Neural antecedents of self-initiated actions in secondary motor cortex

Transcription

1 Neurl nteedents of self-initited tions in seondry motor ortex Msyoshi Murkmi, M Inês Viente, Gil M Cost & Zhry F Minen npg Nture Ameri, In. All rights reserved. The neurl origins of spontneous or self-initited tions re not well understood nd their interprettion is ontroversil. To ddress these issues, we used tsk in whih rts deide when to ort witing for delyed tone. We reorded neurons in the seondry motor ortex (M) nd interpreted our findings in light of n integrtion-to-ound deision model. A first popultion of M neurons rmped to onstnt threshold t rtes proportionl to witing time, strongly resemling integrtor output. A seond popultion, whih we propose provide input to the integrtor, fired in sequenes nd showed tril-to-tril rte flututions orrelted with witing times. An integrtion model fit to these dt lso quntittively predited the oserved inter-neuronl orreltions. Together, these results reinfore the generlity of the integrtion-to-ound model of deision-mking. These models identify the initil intention to t s the moment of threshold rossing while explining how nteedent suthreshold neurl tivity n influene n tion without implying deision. Deision-mking involves the seletion of gols or tions, ut it lso requires determintion of the timing of tion. When there is stimulus or ue to ret to, the prolem of when to t is onstrined y sensory nd motor requirements nd my involve lning of speed versus ury nd other fets of sensorimotor oordintion, whih hve een intensively studied. In retion time tsks, deisions re ssoited with tril-to-tril vritions in response time. These flututions hve een theorized to rise from the integrtion of noisy sensory signls y neurl integrtor, whose rossing of tivtion threshold triggers n tion. In support of this theory, neurons in the primte frontl ortex, prietl ortex nd superior olliulus show grdul inreses in neurl tivity fter presenttion of visul stimuli, rehing onstnt tivity threshold t whih sdi eye movement is generted; retion times re orrelted with rtes of suh rmping tivity 5 7. In the sene of immedite sensory stimuli, the timing of more spontneous tions is lso importnt. Ation initition my e ffeted y internl stte (for exmple, urgeny signls) ut, s with retion times, ontins vriility. An importnt instne of spontneous tion genertion is deiding when to give up witing for n ntiipted event whose ourrene or timing is unertin. This form of inter-temporl hoie 8 etween witing nd giving up is relevnt in the ontext of impulsivity. Humns often hoose to wit for future events, ut susequently suum to n immeditely ville option while witing 9,. Some of the neurl sustrtes of hoies etween immedite nd delyed rewrds hve een identified,, ut omprtively little is known out the timing of deisions to terminte witing during dely. Insight into spontneous tions omes from studies of volitionl or self-initited tions, whih hve used wht re essentilly witing tsks with low time pressure. Clssil studies identified evoked rediness potentils in the midline higher motor, prietl nd prefrontl orties tht preede tions, with slow uilding potentil even preeding the sujet s reported intention to move,. Single units hve een reorded during suh tsks, reveling slow rmping tivity peking round the time of tion initition 5 8. Together, these studies re onsistent with the hypothesis tht n integrtion-to-ound mehnism, ommonly used to explin pereptul deisions nd retion times, might lso e mehnism for spontneous tion timing. We sought to sustntite this hypothesis y providing more rigorous evidene for the existene of popultion of neurons displying rmping tivity resemling the deision vriles or integrted evidene oserved in the lterl intrprietl re. A further ritil issue in the se of spontneous deisions is the origin of the signls tht drive the input integrtor when there is no sensory ue or evidene to umulte. The puttive input neurons would ontriute uslly to the determintion of tion timing, eing prtly preditive, ut individul neurons would need to ooperte to reh threshold for deision. As no suh input neurons for spontneous deisions hve een desried to dte, identifying their properties would e importnt. To test these hypotheses, we devised witing tsk in whih smll rewrd ws ville immeditely, ut lrge rewrd ws signled fter longer, rndomized dely. Rts tested on this tsk frequently orted witing, nd the timing of these orts vried gretly ross trils, with reltively minor ontriutions of tril history. We foused our study on the rostrl seondry motor ortex (M, the nterior region of medil grnulr ortex) n re ssoited with tion plnning nd spontneous tion initition 9, whih is onsidered to e homologous to primte supplementry motor res,. Using multi-eletrode reording from M, we first identified popultion of neurons with rmping tivity tht met strit riteri ssoited with the output of puttive neurl integrtors, ut not previously desried in rodents. Furthermore, we identified seond popultion Chmplimud Neurosiene Progrmme, Chmplimud Centre for the Unknown, Lison, Portugl. Correspondene should e ddressed to Z.F.M. (zminen@neuro.fhmplimud.org). Reeived 7 June; epted Septemer; pulished online 8 Septemer ; doi:.8/nn.8 57 VOLUME 7 NUMBER NOVEMBER nture NEUROSCIENCE

