Olfactory Predictive Codes and Stimulus Templates in Piriform Cortex

Transcription

1 ticle Olfactoy Pedictive Codes and Stimulus Templates in Piifom Cotex Chistina Zelano, 1, pajita Mohanty, and Jay. Gottfied 1 1 Depatment of Neuology, Feinbeg School of Medicine, Nothwesten Univesity, Chicago, IL 6611, US Depatment of Psychology, Stony ook Univesity, Stony ook, NY 11794, US Coespondence: c-zelano@nothwesten.edu DOI 1.116/j.neuon SUMMRY Neuoscientific models of sensoy peception suggest that the bain utilizes pedictive codes in advance of a stimulus encounte, enabling oganisms to infe fothcoming sensoy events. Howeve, it is pooly undestood how such mechanisms ae implemented in the olfactoy system. Combining highesolution functional magnetic esonance imaging with multivaiate (patten-based) analyses, we examined the spatiotempoal evolution of odo peception in the human bain duing an olfactoy seach task. Ensemble activity pattens in anteio piifom cotex (PC) and obitofontal cotex (OFC) eflected the attended odo taget both befoe and afte stimulus onset. In contast, pestimulus ensemble epesentations of the odo taget in posteio piifom cotex (PPC) gave way to poststimulus epesentations of the odo itself. Citically, the obustness of tagetelated pattens in PPC pedicted subsequent behavioal pefomance. Ou findings diectly show that the bain geneates pedictive templates o seach images in PPC, with physical coespondence to odo-specific patten epesentations, to augment olfactoy peception. INTRODUCTION The pocess by which the bain tansfoms sensoy inputs into peceptual events often begins befoe physical contact with the sensoy stimulus (Feeman, 1979; Fiston, 5a; McMains et al., 7; Mesulam, 8; Mumfod, 199; Sylveste et al., 9; Wald and Wolfowitz, 1949). Knowledge and expeience set expectations fo what is likely but not yet to be encounteed, helping to augment the speed and accuacy of subsequent peceptual judgments. These pedictive epesentations confe distinct behavioal advantages upon oganisms aiming to suvive in complex, noisy, and unpedictable sensoy envionments. How pedictive peceptual infomation is encoded in the bain is not well undestood. Seveal influential models of sensoy peception have centeed on the idea that the bain geneates stimulus templates o seach images in advance of a stimulus encounte (Feeman, 1981; Fiston, 3; Mumfod, 199). ccoding to such mechanisms, a sensoy pecept is instantiated though an inteaction between the pestimulus template and the incoming sensoy input. Multiple studies have found effects of anticipatoy attention in the visual and auditoy systems (Kastne et al., 1999; Kuma and Sedley, 11; Luck et al., 1997; Ress et al., ), and moe ecently, effects of anticipatoy attention o top-down seach have also been found fo specific visual objects in highe-ode visual cotex (Esteman and Yantis, 1; Peelen et al., 9; Stokes et al., 9; Summefield et al., 6). y compaison, eseach on pedictive coding in the olfactoy system has been scant at best. Given that odo objects ae outinely expeienced within a highly odifeous backgound (Gottfied, 1; Stevenson and Wilson, 7), it follows that mechanisms to stee selective attention towad an odo of inteest, and away fom an odo of no inteest, would be essential fo ovecoming sensoy noise in the olfactoy envionment. In an ealy model of olfactoy peception (Feeman, 1981), Walte Feeman postulated that spatiotempoally distibuted seach images in the abbit olfactoy bulb povide an active filte that selectively enhances peceptual sensitivity to expected odos, without impaiing esponsiveness to unattended odos (Feeman, 1983). He concluded that abbits smell what they expect, not what they sniff. Moe ecent electophysiological ecodings in odents have identified pestimulus anticipatoy events not only in the bulb, but also in piifom cotex and obitofontal cotex (Kay and Feeman, 1998; Schoenbaum and Eichenbaum, 1995), implying that well befoe an odo aives, much of the olfactoy system geneates a pediction about the upcoming stimulus. Finally, in human piifom cotex, attention to olfactoy content evokes baseline deviations in fmri activity (Zelano et al., 5), although it is unclea whethe these changes meely eflect a geneal attentional gain o eflect featue-based pedictive codes about specific odos. Olfactoy studies in humans and othe animals inceasingly show that cotical epesentations of odo in piifom cotex ae encoded as spatially distibuted ensembles (Feeman, 1979; Habely, 1985; Habely, 1; Hasselmo et al., 199; Howad et al., 9; Illig and Habely, 3; Kay and Stopfe, 6; Matin et al., 4; Spos and Ginvald, ; Stettle and xel, 9; Wilson and Stevenson, 3) evolving ove a time span of seconds (Rennake et al., 7). Theefoe, on the basis of these obsevations, we combined an olfactoy attentional seach task with functional magnetic esonance imaging (fmri) techniques and patten-based multivaiate analyses to test thee 178 Neuon 7, , Octobe 6, 11 ª11 Elsevie Inc.

