Differential neural coding of acoustic flutter within primate auditory cortex

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2 Differentil neurl coding of coustic flutter within primte uditory cortex Dniel Bendor & Xioqin Wng A sequence of coustic events is perceived either s one continuous sound or s strem of temporlly discrete sounds (coustic flutter), depending on the rte t which the coustic events repet. Acoustic flutter is perceived t repetition rtes ner or elow the lower limit for perceiving pitch, nd is kin to the discrete percepts of visul flicker nd tctile flutter cused y the slow repetition of sensory stimultion. It hs een shown tht slowly repeting coustic events re represented explicitly y stimulussynchronized neuronl firing ptterns in primry uditory cortex (AI). Here we show tht second neurl code for coustic flutter exists in the uditory cortex of mrmoset monkeys (Cllithrix jcchus), in which the firing rte of neuron is monotonic function of n coustic event s repetition rte. Wheres mny neurons in AI encode coustic flutter using dul temporl/rte representtion, we find tht neurons in corticl fields rostrl to AI predominntly use monotonic rte code nd lck stimulussynchronized dischrges. These findings indicte tht the neurl representtion of coustic flutter is trnsformed long the cudl-to-rostrl xis of uditory cortex. A fundmentl role of the uditory system is to encode the timevrying structure of n coustic signl. Acoustic events, such s rief sound or trnsient chnge in mplitude or frequency within n coustic signl, repet qusi-periodiclly t specific rte for mny nturl nd iologiclly relevnt sounds 1,2. For repetitions of n coustic event t rtes etween pproximtely nd 45 Hz, such s the tpping sound produced y woodpecker, we her discretely sounding percept known s coustic flutter 3 5 (Supplementry Audio 1 online). Slow repetition rtes (or modultion frequencies) in this rnge re importnt for identifying consonnts nd understnding sentences in speech 6, s well s for the phrsing of mny niml vocliztions (such s mrmoset s trill cll) 7,8. Repetition rtes ove the upper limit of the flutter percept cn generte pitch, which is more continuous sounding percept thn flutter 4,5 (Supplementry Audio 2 online). For repetition rtes elow the lower limit of flutter we no longer perceive repetition rte, ut insted her individul coustic events tht occur distinctly in time 3 (Supplementry Audio 3 online). Slow repetition rtes in n coustic signl (in the rnge of coustic flutter) re represented explicitly in AI y supopultion of neurons tht cn synchronize their spike timing to ech coustic event 9.Fster repetition rtes, ove the perceptul rnge of flutter, re encoded y the dischrge rtes of different neuronl popultion tht does not synchronize to repeted coustic events nd contins no informtion out repetition rte in its temporl dischrge ptterns,11. Given tht AI neurons generlly cnnot synchronize to stimulus repetitions t fst rtes, neurl code sed on dischrge rte rther thn spike timing explins why we cn still discriminte nd perceive these repetition rtes. However, if slow repetition rtes re encoded y the temporl pttern of neuronl firing (which explicitly represents when ech coustic event occurs), re dischrge rtes used in prllel to encode the repetition rte of the coustic signl? Even if AI neurons only use spike timing to encode slow repetition rtes, stimulus synchroniztion seems to e poorer in corticl res outside AI 12, nd uditory cortex might therefore hve to use dischrge rte to encode slow repetition rtes tht cnnot e represented temporlly. In the somtosensory system, the frequency of tctile virtion (nlogous to the repetition rte of coustic signls) is differentilly encoded y distinct neurl popultions in primry somtosensory cortex, such tht rpidly dpting neurons encode low-frequency virtion (flutter) wheres pcinin neurons encode high-frequency virtion 13. The neurl encoding oundry etween these two popultions occurs ner virtion frequency of pproximtely 4 Hz, which is close to the encoding oundry etween the temporl nd rtecoding popultions in AI (of wke mrmoset monkeys). Furthermore, for oth the uditory nd somtosensory systems, this neurl encoding oundry lso mtches the perceptul discrete/continuous oundry for sequence of sensory events 4,5,13,14. Given these similrities, we hypothesized tht other spects of the wy in which the percept of flutter is encoded in somtosensory cortex might lso e found in uditory cortex. Previous work hs shown tht temporl informtion from spike timing in rpidly dpting neurons ws sufficient to determine the frequency of tctile virtion More recently, nother group found second neurl code in suset of rpidly dpting neurons, in the form of dischrge rte tht increses monotoniclly s function of virtion frequency over the perceptul rnge of flutter 18,19. Although Lortory of Auditory Neurophysiology, Deprtment of Biomedicl Engineering, Johns Hopkins University School of Medicine, 7 Rutlnd Avenue, Trylor Building 412, Bltimore, Mrylnd 215, USA. Correspondence should e ddressed to D.B. (dendor@jhu.edu) or X.W. (xioqin.wng@jhu.edu). Received 31 Jnury ; ccepted 7 Mrch; pulished online 29 April 7; doi:.38/nn1888 NATURE NEUROSCIENCE VOLUME [ NUMBER 6 [ JUNE 7 763