2 npg Nture Ameri, In. All rights reserved. of trnsiently tive neurons whose rtes flututed sustntilly from tril-to-tril in mnner tht orrelted with witing time. Using simple quntittive model, we estimted tht to mth the oserved strength nd frequeny of orreltion etween individul trnsient neurons nd witing time, sustntil orreltions would hve to exist etween pirs of trnsient neurons. Tril-y-tril orreltion nlysis of simultneously reorded pirs onfirmed this predition. Thus, prsimonious ount of our dt suggests tht the origin of the vrile timing of spontneous tions reflets, in prt, neurl trnsients in M tht re integrted to produe rmping tivity. The results reinfore the generlity of the neurl integrtion-to-ound theory of deision-mking nd identify previously unknown popultion of neurons in the motor system itself prtiipting in self-initited tions. Furthermore, they help to lrify the interprettion of wellknown experiments onduted in humn sujets onerning the neurl nteedents of onsious deisions to t. RESULTS Behvior In the witing tsk (Fig. nd Online Methods), rt initited witing y inserting its snout into the witing port. Shortly therefter (T dely =. s), the first tone (tone ) ws plyed, fter whih the rt ould grner smll mount of wter rewrd t the rewrd port. If the rt wited for seond tone (tone ), with dely drwn rndomly from n exponentil distriution (T dely), it ould grner lrger Proility Witing port Poke in Rewrd port Tone dely distriution T dely. T dely.5 Tone dely (s) Tone Witing port Rewrd port Rewrd delivery Wit Poke out Short poke tril T dely Tone Tone Wit T dely Poke out Witing time Imptient tril Smll rewrd Poke out Ptient tril Lrge rewrd Response time Movement time Figure The witing tsk nd the ehviorl results. () Shemti of tril events in the witing tsk (top). In eh tril, fter witing for ertin period t the witing port, the rt reeived tone(s), moved to the rewrd port nd reeived wter rewrd, the size of whih depended on the numer of the tones presented. Inset, proility distriutions of the delys to tone (T, light green) nd tone (T, drk green). Bottom, timeline of the tsk events nd the definition of the ehvior prmeters. The light green retngle indites the presenttion of tone, the drk green retngle represents tone nd the light lue retngle indites rewrd. Tone is represented y hthed retngle to indite it ws not plyed in the imptient trils. rewrd (two- to fourfold lrger thn the smll rewrd). Thus, rt witing pst tone experiened n ongoing onflit etween ontinuing to wit for tone nd leving the port to ollet smll rewrd. A vlue of T dely ws hosen so tht sujets performed with n ~% suess rte in witing trils (Online Methods). Trils ould e lssified into three types (Fig. ). In smll frtion of trils, rts left the port efore tone (short-poke trils, 8. ±.%, men ± s.d., n = 7 rts). In seond lss of trils, the rt responded fter tone (ptient trils,.9 ±.%). In the third lss, rts left the port fter tone, ut efore tone (imptient trils, 58.8 ±.9%). Notly, in the imptient trils, the witing time showed sustntil tril-to-tril vriility, s indexed y the differene etween the 9th nd th perentiles witing time ( WT [..9]: medin =. s, rnge =.59. s; Fig.,d) nd the verge differene in witing times from tone of two onseutive imptient trils normlized y sum (CV,. ±.; Online Methods nd Fig. e). Medin witing time ws highly orrelted with WT [..9] (R =.8, P < ). In imptient trils, rts did not usully respond promptly to tone, ut often stopped witing fter hundreds of milliseonds or seonds, ut efore tone. Two oservtions indite tht, in imptient trils, rts intended to wit for the lrge rewrd nd were not simply responding slowly to the first tone nd understood the rules of the tsk. First, when rts sueeded in witing for the seond tone, they responded promptly (7 ms, medin ross rts, omprle to Frtion of trils... e Numer of rts 8 Tril Rt I Cumultive frtion of trils rts WT [..9] Witing time CV f Frtion of trils. d Numer of rts 8.5 Response time to tone (s) 7 rts Rt I WT [..9] (s) g Numer of rts 8. 7 rts Pek resp. time (s) () Snpshot of the witing ehvior. The witing period in eh tril is indited s gry r. Light green tiks represent presenttion of tone nd drk green tiks represent tone. () Witing time histogrms of short poke trils (gry), imptient trils (red) nd ptient trils (lue) of n exmple rt. The histogrms show dt pooled ross sessions. Inset, umultive histogrm of witing times in imptient trils from this rt. The rrow indites the rnge from th to 9th perentile witing times ( WT [..9]). (d) Distriution of WT[..9] ross rts. Filled rs indite eletrophysiology rts. (e) Distriution of CV ross rts. Filled rs indite rts used for eletrophysiology. (f) A histogrm of response time to tone of n exmple rt (drk lue, n =,5 trils). Light lue shded re indites 95% rnge of response time histogrms from shuffled dt. The pek response time is indited y n rrowhed. (g) Distriution of pek response time ross rts. Signifint pek is shown in drk lue nd non-signifint pek in lk. Filled rs indite rts used for eletrophysiology (ll were signifint). nture NEUROSCIENCE VOLUME 7 NUMBER NOVEMBER 575

3 npg Nture Ameri, In. All rights reserved. Figure Differene in movement times in imptient nd ptient trils. () A stter plot inditing medin movement time in the imptient nd the ptient trils of different sessions of n exmple rt. Eh gry irle indites medin movement time of the imptient trils nd tht of the ptient trils from one session. The lk irle indites the men of the medin movement times of the imptient trils nd tht of the ptient trils. Error r represent ±s.e.m. () Normlized men movement times for imptient (red) nd ptient (lue) trils. For eh rt, the movement time is normlized with movement time of the imptient tril. Error r represents ±s.e.m. Gry irles represent the normlized movement times of the ptient trils of individul rts. Filled irles indite rts used for eletrophysiology. Movement time in ptient trils ws signifintly fster thn tht in imptient trils (Wiloxon signed-rnk test, P <., n = 7 rts). ms in n uditory response tsk ; Fig. f,g nd Supplementry Fig. ). Seond, rts moved more quikly to the wter port on ptient thn on imptient trils (Fig. ), inditing tht imptient nd ptient trils of similr witing times were ssoited with different rewrd expettions 5. Rmp-to-threshold tivity in M To determine speifi omputtions performed y M for witing time deisions, we next used hroni tetrode rrys to reord neuronl tivity while rts performed the witing tsk. We reorded totl of 85 neurons in 8 rts from M. A lrge frtion of neurons in M showed tsk-modulted tivity in different phses of the witing tsk (Supplementry Fig. ). We minly foused on imptient trils euse, in those trils, the rts deided when to leve the port (stop witing), independent of overt ues. The high tril-to-tril vriility of witing time in imptient trils provided strong signl with whih to orrelte with neurl tivity. We first serhed for neurons with rmp-to-threshold tivity tht might serve s n internl trigger for inititing response. We seleted for neurons meeting two riteri: the firing rte rehed onstnt Figure Rmp-to-threshold