnce of the trget. The monkeys were rewrded rndomly for sccdes to either stimulus when the two stimuli were equl in luminnce. Electrophysiologicl recordings. Monkeys were implnted with hed-restrining device, nd n MRI-guided crniotomy ws done to expose circulr perture over the prefrontl cortex. Neuronl ctivity ws recorded using vrnish-coted tungsten electrodes (1 4 MΩ t 1 khz). One to four electrodes were plced in stinless steel guide tues nd independently dvnced into the cortex through set of micromotors (Alph-Omeg Engineering, Isrel). Neuronl ctivity ws smpled with 30-µs resolution nd recorded wveforms were sorted into seprte units using templtemtching lgorithm (CED, Cmridge, UK). All niml trining, surgeries nd experimentl procedures were done in ccordnce with NIH guidelines, nd pproved y the Yle Animl Cre nd Use Committee. Dt nlysis. Firing rte ws clculted in three epochs: cue (0.5 s), dely (3 s following the offset of the cue) nd sccde (0.25 s following the offset of the fixtion point). Neurons were included in the nlysis if they stisfied two criteri. First, their firing hd to e significntly elevted from seline fixtion for t lest one tsk epoch (pired t-test, p < 0.05). Second, responses to stimulus presented t the two dimetric loctions of the discrimintion tsk hd to e relily distinguishle from ech other (ROC nlysis, see elow, proility 0.9). The ltter criterion ws necessry ecuse multiple neurons with disprte receptive fields were recorded in ech ehviorl run, nd some neurons were tested with stimuli plced t su-optiml loctions (sometimes oth in, or oth out of the receptive field). The numer of neurons tht fulfilled the selection criteri in the cue, dely nd sccde periods were 22, 25 nd 21 for the 3-s dely experiment nd 13, 20 nd 17 for the vrile dely experiment, respectively. Mny neurons with predominntly cue or sccdic responses were ctive during the eginning or end of the dely period. We sed the nlysis of our results on the entire smple, rther thn ignore the contriution of primrily cue nd sccde neurons to the dely period ctivity. We defined contrst rtio C s L d / L t where L d is the luminnce Fig. 8. Model. Top, pttern of ROC proility curves tht would e predicted if prefrontl neurons were representing the formtion of decision sed on ccumultion of sensory evidence. After the presenttion of the cue, neuronl responses should only represent the motor decision, nd ROC curves should converge. The experimentl results (ottom) cn e etter represented s the sum of two processes: sensory representtion tht remins firly constnt or decys slowly during the dely, nd response preprtion component reflecting the niml s choice, which increses during the dely. nture neuroscience volume 4 no 3 mrch

6 rticles of the distrctor minus the luminnce of the ckground, nd L t is the luminnce of the trget minus the luminnce of the ckground. We determined the effect of contrst rtio on neuronl firing rte y performing liner regression using the following model. Y = + C (1) Y represents the firing rte in the dely period of ech tril. Firing rtes were normlized y the neuron s verge firing rte during the dely period following trget stimulus. C represents the logrithm of the contrst rtio. A regression nlysis ws done seprtely for the trget ppering inside nd outside the receptive field. Trils recorded when no distrctor stimulus ws present were not used for the regression, s they correspond to contrst rtio of zero, which cnnot e trnsformed into logrithmic vlue; ll other ville trils from ll neurons were included in the model. To ensure tht ny effect of luminnce ws not ccounted for simply y vritions in sccdic eye movements, we repeted the regression nlysis including five descriptors of the sccde metrics in the model: ltency, mplitude, ccurcy, mximl speed nd durtion. All models were tested with the sttisticl softwre SYSTAT (SPSS, Chicgo, Illinois). We used receiver-operting chrcteristic (ROC) nlysis 48 to determine the ility of ech neuron to distinguish etween trget nd distrctor plced in its receptive field. The re under the ROC curve represents the proility tht of given pir of responses, one elonging to trget nd one to distrctor, the trget will evoke the higher dischrge rte. ROC curves were constructed using the spike count in successive 250-ms windows spnning the entire ehviorl tril. The time course of the predictive ctivity ws ssessed with liner regression model of the following form. Y = + 1 C + 2 T (2) Here, Y represents the re under the ROC curve (proility of correct discrimintion) for ech neuron, T, the corresponding time from the eginning of the dely period, nd C, the contrst rtio, s ove. ACKNOWLEDGEMENTS We thnk V. Bernrdo for technicl ssistnce nd D.T. Blke for his comments on previous version of the mnuscript. This work ws supported y NIMH grnt MH38546 to P.S.G.-R., fellowship MH11812 to M.N.F. nd McDonnel- Pew Progrm in Cognitive Neuroscience Awrd to C.C. RECEIVED 21 NOVEMBER; ACCEPTED 22 DECEMBER Goldmn-Rkic, P. S. Topogrphy of cognition: prllel distriuted networks in primte ssocition cortex. Annu. Rev. Neurosci. 11, (1988). 2. Bddeley, A. Working memory. Science 255, (1992). 3. Milner, B. Effects of different rin lesions on crd sorting. Arch. Neurol. 9, (1963). 4. Goldmn-Rkic, P. S. in Hndook of Physiology (eds. Plum, F. & Mountcstle, V. B.) (Americn Physiologicl Society, Bethesd, Mrylnd, 1987). 5. Butters, N. & Pndy, D. 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