3 .6 Synchronized (n = 83) Unsynchronized (n = 7) fields rostrl to AI predominntly use monotonic rte code tht is unsynchronized to coustic flutter. Percent of smples < Flutter perception >45 f mx (Hz) neurons in primry somtosensory cortex (S1) hve dul temporl/ rte representtion of flutter, secondry somtosensory cortex (S2) encodes flutter using only monotonic rte code, nd lcks the stimulus-synchronized dischrges oserved in S1 (refs. 18,). Rte codes, in which the dischrge rte is monotonic function of stimulus prmeter, re not unique to the somtosensory system nd hve lso een reported in oth the visul nd uditory systems Monotonic rte codes re typiclly not nrrowly tuned, nd thus might encode informtion y their response function s slope rther thn its pek. Theoreticl studies hve shown tht the slope of neuron s tuning function cn hve n importnt role in coding sensory stimuli 24,25. Auditory cortex contins two min regions: the core region responds to spectrlly nrrownd sounds nd the elt region to widend sounds 26,27. The core nd elt regions re further divided into multiple fields, ech with its own cochleotopic representtion In this study we hve focused our recordings on the three core fields: AI (primry uditory cortex), R (rostrl field) nd RT (rostrl temporl field). Fields AI, R nd RT shre reciprocl connections with the ventrl division of the medicl geniculte ody (vmgb) s well s with ech other (lthough the connections etween AI nd RT re more limited) 26. Little is known out the physiologicl properties of field RT, wheres severl differences etween R nd AI hve een oserved, most notly slightly longer (B ms) response ltency in field R 29. Along the medil-to-lterl xis of the superior temporl gyrus (strting from AI), the spectrl preference of neurons chnges from nrrownd to widend 27,,31, nd it hs een postulted tht corticl fields hve similr spectrl preferences long the cudl-to-rostrl xis 26. In this study, we hve compred the neurl encoding properties of the three core fields (AI, R, nd RT) ligned long the cudl-to-rostrl xis of the superior temporl gyrus. Our findings indicte tht coustic flutter is encoded differently long the cudl-to-rostrl xis of uditory cortex: AI contins dul temporl/rte representtion wheres corticl Men vector strength.4.2 RESULTS We recorded from the uditory cortex of four wke mrmoset monkeys totl of 274 wellisolted single neurons tht responded significntly, either y stimulus synchroniztion nd/or dischrge rte (see Methods), to coustic pulse trins spnning the perceptul rnge of coustic flutter. The most common stimulus set used in these experiments hd repetition rte tht vried linerly in 4-Hz intervls etween 4 nd 48 Hz (see Methods). The coustic pulse trins used in these experiments were sequences of rief tone or noise ursts (Supplementry Fig. 1 online) centered t the neuron s chrcteristic frequency (CF). Neurons generlly could synchronize t repetition rtes ner the upper limit of flutter (B45 Hz) or could not synchronize to ny of the repetition rtes tested tht were ove the lower limit of flutter (B Hz; Fig. 1), which is consistent with previous studies of stimulus synchroniztion in the uditory cortex of wke mrmosets. Bsed on these results, we clssified neurons into one of three groups ccording to their ility to synchronize (Ryleigh test, P o.1) to repetition rtes within the flutter rnge: synchronized (7/274), mixed response (29/274) nd unsynchronized (138/ 274). Synchronized neurons typiclly hd short-ltency responses with stimulus-synchronized dischrges up to stimulus repetition rte of t lest 4 5 Hz. Unsynchronized neurons typiclly hd longer-ltency responses thn synchronized neurons, nd generlly did not show significnt stimulus synchroniztion t repetition rtes ove Hz (Fig. 1). Some unsynchronized neurons could synchronize t repetition rtes elow Hz, nd therefore our use of the term unsynchronized refers only to neuronl responses t repetition rtes within the perceptul rnge of flutter. All unsynchronized neurons nd most synchronized neurons (92/7) hd significnt dischrge rtes for t lest suset of coustic pulse trins with repetition rtes within the Flutter perception 4 5 Repetition rte (Hz) Figure 1 Stimulus synchroniztion to coustic pulse trins. () Distriution of the repetition rte limit for stimulus-synchronized dischrges (f mx ) for ll neurons in this study. Of the neurons tested with repetition rtes etween 4 Hz, 58% (5/86) did not synchronize to the stimulus, 16% (14/86) synchronized t 4 Hz, nd 26% (22/86) synchronized t 8 Hz. n ¼ 274. () Popultion verge vector strength of synchronized (green) nd unsynchronized (lue) neurons. Error rs represent s.e.m. Numer of units Monotonic (n = 184) Non-monotonic (n = 9) Spermn correltion coefficient Normlized response Positive monotonic (n = 75) Negtive monotonic (n = 63) Flutter perception Repetition rte (Hz) 4 5 Figure 2 Monotonic response properties. () Distriution of the Spermn correltion coefficient for neurons with monotonic (filled rs) nd non-monotonic (unfilled rs) response functions of repetition rte. Spermn correltion coefficients of 1 nd 1 hve perfect positive nd negtive monotonicity, respectively. Neurons with sttisticlly significnt Spermn correltion coefficient (P o.5) re considered monotonic. () Normlized dischrge rtes for positive (lue) nd negtive (red) monotonic neurons. This figure includes dt from ll synchronized, mixed nd unsynchronized neurons. Only dt collected with stimulus set 1 (see Methods) re shown. Error rs represent s.e.m. 764 VOLUME [ NUMBER 6 [ JUNE 7 NATURE NEUROSCIENCE

4 Repetition rte (Hz) c Positive monotonic (synchronized) Popultion verge dischrge rte (spikes per s) rnge of flutter perception. Severl neurons in our study could e clssified s synchronized or unsynchronized depending on sound level or coustic pulse durtion, nd we refer to these s hving mixed response. Prevlence of monotonic rte coding Next, we investigted whether the dischrge rtes of neurons vried s monotonic function of repetition rte over the perceptul rnge of flutter. We quntified monotonicity y clculting the Spermn correltion coefficient etween dischrge rte nd repetition rte (see Methods). Our justifiction for quntifying monotonicity y mesuring correltion non-prmetriclly (s opposed to fitting the dt to function) is Negtive monotonic (synchronized) , 5 5 1, 8 Hz 16 Hz 24 Hz 32 Hz 4 Hz 48 Hz Figure 4 Exmples of positive nd negtive monotonic unsynchronized responses. () Rster plot of positive monotonic unsynchronized neuron s response (unit M32Q-2) for repetition rtes etween 4 nd 48 Hz. The neuron did not show significnt stimulus synchroniztion t ny of the repetition rtes tested. The shded portion of the plot indictes the time period