type preditive tivity. ( f) Exmple M neuron with rmp-to-threshold type tivity. () Perievent time histogrms (PETHs) for n M neuron in different witing time trils, ligned to poke in nd smoothed with Gussin filter (s.d. = 5 ms). Imptient trils re grouped ording to the witing time, indited y the olor sle in, nd onsistent throughout the figure. Dshed lines in PETHs indite times t whih rt lredy left the port in some of the trils in tht group. Threshold (57 spikes per s) is indited y the horizontl solid line. () PETHs for the neuron presented in, ligned to poke out. () Time to ross threshold firing s funtion of men witing time. The nlyses with the highest nd lowest thresholds with signifint orreltion (57 spikes per s (tringle) nd spikes per s (inverted tringle), respetively) re shown. R =.99, P <., n = 9 for the 57 spikes per s threshold; R =.8, P =., n = for the spikes per s threshold. Dshed lines indite the regression line. (d) The rte of rmping tivity s funtion of men witing time. The dshed line indites the regression line. R =.9, P <., n = 9. (e) The firing Firing rte (spikes per s) d Rmp rte (spikes per s ) g Numer of neurons Movement time (ptient tril) Rt I Movement time (imptient tril) threshold efore movement initition nd the timing of threshold rossing ws orrelted with witing time with regression slope lose to unity (Online Methods). An exmple neuron meeting these riteri is shown in Figure. The firing rte of this neuron grdully rmped up during the witing period (Fig. ), rehing the sme firing rte just efore the poke out (Fig. ). The time for the firing rte to ross 57 spikes per s threshold, the highest threshold level we tested for this neuron, ws highly orrelted with the witing time of the rt (Fig. nd Online Methods). The regression slope ws lose to unity, suggesting tht the lteny to the poke out from the threshold rossing time ws onstnt. We foused on 5 of 85 reorded neurons tht showed relile tivtion (8) or suppression (57) t the poke-out periods (Online Methods). Among this popultion, 7 neurons ( of 8 tivted neurons, 7 of 57 suppressed neurons, 7.% of ll reorded) met the riteri for rmp-to-threshold neuron (threshold rossing time orrelted with witing time with regression slope lose to unity) (Supplementry Fig. ). By ompring the oserved frtion of rmp-to-threshold neurons (7.%) to tht otined when rndomly permuting the witing times nd neurl dt ross trils, Correltion oeffiient etween log witing time nd log rmp rte Firing rte (spikes per s) 8 Time from poke out (s) e Firing rte t poke out (spikes per s) h Numer of neurons 8 8. Correltion oeffiient etween witing time nd firing rte Time to ross threshold (s) f Predition time (s) i Numer of neurons Normlized movement time Imptient tril 57 spikes per s 7 rts Ptient tril spikes per s 5 Threshold (spikes per s) 8.5 Erliest predition time (s) rte t the poke-out period (5-ms window efore the poke out) is plotted ginst the men witing time for eh group. Note tht firing rte rehed lmost the sme level t the poke out. R =.58, P =.7, n =. (f) Differene etween time to ross threshold nd the witing time (predition time) is plotted ginst the threshold tested. Blk irles represent men predition time ross groups, error rs represent ±s.e.m. nd filled lk irles represent signifint threshold. (g i) Popultion dt (n = 7 neurons). (g) Distriution of orreltion oeffiients etween the rte of rmping nd the witing time. Rmp-up neurons re shown in pink, rmp-down neurons in lue nd neurons with signifint orreltion in vivid olor. (h) Distriution of orreltions etween the firing rte t the poke-out period nd the witing time. (i) Distriution of the erliest predition time (Online Methods). 57 VOLUME 7 NUMBER NOVEMBER nture neuroscience

4 npg Nture Ameri, In. All rights reserved. Figure An M neuron with trnsient preditive tivity. () Rster plots (top) represent tivity of n M neuron, with eh row orresponding to single tril ligned to poke in (white line) nd eh lk tik to single spike. The imptient trils re shown on the pink kground nd the ptient trils on the lue kground. Trils re hronologilly ordered from top to ottom in eh type of trils. Color tiks represent tone (light green), tone (drk green), poke out (white) nd poke in into the rewrd port (light lue). PETHs t the ottom represent tivity in the imptient (red) nd ptient trils (lue), smoothed with Gussin filter (s.d. = 5 ms). () The sme neuron in the imptient trils. Trils re sorted in sending order of the witing time. PETHs (ottom) of trils grouped y witing time, s indited y olor sle. () Men witing time is plotted ginst men firing rte t. s from poke in. Trils re grouped ording to firing rtes ( spikes per s in) for the visuliztion purpose only. Error rs represent ±s.e.m. Cirles without error rs represent groups with or trils. Dshed line: regression line. (d) Signifine (P vlue) of the Person s orreltion oeffiient ws lulted t eh.-s non-overlpping in nd plotted s funtion of time (orreted for the multiple omprisons). Signifine level (P =.5) is indited y the dshed line. The signifine of eh time in is lso indited y the olor r on top. N.S., not signifint; N.D., no dt. we estimted the proility of otining this result y hne t P <. (permuttion test, Online Methods). After seleting popultion using reltively strit riteri, we onsidered in detil further properties of this popultion tht were not inluded in the seletion riteri. Briefly, this popultion of neurons showed strong positive or negtive orreltion etween rmp rte nd witing time (Fig. d,g nd Supplementry Fig. ), ut smll or zero orreltion etween firing rte t movement time (poke out) nd witing time (Fig. e,h). Finlly, individul neurons threshold rossing times predited future witing times sustntilly in the future, up to round s in dvne (Fig. f,i). Trnsient witing-time preditive tivity We next looked for neurons tht lso showed witing time preditive tivity tht did not tke the form of rmp-to-threshold. Speifilly, we serhed for neurons exhiiting different firing rtes for different witing time trils, whih ould serve s input to n integrtor nd therefore ontriute to the different rtes of rmping tivity. Firing rte (spikes per s) Neuron numer. 8 d Frtion of preditive neurons..5 < <....5 N.S. N.D..5.5 P vlue Not signifint No dt Numer of trils Firing rte (spikes per s) R =.5 Firing rte (. s, spikes per s) Numer of trils Firing rte (spikes per s) d P vlue This nlysis reveled lrger seond popultion of M neurons, n exmple of whih is shown in Figure. This neuron showed trnsient tivtion when the rt poked into the witing port (Fig. ). The tivtion ws stronger in imptient trils with longer witing times (Fig. ), nd the firing rte of this neuron ws signifintly orrelted with witing time (R =.5, P <., n = 8 trils; Fig. ). The orreltion ws signifint only in the time window etween poke in nd tone presenttion (Fig. d). The tivity of this neuron fter the poke in ws le to predit the witing time in eh tril to the extent of explining % of the vrine. M neurons with trnsient witing time orreltions showed vriety of different dynmi profiles, inluding different times nd durtions of firing. Figure 5 shows n exmple of neuron showing more prolonged tivtion during the dely period. Figure 5 shows n exmple of neuron with the opposite orreltion: witing time deresed s firing rte inresed. Overll, of 5 M neurons.9... <....5 N.S. N.D. Figure 5 Popultion dt of preditive tivity. (,) Other exmples of M neurons with preditive tivity. () Shown is n M neuron with sustined tivtion during witing nd whose firing rte ws positively orrelted with the witing time. Dt re presented s in Figure,d. () Shown is n M neuron with negtive orreltion etween the firing rte nd the witing time. Dt re presented s in Figure,d. The olor sle in green indites positive orreltion nd ornge negtive orreltion. () Time ourse nd the sign of the orreltion for ll the preditive neurons (n = neurons). The signifine of the orreltion is lulted for.-s overlpping time window in every.-s time step for eh neuron nd indited in eh row. Neurons re sorted ording to enter of mss of log(p vlue). Only the time ins with signifint P vlue were used to lulte the enter of mss. The olor ode is the sme s in. Bonferroni orretion for multiple omprisons ws used to selet neurons with trnsient orreltion, ut the P vlue here is not orreted for the multiple omprisons, s the min points re the time ourse nd the sign of the preditive tivity, not its solute vlue. (d) Time ourse of frtion of preditive neurons. For eh neuron, witing time orreltion with firing rte ws tested on susmples of imptient trils, llowing omprisons ross time ins. Susmpling ws performed, times nd error rs represent 95th perentile rnges. The white dshed line indites hne level of.5. P vlue nture NEUROSCIENCE VOLUME 7 NUMBER NOVEMBER 577

5 npg Nture Ameri, In. All rights reserved. Nose-poke lok Lever-press lok Nose-poke lok 7 ~ trils 7 ~ trils 7 ~ trils Firing rte (spikes per s) 8. Figure Ation speifiity of preditive tivity. () A shemti digrm of witing tsk with interleved loks of the nose-poke witing trils nd the lever-press witing trils (Online Methods). () An exmple of nose poke speifi preditive neurons. PETHs indite tivities of the neuron in the nose-poke witing trils (left) nd in the lever-press witing trils (right). The olor of the r on top indites the signifine of the time ins. Dt re presented s in Figure,d. () The preditive tivities of the two types of witing trils re represented independently in M. Eh irle represents one neuron, inditing the orreltion oeffiient etween the firing rte nd the witing time in the nose-poke trils on the x xis nd the orreltion oeffiient etween the firing rte nd the witing time in the lever-press trils on the y xis. The orreltion oeffiient ws lulted t the most signifint time in for eh type of trils. exmined in popultion nlysis, (8%, P <. with permuttion test with tril shuffling) showed trnsient witing-time preditive tivity (Supplementry Fig. nd Online Methods). Aross the entire popultion of witing time preditive neurons, two fetures re ritil (Fig. 5). First, different neurons showed preditive tivity, spnning the witing period (Fig. 5,d). Seond, pproximtely equl numers of neurons were positively nd negtively orrelted with witing time (Fig. 5). This is onsistent with the ide tht individul neurons ontriute to push witing time longer or shorter, through either positive or negtive oupling to the puttive integrtor iruit. Ation speifiity of witing-time preditive tivity If witing-time preditive tivity represents signl relted to prepring prtiulr tion, it should e tion speifi. Alterntively, preditive tivity might represent n strt signl, suh s level of ptiene or the vlue of the ntiipted outome of the tril, whih would not e expeted to e tion speifi. To differentite these possiilities, we trined three rts to perform, in ddition to the nose-poke Figure 7 Ation speifiity of rmp-to-threshold tivity. () An exmple of nose poke speifi preditive neurons. PETHs indite tivities of the neuron in the nose-poke witing trils (left) nd in the lever-press witing trils (right). Dt re presented s in Figure. () Poke-out/dely seletivity index nd lever-relese/dely seletivity index for ll of the nose-poke preditive neurons (rmp-tothreshold type). Of six nose-poke preditive neurons, two neurons did not show signifint differene etween tivity t the lever-relese period nd tivity t the dely period (open irle), nd were therefore not tested with threshold-type preditive tivity. The other four neurons showed signifint differene in tivity t the lever-relese period nd dely period (lk nd red filled irles), nd were therefore tested with the threshold-type preditive tivity for the lever-relese time. One Firing rte (spikes per s) Firing rte (spikes per s). 