when the coustic stimulus ws plyed. () Rster plot of negtive monotonic unsynchronized neuron s response (unit M2P-388) for repetition rtes etween 4 nd 48 Hz. The neuron did not show significnt stimulus synchroniztion t ny of the repetition rtes tested. (c,d) Instntneous dischrge rtes plotted over the durtion of the stimulus for positive (c; n ¼ 47) nd negtive (d; n ¼ 25) monotonic unsynchronized neurons. The r underneth the plot indictes the time period when the coustic stimulus ws plyed. Only dt collected with stimulus set 1 (see Methods) re shown. Repetition rte (Hz) d Popultion verge dischrge rte (spikes per s) Repetition rte (Hz) 5 tht this method does not ssume liner or sigmoidl reltionship etween dischrge rte nd repetition rte. Roughly two-thirds of the smpled neurons (184/274) incresed or decresed their dischrge rte monotoniclly s function of repetition rte (Spermn correltion coefficient, P o.5; Fig. 2). We refer to these two response types s positive monotonic nd negtive monotonic, respectively. The verge dischrge rtes of positive (negtive) monotonic responses incresed (decresed) linerly with incresing repetition rte over the rnge ssocited with flutterperception(fig. 2, Supplementry Fig. 2 online). Of 7 synchronized neurons, 34 neurons incresed nd 33 neurons decresed their dischrge rte monotoniclly s function of repetition rte (Fig. 3). Around two-thirds of the unsynchronized popultion Hz 16 Hz 24 Hz 32 Hz 4 Hz 48 Hz Positive monotonic (unsynchronized) Negtive monotonic (unsynchronized) , 5 5 1, c 8 Hz d 8 Hz Popultion verge dischrge rte (spikes per s) Hz 24 Hz 32 Hz 4 Hz 48 Hz Figure 3 Exmples of positive nd negtive monotonic synchronized responses. () Rster plot of positive monotonic synchronized neuron s response (unit M2P-785) for repetition rtes etween 4 nd 48 Hz. This neuron hd significnt vector strength (Ryleigh test, P o.1) over the entire rnge of repetition rtes. The shded portion of the plot indictes the time period when the coustic stimulus ws plyed. () Rster plot of negtive monotonic synchronized neuron s response (unit M32Q-46) for repetition rtes etween 4 nd 48 Hz. This neuron hd significnt vector strength (Ryleigh test, P o.1) over the entire rnge of repetition rtes. (c,d) Instntneous dischrge rtes plotted over the durtion of the stimulus for positive (c; n ¼ 22) nd negtive (d; n ¼ 29) monotonic synchronized neurons. The r underneth the plot indictes the time period when the coustic stimulus ws plyed. Only dt collected with stimulus set 1 (see Methods) re shown. Repetition rte (Hz) Popultion verge dischrge rte (spikes per s) Hz 24 Hz 32 Hz 4 Hz 48 Hz NATURE NEUROSCIENCE VOLUME [ NUMBER 6 [ JUNE 7 765

5 Respones slope (spikes per s/hz) Normlized response Normlized response 4 (91/138) hd dischrge rtes tht vried s either positive (n ¼ 61) or negtive (n ¼ ) monotonic function of repetition rte over the perceptul rnge of flutter (Fig. 4, Supplementry Fig. 3 online). In ddition to neurons with strictly synchronized or unsynchronized responses, we recorded 29 neurons tht switched etween stimulus-synchronized nd unsynchronized responses (with significnt dischrge rtes) depending on the sound level or pulse width of the coustic stimulus. These neurons were clssified s hving mixed response, nd were nlyzed seprtely from the synchronized nd unsynchronized neuronl popultions. Most of these neurons (25/29) hd dischrge rtes tht vried s monotonic function of repetition rte (Supplementry Tle 1 online) Although the slopes of monotonic responses were generlly either strictly positive or negtive cross different coustic signls, we found few exmples (n ¼ 4) of neurons tht switched etween positive nd negtive monotonic responses, depending on the sound level or crrier frequency used (Supplementry Tle 1). The neurons tht did not show significnt monotonic reltionship etween dischrge rte nd repetition rte were clssified s non-monotonic (Fig. 2). Although positive nd negtive monotonic responses were firly homogenous, there were severl different types of non-monotonic response (Supplementry Fig. 4 online). The most common non-monotonic responses were ll-pss, in which dischrge rte vried minimlly with repetition rte over the perceptul rnge of flutter (Supplementry Fig. 4). We lso oserved ndpss, low-pss, high-pss nd multi-pek (complex) responses (Supplementry Fig. 4 e). Synchronized Positive (n = 22) Negtive (n = 29) Unsynchronized Positive (n = 47) Negtive (n = 25) Dischrge rte (spikes per s) Synchronized Positive (n = 21) Negtive (n = 22) Unsynchronized Positive (n = 39) Negtive (n = 17) 15 5 Repetition rte (Hz) Figure 5 Temporl response dynmics of synchronized nd unsynchronized neurons. () Chnges in the instntneous response slope for synchronized (dshed lines) nd unsynchronized (solid lines) neurons with positive (lue) or negtive (red) monotonic responses, otined y liner interpoltion of the men popultion neuronl responses (shown in Fig. 3c,d nd Fig. 4c,d) cross ll repetition rtes etween 8 nd 48 Hz. The r underneth the plot indictes the time period when the coustic stimulus ws plyed. () Normlized popultion PSTH of synchronized nd unsynchronized neurons with positive nd negtive monotonic responses for pure tone t the sound level eliciting the mximum dischrge rte. The inset shows mgnified version of the plot for the first ms of the response. Pek ltencies were 31 ms for the positive monotonic synchronized popultion, ms for the negtive monotonic synchronized popultion, nd 63 ms for oth the positive nd negtive monotonic unsynchronized popultions. Synchronized nd unsynchronized popultions with similr direction of monotonicity hd sttisticlly significnt differences in pek ltencies (Wilcoxon rnk sum test, positive monotonic: P o 5. 4, negtive monotonic: P o 5. 