8. Time from lever press (s) Correltion of firing rte nd lever-press witing time Nose-poke preditive Lever-press preditive Both preditive Not preditive Correltion of firing rte nd nose-poke witing time witing tsk, lever-press witing tsk (Fig., Supplementry Fig. 5 nd Online Methods) nd reorded 75 units in M during performne of the dul nose-poke/lever-press witing tsk. An exmple M neuron tht showed trnsient tivtion in nosepoke trils orrelted with witing time is shown in Figure. The tivity of this sme neuron ws wek during the lever-press trils nd ws not orrelted with lever-press witing time. To quntify the tion speifiity of preditive tivity in the popultion of M neurons, we ompred the strength of orreltion etween firing rte nd witing time in nose-poke trils with tht in lever-press trils (Fig. ). The orreltion oeffiients for those two tril types ppered independent (R =.7, P =. for ll 9 neurons; R =., P =., for ll nose-poke preditive neurons; R =., P =.8 for ll lever-press preditive neurons). The perentge of lever-press preditive neurons mong ll the nose-poke preditive Time from lever press (s) Time from lever press (s) Lever-relese/dely seletivity index d Poke-out/dely seletivity index Poke-out/dely seletivity index Lever-relese/dely seletivity index of them showed signifint preditive tivity in the lever-press trils, ut the diretion of rmping tivity ws the opposite (red filled irle). () An exmple of the lever press speifi preditive neurons. Dt re presented s in Figure. (d) Lever-relese/dely seletivity index nd poke-out/dely seletivity index for ll the lever-press preditive neurons (rmp-to-threshold type). Of 5 lever-press preditive neurons, nine neurons did not show signifint differene etween tivity t the poke-out period nd tivity t the dely period (open irle). Six neurons showed signifint differene in tivity t the poke-out period nd dely period (lk nd red filled irle), nd were therefore tested with the threshold-type preditive tivity for the poke-out time. One of them (the sme s the red neuron in ) showed signifint, ut opposite, preditive tivity in the nose-poke trils. 578 VOLUME 7 NUMBER NOVEMBER nture neuroscience

6 Ativity Model input neurons I I I I I I Model integrtor neurons 5 Frtion of trils.. Cell numer per time Prtil orreltion Neurons per time: Frtion ommon noise:.5 Cell s time of tivtion (s)... Dt Neurons per time: Frtion ommon noise:. Time differene of preditive tivity (s).5 Cell s time of tivtion (s) Prtil orreltion... Model Neurons per time: Frtion ommon noise:. Sme sign Opposite sign Others. Time differene of preditive tivity (s) Cell s time of tivtion (s) d Frtion of preditive neuron... β =. β =. <....5 Not signifint P vlue β =. β = Numer of neurons per time step npg Nture Ameri, In. All rights reserved. Figure 8 Integrtor model. () A shemti digrm of n integrtor model. Cirles with I indite input neurons. A irle with indites n integrtor neuron. A smll tringle indites n exittory synpse nd smll irle indites n inhiitory synpse. Inset pnels show PETHs of exmple model neurons (top three pnels re exmple input neurons nd the ottom left pnel is n integrtor neuron; dt re presented s in Fig. ). The ottom right inset pnel shows witing time histogrm of the model (men ± s.e.m. of, model sessions of trils). () Witing time orreltion for ll the input neurons from three exmple models with different prmeters (numer of neurons per time: (left), (middle nd right); frtion of ommon noise (β): (left nd middle),. (right)). Color indites P vlue of witing time orreltion. Neurons re rrnged ording to its tivtion time (x xis) nd synpti weight (y xis, positive weight t the top nd negtive weight t the ottom). () Left, pirwise prtil orreltion etween simultneously reorded neurons s funtion of time differene of the most preditive time ins of eh neuron. Pirs re tegorized s the sme sign (green), opposite sign (lue) or other (gry) ording to the sign of witing time orreltion of eh neuron. Error rs indite s.e.m. N =,8 pirs. Right, pirwise prtil orreltion etween input neurons in the model s funtion of time differene of their tivities (numer of neurons per time, ; frtion of ommon noise (β),.). Men ± s.e.m. of model sessions. Error rs re too smll to e visile. (d) Frtion of preditive neurons s funtion of the numer of neurons per time step nd frtion of ommon noise in the input neuron tivity (β). Men ± s.e.m. of, model sessions. neurons (.%, of neurons) ws not more thn would e expeted from the perentge of lever-press preditive neurons mong ll the neurons ( of 9 neurons, 9.%; χ test, χ () =.8, P =.7). We lso exmined tion speifiity in neurons with the rmp-tothreshold type preditive tivity (Fig. 7). We only found one neuron tht showed rmping type preditive tivity in oth types of witing trils, ut the sign of rmping tivity in this neuron ws opposite for the two types of trils. These results suggest tht the preditive tivity in M is tion speifi rther thn tied to generl sttes or outome preditions, lthough we ould not speify whether oserved tion speifiity ws result of effetor speifiity (nose-poking or leverpressing), tion-diretion speifiity (pln to move left or right) or other forms of speifiity. Further hrteriztion of tivity of witing time preditive neurons reveled tht weker preditive tivity ws lredy present during the intertril intervl (Supplementry Fig. ), tht tivity in ptient trils ws onsistent with tivity in imptient trils (Supplementry Fig. 7), nd tht trnsient neurons witingtime preditive tivity n e prtly explined y somti motor input (Supplementry Fig. 8) nd tril histories (Supplementry Fig. 9). Integrtor model To test whether neurl integrtion proess ould explin the reltionship etween the oserved eletrophysiology nd ehvior, we instntited this theory in model sed on our oservtions. The input to the integrtor onsisted of popultion of trnsiently tive units onneted to n idel temporl integrtor y synpti weights rndomly distriuted round ner-zero men (Fig. 8). When the integrtor rehed given threshold, n tion ws eliited. Eh trnsient neuron ws ssigned speifi dely reltive to witing onset, nd the mplitude of firing ws sled y rndom vrile on eh tril. The output of the integrtion iruit ws indeed similr to the tivity of the oserved rmp-to-threshold neurons (Fig. 8). The mgnitude of tivtion of trnsient neurons gined tril-y-tril orreltion with witing times y ffeting the slope of rmping tivity of the integrtor neuron. However, if we ssumed tht firing of trnsient neurons were independent of eh other, the ontriution of eh neuron to witing time deresed mrkedly s the numer of trnsient neurons inresed (Fig. 8). As it is known tht even smll inter-neuronl orreltions mke the responses of individul neurons orrelted with ehvior even in se of lrge popultion size, we hypothesized tht orreltions indued y shred input might prevent neurl-ehviorl orreltions from eing diluted y the lw of lrge numers. We first nlyzed the tul tril-to-tril firing rte orreltions from susets of simultneously reorded M neurons. To ftor out the ontriution of witing time itself to inter-neuronl orreltions, we used prtil orreltion tehnique (Online Methods; Fig. 8). Despite hving ftored out orreltion with witing time, we oserved lrge inter-neuronl orreltions, the pttern of whih ws suh tht the reltive sign of orreltion etween neurons nd ehviorl output determined whether n inter-neuronl orreltion will e positive or negtive (tht is, two neurons tht were oth positively or negtively orrelted with witing time were on verge positively orrelted to one nother, wheres positive-negtive pirs were negtively orrelted with one nother). Furthermore, the strength of orreltion deyed s funtion of time differene of the tivity of eh neuron. To test whether the integrtion-to-ound model ws onsistent with these oservtions, we introdued ommon noise soure tht ws injeted into ll trnsient units with sign nd strength nture NEUROSCIENCE VOLUME 7 NUMBER NOVEMBER 579

7 npg Nture Ameri, In. All rights reserved. proportionl to its synpti weight (Fig. 8). By vrying the numer of neurons nd the reltive mgnitude of shred versus privte noise, we hrterized the reltionship etween neurl-ehviorl nd interneuronl orreltions. We found tht, s the frtion of shred noise ws inresed, the frtion of trnsient neurons signifintly orrelted with witing time inresed, even for lrge popultion sizes (Fig. 8d). At level of ommon noise suffiient to reprodue the oserved neuronl-ehviorl orreltions, we otined predition for oth the mgnitude nd signs of tril-y-tril orreltions etween neurons. This predition ws quntittively onsistent with those tully reorded (Fig. 8). Thus, the integrtion-to-ound model provided simple nd self-onsistent ount of the neurl-ehviorl orreltions nd inter-neuronl orreltions oserved in the dt. DISCUSSION Witing tsk We developed tsk in whih sujets hd to wit for two tones to otin lrge rewrd, ut ould respond fter the first tone to otin smll rewrd. Studies on stndrd inter-temporl hoie tsks, hve foused on single hoie point t whih sujets deide etween n immedite nd delyed rewrd. In ontrst, sujets in our tsk were le to respond for the smll rewrd while witing, similr to previous humn studies 9,. As fr s we re wre, there re no studies investigting neurl mehnism of spontneous giving up in suh inter-temporl hoie proedures. We provide evidene for the involvement of the ortil motor system in suh ehviors. Neurl tivity nd lsses We reorded two types of neurons whose tivity orrelted with witing time, even hundreds of milliseonds to seonds efore movement onset. One lss of neurons showed rmping tivity tht rehed threshold just efore movement initition nd rmping rte tht ws inversely orrelted with witing time. This pttern of tivity is reminisent of neurons in the frontl eye field, premotor nd primry motor ortex, lterl intrprietl re, nd superior olliulus reorded from monkeys performing sensorimotor tsks 5 7,8,7. The seond lss of preditive tivity ourred trnsiently nd tiled ll periods of witing period nd t lest s eforehnd. To some degree, they resemle neurons reported in posterior prietl ortex 8, medil prefrontl ortex 9 nd stritum. However, unlike those previously desried trnsients rrying signls relted to movement lotion, here the trnsient neurons rried informtion out movement timing. Neurons in primte supplementry eye field show similr form of trnsient signl prediting retion time in stop signl tsk, ut with only out % of the dely nd vrine tht we oserved. Although the nlyses tht we performed identified two lsses, we nnot sertin whether these lsses re truly distint or reflet spetrum. There ws no evidene for segregtion of these popultions ross the surfe of M (Supplementry Fig. ) nd we were not le to determine whether the profiles segregted y lyer. An intriguing possiility is tht the trnsient tivity reflets neurons in lyer /, s sequenes imged in posterior prietl ortex 8. Integrtion model The dt supported our hypothesis tht tion timing ould e explined y n integrtion-to-ound proess, omputtion hypothesized to underlie hoies sed on pereptul, mnemoni, vlue nd other forms of deision vriles,,. Our dt strengthen the evidene for the ppliility of this lss of models to ses where there is no evidene per se. In the model, trnsient witing-time preditive neurons onstitute the input, voting, for short or long witing times. They fire with different rtes from tril-to-tril nd re onneted to the integrtor with positive or negtive weights. Rmping neurons, on the other hnd, re represented y the output of the integrtor. By implementing model sed on this integrtion-to-ound theory, we were le to ompre preditions of the theory to our dt. The integrtion-to-ound model explins numer of slient fetures of the dt prsimoniously. First, it explins the properties of rmping neurons, oth the orreltion etween rmp rte nd witing time nd the existene of uniform threshold t tion initition. It lso explins the oservtion tht rmping neurons reh lower threshold when the rt responds to tone tht rrives while witing. Seond, y using inputs modeled on the oserved trnsient responses, the model explins the neuronl-ehviorl orreltions etween trnsient neuron tivity nd witing time. Notly, despite the existene of orreltions, in this model, the deision to t is only mde just efore movement is oserved. The oservtion of orreltions of nteedent neurl tivity with tion timing is onsequene of their usl onnetion through the integrtor nd do not imply deision. In ddition to explining these oservtions, the model lso led to preditions onerning inter-neuronl orreltions tht we did not ntiipte. We hose to introdue orreltions in the model using single shred noise soure. The ontriution of the shred noise to eh input neuron s firing rte ws proportionl to the weight of its onnetion to the integrtor. The model predited tht trnsient neurons must hve speifi inter-neuronl orreltions if individul neurons orreltions with ehvior re to e mintined in lrge pools of neurons. It is notle tht two spets of this predition were met. First, the mgnitude of shred noise required