3 ). The r underneth the plot indictes the time period when the coustic stimulus ws plyed. Comprison of synchronized nd unsynchronized responses We found monotonic responses in oth synchronized nd unsynchronized neurons. If synchronized neurons contin dditionl informtion out the coustic stimulus in their temporl firing ptterns, does the loss of stimulus-synchronized dischrges provide neurl coding dvntge for unsynchronized neurons? Becuse of stimulus synchroniztion, dischrge rte mesured over short time window fluctutes rpidly during the coustic stimulus (Fig. 3c,d). As such, synchronized neuron s response slope the liner reltionship etween dischrge rte nd repetition rte (see Methods) ecomes n unrelile description of the coustic signl s repetition rte when clculted over short time windows. However, unsynchronized neurons lck stimulus synchroniztion (Fig. 4c,d) nd, s such, cn provide similr monotonic response slopes throughout the durtion of the stimulus. We compred the temporl dynmics of the response slopes of monotonic synchronized nd unsynchronized neurons over the time course of the stimulus (Fig. 5). Unsynchronized neurons showed much less vrition in their response slope during the stimulus % jitter (regulr) 25% jitter (irregulr) 5% jitter (irregulr) 4 5 Numer of units 4 Dischrge rte (spikes per s) Dischrge rte (spikes per s) 45 Jitter (%) 5 45 Jitter (%) Sensitivity to temporl irregulrity (chnge in spikes per s per % jitter) Figure 6 Flutter rte codes re insensitive to temporl irregulrity. () Repetition rte tuning of negtive monotonic unsynchronized neuron (unit M41O-6) for regulr (% jitter) nd irregulr (25% nd 5% jitter) coustic pulse trins. The dshed lck line indictes the significnce level for dischrge rte (2 s.d. wy from the spontneous dischrge rte). () Distriution of the interpolted chnge in dischrge rte per % jitter for 64 neurons: synchronized (n ¼ 25), mixed (n ¼ 11) nd unsynchronized (n ¼ 28). These neurons were locted in AI (n ¼ 23) or the rostrl fields (n ¼ 37), or were on the order or outside the core fields (n ¼ 4). Both monotonic (n ¼ 48) nd non-monotonic (n ¼ 16) response types were included here. Insets show two exmples of n unsynchronized neuron s response to irregulr pulse trins: jitter insensitivity in monotonic neuron (unit M32Q-217; top) nd jitter sensitivity in neuron with non-monotonic response to repetition rte (unit M2P-44; ottom). Error rs represent s.e.m. 766 VOLUME [ NUMBER 6 [ JUNE 7 NATURE NEUROSCIENCE

6 c Lterl sulcus Core Lterl elt/ prelt Percent of smples within corticl region Rostrl fields mm Rostrl fields (n = 5) thn did synchronized neurons (Fig. 5), thus providing temporlly more stle monotonic rte code for repetition rte. Neurons with unsynchronized responses hd significntly longer ltencies in their pek responses to pure tones thn neurons with synchronized responses (Fig. 5), indicting tht this neurl coding dvntge might cuse these neurons to incur processing time cost. Periodicity is not encoded y dischrge rte In humns, verge discrimintion thresholds for repetition rte re similr for periodic nd periodic coustic pulse trins with low repetition rtes 32. At higher repetition rtes (in the rnge of pitch perception), verge repetition rte discrimintion worsens for periodic pulse trins 32. To determine whether the dischrge rte-sed representtion of flutter ws sensitive to chnges in the temporl regulrity of the stimulus, we compred the neuronl responses evoked y regulr nd irregulr pulse trins. A representtive exmple of n unsynchronized neuron s response function to repetition rte for oth regulr nd irregulr pulse trins is shown in Figure 6. This neuron showed similr negtive monotonic responses for regulr nd irregulr coustic pulse trins. Irregulr pulse trins were generted y temporlly shifting ech coustic trnsient in regulr pulse trin y n mount rndomly selected from uniform distriution (see Methods). The temporl irregulrity in the pulse trin ws incresed prmetriclly, without ffecting the verge repetition rte, y expnding the width of this uniform distriution. For exmple, the mximum temporl jitter for pulse trin with repetition rte of Hz (5 ms interpulse intervl) rnged from ±2.5 ms (5% mximum jitter) to ±25 ms (5% mximum jitter). The chnge in dischrge rte etween regulr nd mximlly irregulr pulse trins (5% jitter), determined using liner interpoltion, ws less thn 5 spikes per s for roughly 81% (52/64) of the neurons tested. Although few neurons did show some sensitivity to temporl irregulrity (Fig. 6, lower inset), most neurons tested with irregulr pulse trins showed little vrition AI AI (n = ) R Synchronized Non-monotonic Monotonic M L C Synchronized (n = 37) Unsynchronized (n = 46) Chrcteristic frequency (khz) Unsynchronized Non-monotonic Monotonic Numer of units Distnce from lterl sulcus (mm) 1 2 Synchronized (n = 96) Recording site Rostrl fields Unsynchronized (n = 9) Recording site RT High freq. reversl R Low freq. reversl AI High freq. reversl Normlized distnce long cudl-to-rostrl xis Figure 7 Comprison of the proportion of response types y corticl region. () Corticl frequency mp from one suject (M32Q, left hemisphere), with the recording sites of synchronized (crosses) nd unsynchronized (circles) neurons indicted. The upper right portion of the figure shows digrm of the mrmoset s rin nd the loction of the corticl mp. R, rostrl; C, cudl; M, medil; L, lterl. () A normlized corticl mp for four hemispheres (three left, one right). Normlized recording site positions re indicted for synchronized (crosses) nd unsynchronized (circles) neurons. A histogrm showing the sptil distriution for these two neuron types is shown ove the mp. Green, synchronized; lue, unsynchronized. (c) Comprison of the proportion of monotonic nd non-monotonic responses to repetition rte for synchronized nd unsynchronized neurons in AI nd the rostrl fields (R, RT). Green, synchronized; lue, unsynchronized. Filled r, monotonic; unfilled r, non-monotonic. in their dischrge rtes (Fig. 6). We found no significnt effect on the sensitivity to temporl irregulrity resulting from either neuron type (synchronized or unsynchronized) or neuron loction (Kolmogorov- Smirnov