to hieve the oserved frtion of neurons with signifint ehviorl orreltions t popultion sizes on the order of to imply mgnitude of inter-neuronl orreltions of round., s seen in the dt. Seond, in this model, pirs of neurons with the sme sign of ehviorl orreltions will themselves e positively orrelted nd pirs of neurons with the opposite sign will e negtively orrelted. The model nd dt lso suggest n overll men orreltion level ner zero, onsistent with lned network theory 5. We elieve these preditions to e generl fetures of the proposed theory. The iophysil mehnisms supporting integrtion re n importnt nd unresolved issue. One lss of iophysil models suggests tht rmping rises from ttrtor dynmis depending on reurrent exittory onnetions. However, we hve not tested the preditions of these models. Further elements introdued into the present model, suh s vrile weighting of inputs hve lso een onsidered iophysilly. The integrtion-to-ound mehnism represents ognitive primitive tht my e ssemled into diverse omputtions together with other motifs, suh s divisive normliztion, spike timing dependent plstiity or reinforement lerning. Antomil ontext As to the neurl sustrtes of the proposed integrtor, two generl hypotheses ould e onsidered. Beuse we oserved ll the onstituents of the model in M, it ould e tht M is ple of supporting integrtion in lol iruitry. Alterntively, integrtion ould our with lrger iruit omprising lrger network of ortil nd suortil regions to whih M is onneted. Although the dt do not present muh evidene ering on this question, our defult is to onsider the ltter hypothesis to e more likely. One oservtion fvoring this lterntive is tht rmp-to-threshold tivity hs lredy een oserved in mny other res 5 7,8,7. A seond rgument fvoring widely distriuted network is tht this would llow more kinds of evidene to e integrted into the sme proess. Finlly, we lso onjeture tht the slow dynmis tht we oserved, ompred with the muh more rpid 58 VOLUME 7 NUMBER NOVEMBER nture neuroscience

8 npg Nture Ameri, In. All rights reserved. dynmis in stimulus-driven response, would e produed more redily in lrger size networks (R. Chudhuri et l., So. Neurosi. Astr. 597., ). A speifi possiility worth investigting is tht integrtion tkes ple s reverertion in the gol-direted iruit inluding not only M (ref. 7), ut lso ventrolterl oritofrontl ortex (VLO),,8, prelimi ortex 9, nd dorsomedil stritum,8. Rt M, lso known s medil grnulr ortex (AGm), nd prtly overlpping with lterl grnulr ortex (AGl, ), is onsidered on ntomil nd physiologil grounds to e homologous to the primte higher motor orties, inluding premotor ortex, supplementry motor omplex nd frontl eye field 9,,. At single-neuron level, M (inluding res t round nterior-posterior xis (AP) mm from Bregm, somewht more udl thn our enter of reordings) ontins tion preditive hoie signls 9. Our reordings spnned lrge re of rostrl M (AP.8 5., medil-lterl xis (ML).8. mm from Bregm) nd witing time preditive neurons were present uniformly throughout this extent. The udl prt of M prtly overlps with whisker-relted re of medil grnulr ortex (AP.5.5 mm),, ut the mjority of our reordings (7%) were from more rostrl suregion of M (>AP +. mm Supplementry Fig. ). Importnt M outputs inlude primry motor ortex, the dorsoentrl region of the stritum nd the suthlmi nuleus, s well s rin stem motor nulei, the superior olliulus nd other midrin motor regions,. In prtiulr, the superior olliulus, whih is involved in orienting deisions in rts, hs een proposed to e key element supporting the threshold nonlinerity in integrtion 5. Origin of tril-y-tril flututions In our tsk, witing times exhiited ner Poisson vriility. To ount for this vriility with the integrtion-to-ound model, it ws neessry to introdue lrge mounts of noise in model units. We do not tke this s evidene for noise introdued y the rin, ut rther s ll for further srutiny of the ontriutors to this vriility. One soure of vriility in tril-y-tril neurl tivity might e vriility in movements or posture during witing. To test this, we performed video trking nd extrted time series of position nd orienttion of the rt s ody. Although the rts ehvior during witing ws reltively onstrined y the requirement of keeping the snout inside the witing port (or pw on the lever), multiliner regression nlysis showed tht round % of witing time preditive neurons tivity ould e explined y these fetures, wheres 8% remined signifint (Supplementry Fig. 8). We onsider it plusile tht trnsients reflet input from sensory res, espeilly somtosensory nd proprioeptive input, given the strong onnetions etween motor orties nd somtosensory orties. A reent ntomil study suggested the existene of n entire ody mp in the rodent M (ref. ). We did not determine preisely the somti lotions linked to the reording lotions, ut the wide distriution of witing time orrelted tivity suggests the reruitment of multiple ody res in this tsk. Speifi miro-movements my hve een inidentlly reinfored, leding to superstitious ehvior (R. Kwi et l., So. Neurosi. Astr. 79., ) nd mplifying the tril-to-tril vriility. In ddition to these somti-motor loops, we ould expet dditionl ontriutions to trnsient flututions from interoeptive systems nd other sensory systems. Under the hypothesis tht M is generl lous of integrted signls, in tsks in whih rewrd is ontingent on speifilly ontrolled sensory input, we would expet to oserve similr rmping tivity, ut with inputs dominted y the pproprite sensory modlities. Vlue nd intertemporl hoie Another likely soure of vriility in witing time preditive neurons is vriility in deision vlues originted from the pst tril history of witing deisions nd rewrd outomes. Witing nd responding were ssoited with different deision outomes (smll versus lrge wter mount) nd different osts (witing time), whih might e updted through experiene. Witing-time preditive neurons might therefore reflet, in prt, deision vlues s well s tion plns. Although sustntil evidene ginst strt vlue oding is provided y our experiment showing tht M neurons re strongly seletive for speifi tion sequenes, even when they were ssoited with similr rewrd sizes nd witing times (Fig. ), it is possile tht the deision