test, P 4.1). This finding indictes tht neurl encoding of flutter solely on the sis of dischrge rte is lrgely insensitive to the coustic signl s periodicity, nd reflects the verge repetition rte. This is in shrp contrst to the sensitivity for temporl irregulrity oserved in pitchselective neurons, which re non-monotoniclly tuned to repetition rtes ove the rnge tht genertes percept of flutter 33.Humn sujects cn discriminte etween regulr nd irregulr coustic pulse trin, lthough jitter detection thresholds re higher for repetition rtes in the rnge of flutter compred to pitch 34. Given tht synchronized responses lso occur for periodic pulse trins, the informtion contined in stimulus-synchronized dischrge ptterns could potentilly e used y the uditory system to distinguish etween periodic nd periodic pulse trins. Comprison of AI nd the rostrl core fields We compred the sptil distriution of response types long the cudl-to-rostrl xis of uditory cortex. The order etween AI nd the rostrl core fields (R nd RT) ws identified y locting the reversl in the cochleotopic mp etween AI nd R (Fig. 7, see Methods). This order ws identified in the four hemispheres tht we mpped (one hemisphere per monkey). We found higher proportion of synchronized neurons thn unsynchronized neurons in AI, wheres in the rostrl fields there ws higher percentge of unsynchronized neurons. An exmple of the recording site loctions of these two neuron types from one corticl frequency mp is shown in Figure 7. Differences in the sptil distriution of synchronized nd unsynchronized neurons were ssessed y first creting normlized mp of recording sites cross ll four monkeys, sed on the cochleotopic grdient (see Methods), AI NATURE NEUROSCIENCE VOLUME [ NUMBER 6 [ JUNE 7 767

7 db SPL + db db SPL c 2 d AI (n = 27) + db 6 db SPL Rostrl fields db SPL + db 6 db SPL (n = 21) + 4 db db SPL db Dischrge rte (spikes per s) Dischrge rte (spikes per s) Repetition rte (Hz) Repetition rte (Hz) nd then compring recording site loctions long the cudl-to-rostrl nd medil-to-lterl xes. Synchronized nd unsynchronized neurons showed significntly different sptil distriutions (Wilcoxon rnk sum test) long the cudl-to-rostrl xis, prllel to the lterl sulcus (P o 7. 7 ; Fig. 7) ut not long the medil-to-lterl xis perpendiculr to the lterl sulcus (P ¼.37). Furthermore, there ws no significnt difference (P ¼.59) in the distriution of synchronized nd unsynchronized neurons within AI long the cudl-to-rostrl xis (neurons on the AI/R order were excluded from this nlysis). Roughly two-thirds of the synchronized neurons were locted in AI, wheres two-thirds of the unsynchronized neurons were locted in the rostrl fields (Fig. 7c, Supplementry Tle 1). These proportions remined similr even if neurons ner the AI/R order were excluded from the nlysis (Supplementry Tle 1). The difference in the sptil distriutions long the cudl-to-rostrl xis ws still oserved if we limited the comprison to synchronized nd unsynchronized neurons with monotonic responses (P o ). However, if the comprison ws limited to the non-monotonic neurons, there ws no longer significnt difference etween the sptil distriutions of synchronized nd unsynchronized neurons long the cudl-to-rostrl xis (P ¼.9). Therefore the chnge from synchronized to n unsynchronized response etween AI nd the rostrl fields occurred minly in the monotonic popultion (Fig. 7c). Similr proportions of neurons with positive (54%) nd negtive (46%) monotonic responses were oserved in the rostrl fields, wheres most AI neurons (B7%) were positive monotonic (Supplementry Tle 1). Synchronized neurons in oth AI nd the rostrl fields hd stimulussynchronized dischrges over the entire frequency rnge of flutter (Supplementry Fig. 5 online). Unsynchronized neurons in oth AI nd the rostrl fields did not synchronize within the rnge of flutter ut hd significnt men popultion vector strengths (Wilcoxon rnk sum, P o.1) t repetition rtes elow the lower limit of flutter (Supplementry Fig. 5). In the rostrl fields, responses to pure tones were generlly weker nd hd longer pek ltencies thn in AI, for oth the synchronized nd unsynchronized neuronl popultions (Supplementry Fig. 5c,d). Effect of sound level on monotonic rte codes The dischrge rtes of neurons in uditory cortex generlly depend on the sound level 35, creting potentil miguity for dischrge rtesed representtion of repetition rte. However, the response slopes of mny of the neurons we studied were lrgely unffected y moderte chnges ( 5 db) in sound level (Fig. 8,). We quntified the extent 5 Response slope (spikes per s/hz) t higher sound level 1 AI (n = 27) Rostrl fields (n = 21) to which the response slope chnged etween sound levels tht differed y 5 db. Neurons in oth AI nd the rostrl fields showed significnt correltion (Person correltion coefficient, AI: r ¼.76, P o ; rostrl fields: r ¼.94, P o 3.4 ) etween their response slopes for pulse trins t two different sound levels (Fig. 8c). We next determined how much the response slope chnged for -db increse in sound level using liner interpoltion (see Methods). Significntly more neurons in the rostrl fields thn in AI vried their response slopes y less thn.5 for -db sound level chnge (Kolmogorov-Smirnov test, P o.2; Fig. 8d). However, we found no significnt difference in sound level-dependent chnges in the response slope etween synchronized, mixed nd unsynchronized neurons (Supplementry Fig. 6, online; Kolmogorov-Smirnov test, P 4.1). The coustic pulse trins used in these experiments were normlized for mplitude (reltive to other pulse trins in the stimulus set), nd s such coustic signls with fster repetition rtes hd greter overll energy. Although neurl dischrge rtes in uditory cortex generlly depend on the energy level of the coustic stimulus, neuronl response slopes were similr (Person correltion coefficient, r ¼.81, P o ) for equl mplitude nd energy-normlized pulse trins (Supplementry Fig. 6c). DISCUSSION How does the uditory