vlue ssoited with speifi tions is multiplexed with witing time preditive signls. A multiple regression nlysis did revel ontriution of pst tril deisions nd outomes to tivity in susequent trils, ut this refleted only 9% of the tril-y-tril vrine. Smll inrements nd derements in tivity ording to the tril history would llow sujets to djust their men witing time in the fe of hnging motivtionl onditions. Finlly, from these onsidertions, we infer tht other funtionlly relevnt vriles my gin ess to influening M input, therey suggesting hypothesis for how onfidene signls 7 my e red out y witing time 8. Implitions for self-initited tions Slow uilding tivity hs een theorized for nerly 5 yers s neurl mehnism for genertion of self-initited tions 7. Here, we hve strengthened these onepts in four dimensions. First, our dt strengthen the evidene tht n oserver n forest simple deision y oserving the stte of the rin efore deision on single tril sis 7,8. Seond, our results provide the strongest level of quntittive evidene supporting the involvement of n integrtion-to-ound mehnism. Notly, our model predited previously unoserved ptterns of inter-neuronl orreltion. Third, these reordings provide ompelling evidene linking neurons in the rt premotor ortex to neurl tivity oserved oth in humn eletroenephlogrm (rediness potentil, ) nd primte frontl orties 5 8. These orties re onsidered funtionlly homologous to rodent M (refs.,). Our experiments provide rodent model of n importnt ognitive phenomenon with physiologil nd ntomil justifition nd extend the ppliility of this lss of experiments ross speies. Fourth, these results identify, to the est of our knowledge for the first time, possile driving fore or usl nteedent for rmping tivity (tht is, trnsient input neurons; Figs. nd 5). This finding strengthens the plusiility of the integrtion-to-ound model to the se of voluntry tions. It lso opens doors to further studies to eluidte the properties of these nteedent signls nd disset neurl mehnisms underlying onepts suh s will nd self tht re used to desrie this lss of tions. Supported y these onsidertions, n integrtion-to-ound theory of voluntry tion provides potentil resolution to the long-stnding ontroversy over the interprettion of previous experiments showing tht rediness potentils preede the sujetive onsious intention to move. The theory explins how tivity preeding ound rossing, either input or umulted tivity, n e sid to prtiipte uslly in the timing of n tion, ut does not uniquely speify it. The integrtion-to-ound theory implies tht no deision hs een mde until the ound hs een rehed. Thus, ssuming threshold ove the size of n individul input, more thn one individul input must our to reh deision; no individul neuron ontriuting to the integrtor is unique use. The rossing of n ritrry lower threshold y rmping tivity, my prtilly forest tion, ut logilly it nnot fully predit tion, s t ny moment up to ound rossing the rrivl of opposing inputs my vert n tion no mtter how strongly it is forested 9. In ontrst, fter rehing the tion ound, n tion is inevitle. Thus, su-ound tivity my e ssoited with preditive, usl tivity of qulittively nture NEUROSCIENCE VOLUME 7 NUMBER NOVEMBER 58

9 npg Nture Ameri, In. All rights reserved. different nture thn super-ound tivity, similr to proposed distintion etween suonsious nd onsious neurl proesses 5. The reltive dely etween threshold rossing nd movement initition oserved in rt M (round 5 ms) were onsistent with the dely etween humn sujets wreness of their intention to t nd movement (round ms). It ould therefore e inferred tht rossing the threshold from unwreness to wreness is refletion of ound rossing. In this wy, the integrtion-to-ound theory my help to resolve the ontrdition etween the sujetive report of free will nd the requirement for usl nteedents to non-priious, willed tions. Finlly, insofr s simple voluntry tions onstitute n pproprite experimentl ontext, our results provide strting point for investigting mehnisms underlying onepts suh s self, will nd intention to t, whih might e onserved mong mmmlin speies. Methods Methods nd ny ssoited referenes re ville in the online version of the pper. Note: Any Supplementry Informtion nd Soure Dt files re ville in the online version of the pper. Aknowledgments We thnk the memers of the Minen lortory for disussion, M. Terrelonge for ssistne with reording experiments, B. Burh nd M. Vinhs for tehnil ssistne, E. Lottem for dily disussions, nd C. Feierstein, H. Shteingrt, Y. Loewenstein, J. Erlih, J. Pton nd B. Atllh for helpful omments on the mnusript. This work ws supported y the Uehr Memoril Foundtion (M.M.), Fundção Bil (7/8, M.M.), Fundção pr Ciêni e Tenologi SFRH/ BPD//8, M.M.; SFRH/BD/7/7, M.I.V.; SFRH/BD/97/, G.M.C.), Europen Reserh Counil Advned Investigtor Grnt (5, Z.F.M.) nd Chmplimud Foundtion (Z.F.M.). G.M.C. ws supported y Fundção pr Ciêni e Tenologi, s prt of the BEB/CNC PhD progrmme. AUTHOR CONTRIBUTIONS M.M. nd Z.F.M. designed the experiments, nlyses nd models nd wrote the mnusript. M.M. onduted the experiments with ssistne from M.I.V. nd G.M.C. M.M. nlyzed the dt nd implemented the model. COMPETING FINANCIAL INTERESTS The uthors delre no ompeting finnil interests. Reprints nd permissions informtion is ville online t reprints/index.html.. Uhid, N., Kepes, A. & Minen, Z.F. Seeing t glne, smelling in whiff: rpid forms of pereptul deision mking. Nt. Rev. Neurosi. 7, 85 9 ().. Wng, X.J. Proilisti deision mking y slow reverertion in ortil iruits. Neuron, ().. Mzurek, M.E., Roitmn, J.D., Johen, D. & Shdlen, M.N. A role for neurl integrtors in pereptul deision mking. Cere. Cortex, 57 9 ().. Gold, J.I. & Shdlen, M.N. The neurl sis of deision mking. Annu. Rev. Neurosi., (7). 5. Hnes, D.P. & Shll, J.D. Neurl ontrol of voluntry movement initition. Siene 7, 7 (99).. Rtliff, R., Cherin, A. & Segrves, M. A omprison of Mque ehvior nd superior olliulus neuronl tivity to preditions from models of two-hoie deisions. J. Neurophysiol. 9, 9 7 (). 7. Roitmn, J.D. & Shdlen, M.N. Response of neurons in the lterl intrprietl re during omined visul disrimintion retion time tsk. J. 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