system encode the repetition rte of coustic flutter? Our results indicte tht repetition rte is dully represented in AI y oth the dischrge rte nd stimulus-synchronized firing ptterns of neurons. In the rostrl fields (R nd RT), stimulus-synchronized ctivity is weker, nd unsynchronized responses to coustic flutter re more common. Neurons in the rostrl fields primrily use rte code in which dischrge rtes either increse or decrese monotoniclly over the rnge of repetition rtes ssocited with flutter perception. The monotonic rte coding of flutter represents the verge repetition rte, s dischrge rtes generlly do not vry significntly etween periodic nd periodic versions of the sme coustic pulse trin. Although mny monotonic neurons showed some degree of sound level invrince (over moderte chnges in sound level), this ws more common in neurons in the rostrl fields. The use of monotonic or slope-sed rte coding in the uditory system is not unique for representing repetition rte, nd hs een reported in uditory cortex for encoding sound level 36 nd source loction 22. The complementry coding (using opponent chnnels) of repetition rte using positive nd negtive, monotoniclly vrying dischrge rtes might e dvntgeous in incresing the coding Percent of smples Response slope (spikes per s/hz t lower sound level Chnge in response slope per db (spikes per s/hz) Figure 8 Sound-level invrince in monotonic rte-coding neurons. () Response of positive monotonic unsynchronized neuron (unit M2P-921) to repetition rte cross three sound levels (, nd 6 db sound pressure level (SPL)). The dshed lck line indictes the significnce level for dischrge rte (2 s.d. wy from the spontneous dischrge rte). () Response of negtive monotonic unsynchronized neuron (unit M32Q-141) to repetition rte cross three sound levels (, nd 4 db SPL). (c) Comprison of the response slope for monotonic rte-coding neurons in AI (gry) nd the rostrl fields (red) t the minimum sound level tested, nd sound level 5 db higher. (d) The chnge in response slope for db increse in sound level for neurons in AI (gry) nd the rostrl fields (red). The distriutions were significntly different (Kolmogorov-Smirnov test, P o.2) with higher percentge of rostrl field neurons hving response slopes tht chnged y less thn.5 per db VOLUME [ NUMBER 6 [ JUNE 7 NATURE NEUROSCIENCE

8 ccurcy y reducing positively correlted noise etween neurons 37.In ddition, monotonic coding llows single neuron to encode more thn one prmeter using dischrge rte, therey voiding inding prolem in higher uditory res 22. For exmple, neuron might monotoniclly increse or decrese its dischrge rte for different stimulus prmeters (such s source loction nd repetition rte). At the popultion level, if positive nd negtive response functions from multiple neurons re dded together, the result is flt response (invrint to the prmeter). However, when similr monotonic response functions re dded together, the monotonic response function is preserved. Therefore, multiple prmeters cn e encoded using monotonic functions of single neurons, nd then single prmeter cn e extrcted y comining the responses of neurons with similr monotonic functions for the desired prmeter, ut opposite monotonic functions for ll other prmeters. Potentil mechnisms of unsynchronized responses Corticocorticl connections etween AI, R nd RT could support cscde of temporl integrtion long the core s cudl-to-rostrl xis. Feedforwrd corticocorticl inputs, comined with the prllel thlmic inputs from vmgb 38 to ech of the core res, could hypotheticlly spred out the rrivl times of inputs nd decrese stimulus synchroniztion in R nd RT reltive to AI, trnsforming temporl representtion into rte code. This model is supported y our oservtion tht the rostrl fields hve higher proportion of unsynchronized responses nd longer pek ltencies. In ddition, longer temporl integrtion window in unsynchronized neurons could cuse the loss of stimulus-synchronized dischrges in the frequency rnge of flutter. It hs een suggested tht higher levels of the uditory system nlyze coustic signls over longer time scles 39. Whether temporl processing lso differs etween the cudl nd rostrl divisions of the non-core res of uditory cortex (for exmple, the lterl elt), etween core nd non-core res long the medil-to-lterl xis, or etween the right nd left uditory cortex 39 remins to e studied in future experiments. Our study investigted synchronized nd unsynchronized responses purely from physiologicl stndpoint. Whether these two response types rise from morphologiclly distinct cell types tht differ in iophysicl properties or thlmocorticl or corticocorticl connectivity is unknown. Perceptul effects relted to temporl nd rte coding Although flutter discrimintion hs not een tested directly in mrmosets, it hs een previously shown tht monkeys cn discriminte etween different repetition rtes in the rnge of flutter 4,41.Flutter perception is ehviorlly relevnt to mrmosets, given tht severl of their species-specific vocliztions contin repetitive temporl ptterns ner or within the flutter rnge (for exmple, twitter cll: B8 Hz; trill cll: B27 Hz) 7,8. However, to our knowledge, it hs not een tested whether mrmosets perceive flutter s discrete rther thn continuous senstion in the sme mnner s humns. A cvet to our experiments is tht we re compring physiologicl dt otined from mrmosets with psychophysicl dt otined from humns. A direct link etween flutter perception nd underlying neurl mechnisms in the sme species remins to e studied. For oth the uditory nd somtosensory systems, the perceptul nd neurl encoding oundry for repetition rtes producing senstion of flutter (tctile nd uditory) nd virtion (tctile) or pitch (uditory) is round 4 Hz (refs. 4,5,13 15). In the uditory system, t lest, this seems to e direct consequence of the temporl integrtion window of AI neurons (B25 ms). Fster repetition rtes cuse multiple coustic events to occur within the temporl integrtion window, nd re consequently represented y the dischrge rtes of neurons tht cnnot synchronize to individul events in the stimulus. With slower repetition rtes, which cuse percept of flutter, only single event occurs within the temporl integrtion window, so tht these rtes cn e represented y neurons tht synchronize to ech event. Thus, the discrete senstion of flutter might e direct result of synchronized responses occurring cross the entire neuronl popultion tht represents this percept. Likewise, fster repetition rtes fil to sound discrete ecuse the neurons tht encode these types of sounds do not synchronize to the stimulus, nd s such their dischrge rtes s popultion do not oscillte in unison with the occurrence of ech coustic event. It is possile tht the neurl responses in our study re lso linked to the uditory percept of roughness, which spns the upper rnge of flutter nd the lower rnge of pitch (B Hz) 42.However,ecuse roughness depends on other prmeters (such s spectrum nd envelope shpe) tht we did not vry in our experiments, it is premture to drw ny conclusions etween the neurl responses we oserved nd the perception of roughness. In contrst to the uditory system, the somtosensory neurl popultions tht encode repetition rtes in the perceptul rnge of virtion nd flutter re segregted in the peripherl somtosensory system. However, potentilly ecuse the primry sensory cortices hve similr temporl integrtion windows, the upper oundries of the percept of flutter re similr in the two sensory systems 3,4,13. The positive nd negtive monotonic unsynchronized responses oserved in the rostrl fields (R nd RT) re similr to the neurl representtion of flutter oserved in primte S2 (refs. 18,). Although temporl processing in these two corticl res might e similr, they might not e functionlly homologous, given tht there is lrge increse in receptive field size etween S1 nd S2 (ref. 43) ut not etween AI nd R 29. In the visul system, the discrete percept of repetition rte is referred to s flicker. Although flicker is typiclly experienced t frequencies elow Hz, for high-luminnce stimuli in the peripherl visul field flicker cn e perceived t frequencies s high s 5 6 Hz (ref. 44). In primry visul cortex, stimulus-synchronized responses to flicker hve lso een oserved t frequencies up to 5 6 Hz (refs. 45,46). This indictes tht t lest suset of neurons in primry visul cortex cn synchronize t the upper limit of flicker perception. Whether the decrese in criticl flicker frequency for low luminnce or fovel stimultion is the direct result of poorer stimulus synchroniztion hs not een tested. Perceptul nd neurl coding similrities for visul flicker, tctile flutter nd coustic flutter might provide sis for cross-modl discrimintion nd plsticity. For instnce, humn sujects cn discriminte etween the repetition rtes of visul flicker nd n coustic flutter stimulus 47. In ddition, intervl discrimintion cn generlize cross modlities, so tht sujects trined on tctile intervl discrimintion tsk lso develop improved intervl discrimintion for uditory stimuli (ut only for similr intervl durtions) 48. In more generl sense, we propose tht t ech corticl level of sensory system where there is conversion from temporl to rte representtion, there is perceptul ctegoricl oundry. The conversion from temporl to rte representtion in primry sensory cortex might underlie the ctegoricl oundry etween percepts of flutter nd pitch (or virtion for tctile perception). Likewise, the conversion from temporl to rte representtion in non-primry sensory cortex, resulting in n overll drop in stimulus synchroniztion, might e responsile for determining the lower limit of flutter. Although perceptul ctegoricl oundries could e formed y other neurl NATURE NEUROSCIENCE VOLUME [ NUMBER 6 [ JUNE 7 769

9 mechnisms, we suggest tht the upper nd lower limit of flutter re direct results of the different temporl nlysis windows used for trnsformtions etween temporl nd rte coding y primry nd non-primry sensory corticl res. METHODS Generl experimentl procedures. We hve recently pulished detils of experimentl procedures 49. Single-unit recordings were mde using highimpednce tungsten microelectrodes (2 5 MO). We detected ction potentils on-line using templte-mtching method (MSD, Alph Omeg Engineering). All recording sessions were crried out in doule-wlled, soundproof chmer (Industril Acoustic Co., Inc.) with n interior covered y 3-inch coustic sorption fom (Sonex, Illruck, Inc.). Acoustic stimuli were generted digitlly nd delivered y free-field speker locted 1 m directly in front of the niml. The niml ws wke nd semi-restrined in custom-mde primte chir, ut ws not performing tsk during these experiments. All experimentl procedures were pproved y the Johns Hopkins University Animl Use nd Cre Committee. Electrophysiologicl recordings nd coustic stimuli. After ech single unit ws isolted, its sic response properties (CF nd sound level threshold) were mesured, most commonly using pure tones or noise. Neurons locted outside AI did not lwys respond to pure tones or noise, nd for these neurons we used mplitude-modulted tones or noise to mesure CF nd sound level threshold. After the preferred crrier (tone or noise) nd sound level were identified, we generted set of coustic pulse trins (ech pulse ws generted y windowing the preferred crrier signl y Gussin envelope) with repetition rtes rnging from 4 to 48 Hz (in 4-Hz steps). This ws the most common stimulus set (referred here to s stimulus set 1) used to test tuning for repetition rte. Another stimulus set in which the time intervl etween coustic pulses ws vried etween nd 75 ms in 5- to -ms steps (effectively vrying repetition rte etween 13 nd 5 Hz) ws lso used for suset of neurons. If neurons could not e driven with Gussin coustic pulse trins, we used rectngulr clicks or coustic pulses with rmped or dmped envelope. Ech stimulus hd durtion of 5 54 ms, depending on the width of the coustic pulse used. Pulse widths rnged from.1 to 1 ms for rectngulr clicks nd s ¼.89 to 4.65 ms for Gussin pulses. All intertril intervls were t lest 1 s long nd ech stimulus ws presented in rndomly shuffled order with other stimuli. Ech stimulus ws repeted t lest five times for ll neurons, nd t lest ten times for most neurons (236/274). Stimulus intensity levels for coustic pulse trins were generlly db ove CF-tone threshold for neurons with monotonic rte-level functions nd t the preferred sound level for neurons with non-monotonic rte-level functions. Dt nlysis. Neurons were considered stimulus synchronized if their vector strength ws greter thn.1 nd sttisticlly significnt (Ryleigh sttistic vlues greter thn 13.8, equivlent to P o.1) 5 for t lest three sequentil repetition rtes etween 8 nd 5 Hz over spn of t lest 8 Hz. The vector strength ws clculted over the time period strting from 5 ms fter stimulus onset to 5 ms fter stimulus offset. Neurons were considered to hve significnt rte response if for t lest three sequentil repetition rtes in the stimulus set (over rnge of t lest 8 Hz) they produced significnt dischrge rte. A significnt rte ws defined s n verge dischrge rte 2 s.d. ove the men spontneous rte, t lest n verge of 2 spikes per stimulus (fter sutrcting the men spontneous rte), nd t lest 1 spike for minimum of 5% of the trils. We clculted verge dischrge rtes for the durtion of the stimulus plus n dditionl ms fter the stimulus. The monotonicity of the dischrge rte versus repetition rte function ws determined y clculting the Spermn correltion coefficient (P o.5 for positive or negtive correltion). We clculted monotonicity over ll repetition rtes tested etween 8 nd 5 Hz. For ech neuron, we lso performed liner regression on neuronl responses to repetition rtes etween 8 nd 5 Hz, nd determined whether the response slope ws significntly different from zero (F-test, P o.5). We found tht 179 out of 184 monotonic neurons nd 16 out of 9 non-monotonic neurons hd sttisticlly significnt response slopes, on the sis of this nlysis. The response slope (chnge in dischrge rte reltive to the chnge in repetition rte) ws otined y liner interpoltion etween repetition rtes of 8 to 5 Hz. Individul peri-stimulus time histogrms (PSTHs) were clculted y convolving Gussin kernel (s ¼ ms) with neuron s spike trin. We otined popultion PSTHs y tking the men of individul PSTHs, nd determined the instntneous response slope for neuronl popultion y clculting the response slope cross the popultion PSTHs for repetition rtes etween 8 nd 48 Hz (stimulus set 1) t prticulr time. Pek ltencies were computed from the popultion PSTH of pure tone responses (t the sound level eliciting the mximum dischrge rte). A sttisticlly significnt difference in pek ltencies etween two neuronl popultions ws determined using Wilcoxon rnk sum test to compre the distriution of pek ltencies otined from individul PSTHs. We quntified sound level invrince y linerly interpolting the response slopes t ech sound level tested. The slope of this liner fit ws used to estimte how much the response slope chnged with -db increse in sound level. A significnt difference in the sound level dependent chnges of the response slopes for two popultions of neurons ws determined using Kolmogorov- Smirnov test (P o.5). Identifiction of corticl res. We identified AI y its response to pure tones nd cochleotopic grdient (high frequency: cudl-medil; low frequency: rostrl-lterl). The rostrl fields R nd RT were identified y reversls in the cochleotopic grdient. The medin CF of neurons tht hd significnt responses to tones ws clculted within n nlysis window moving long the cudl-to-rostrl xis. This ws then smoothed using zero-phse forwrd nd reverse digitl filters nd cochleotopic reversls were identified s minim nd mxim in this curve. Although most recordings were in AI, R nd RT, suset of the neurons studied might hve een in the lterl elt or prelt. We limited our comprison of core res to neurons within mm of the lterl sulcus in regions tht were generlly tone-responsive. Using frequency reversls to define the orders of AI, R nd RT, we creted normlized mps for four hemispheres. We recorded from AI nd R in two hemispheres nd from AI, R nd RT in the other two. We used Wilcoxon rnk sum test (P o.5) to determine whether the sptil distriution of synchronized nd unsynchronized neurons ws different long either the cudl-to-rostrl or medil-tolterl xis. The order re etween AI nd R (Supplementry Tle 1) ws defined s the 1-mm-wide region long the cudl-to-rostrl xis, centered t the AI/R order. In one monkey, we recorded from second hemisphere; however, ecuse it ws not sufficiently mpped, we could not determine the order etween AI nd R, nd s such the dt from this hemisphere were excluded from core re comprisons (n ¼ 27). In ddition, we excluded 19 neurons tht were identified s on the order or outside the core of uditory cortex from core re comprisons. Note: Supplementry informtion is ville on the Nture Neuroscience wesite. ACKNOWLEDGMENTS Support ws contriuted y US Ntionl Institutes of Helth grnts DC 318 (X.W.) nd F31 DC 6528 (D.B.). We thnk A. Pistorio for ssistnce with niml cre nd Y. Zhou for vlule comments nd suggestions relted to this mnuscript. AUTHOR CONTRIBUTIONS D.B. nd X.W. designed the experiment nd co-wrote the pper. D.B. crried out the electrophysiologicl recordings nd dt nlysis. COMPETING INTERESTS STATEMENT The uthors declre no competing finncil interests. Pulished online t Reprints nd permissions informtion is ville online t reprintsndpermissions 1. Rosen, S. Temporl informtion in speech: coustic, uditory nd linguistic spects. Phil. Trns. R. Soc. Lond. B 336, (1992). 2. Singh, N.C. & Theunissen, F.E. Modultion spectr of nturl sounds nd ethologicl theories of uditory processing. J. Acoust. Soc. Am. 114, (3). 3. Miller, G.A. & Tylor, W.G. The perception of repeted ursts of noise. J. Acoust. Soc. Am., (1948). 77 VOLUME [ NUMBER 6 [ JUNE 7 NATURE NEUROSCIENCE

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