2 Stimulus Taget Taget: Taget: y n s y y s y n Figue 1. Expeimental Design and ehavioal Results () Subjects took pat in an olfactoy attentional seach paadigm that confomed to a two-way factoial design in which eithe odo taget o odoant stimulus was vaied. () t the stat of each fmri un, subjects wee infomed whethe the taget smell would be odo o odo fo that un. On a given tial, a countdown cue began 3 s pio to sniff (thick black ba), then one of the odo stimuli was pesented and subjects indicated whethe the assigned taget odo was pesent in the stimulus ( y o n ). hypotheses following fom the pedictive coding model: (1) odospecific pedictive codes in the human olfactoy bain ae established pio to stimulus onset and take the fom of spatially distibuted templates o seach images ; () ensemble activity pattens should evolve in space and time ove the couse of a tial, such that pedictive coding gives way to stimulus coding fom pe- to postodo onset; and (3) a legitimate pestimulus pedictive template should be able to pedict olfactoy behavioal pefomance in the post-stimulus peiod. Subjects paticipated in a simple olfactoy fmri task in which they decided whethe a paticula pedetemined taget smell was pesent on each tial. In taget uns, subjects detemined whethe odo was pesent, and in taget uns, subjects detemined whethe odo was pesent. Stimuli consisted of odo alone (), odo alone (), o a binay mixtue of odos and (), esulting in six conditions: taget with stimulus,, o (j, j, j), and taget with stimulus,, o (j, j, j) (Figue 1). Impotantly, the physical chaacteistics of the stimuli wee identical acoss uns, ensuing that the only diffeing aspect between taget and taget uns was the attentional focus of the subject. y compaing conditions with the taget held constant, to conditions with the stimulus held constant, we wee able to look fo taget-elated and stimulus-elated activity pattens and obseve how those pattens evolved fom pe- to poststimulus. Pincipal egions of inteest (ROIs) included anteio piifom cotex (PC), posteio piifom cotex (PPC), obitofontal cotex (OFC), and mediodosal thalamus (MDT), aeas that have been peviously implicated in human imaging studies of odo quality coding (Gottfied et al., 6; Howad et al., 9), odo imagey (ensafi et al., 7; Djodjevic et al., 5), odo localization (Pote et al., 5), olfactoy woking memoy (Zelano et al., 9), and olfactoy and gustatoy attentional modulation (Plailly et al., 8; Veldhuizen et al., 7; Zelano et al., 5). RESULTS Olfactoy Selective ttention iases ehavioal Pefomance and Enhances Response Times Duing a given taget un (eithe o ), subjects wee cued to sniff and to indicate as accuately and quickly as possible whethe the odo stimulus (,, o ) contained the taget note. ehavioal data wee analyzed with a two-way epeatedmeasues NOV, with factos taget (two levels) and stimulus (thee levels). Thee was no main effect of taget on pefomance accuacy: subjects identified the taget equally well on both and uns (F 1,11 =.54; p = 78) (Figue ). In contast, a significant main effect of odo stimulus was obseved (F 1.83,.11 = 1.8; p =.1), wheeby subjects wee less accuate on stimulus tials than on stimulus and tials ( vesus : T 11 = 4.39, p =.1; vesus : T 11 = 3.96, p <.). Inteestingly, although mean accuacy was compaable fo and odo stimuli (T 11 = 6, p =.6), thee was a significant stimulus-by-taget inteaction (F 1.88,.67 = 8.951; p =.), such that accuacy on taget uns was highe (at tend) fo stimulus than fo stimulus (T 11 =., p <.7), and accuacy on taget uns was highe fo stimulus than fo stimulus (T 11 = 4., p <.) (Figue ). In othe wods, subjects made fewe eos on conguent tials in which the taget was pesent in the stimulus (i.e., j and j), compaed to inconguent tials in which the taget was not pesent (i.e., j and j). This effect is summaized in Figue (conguent vesus inconguent: T 11 = 3.35, p <.6). Moeove, eaction times wee significantly faste on conguent tials when the taget note was pesent in the stimulus compaed to inconguent tials when it was not (T 11 = 3.1, p <.1) (Figue C), highlighting the effect of ou attentional manipulation on behavio. lthough seveal studies have found evidence fo a geneal effect of attending to olfactoy vesus nonolfactoy sensoy modalities (Plailly et al., 8; Sabi et al., 5; Spence et al., 1; Zelano et al., 5), ou esults imply that selective attention within the olfactoy modality also exists, which has been peviously debated (Laing and Glemaec, 199; Takiguchi et al., 8). ecause of the known influence of sniffing on olfactoy activation pattens in humans (Mainland and Sobel, 6), we also examined condition-specific espiatoy pattens acoss subjects and confimed that thee was no effect of attended taget (F 1,11 = 1.7, p =.159), odo stimulus (F 1,11.1 =.73, p = 11), o taget-by-stimulus inteaction (F 1,11 =.914, p =.36) on inspiatoy sniff volume (data not shown). Thus, the only salient cognitive diffeence between taget and taget uns was the attentional focus of the subject. Neuon 7, , Octobe 6, 11 ª11 Elsevie Inc. 179

3 ccuacy ccuacy cong. Taget incong. mix. Conguent (taget pesent) C 4 Pestimulus Ensemble Pattens in Olfactoy Cotex Reflect the Odo Taget We fist examined whethe odo-specific ensemble pattens wee fomed pio to the aival of the stimulus. The cental hypothesis was that pio to odo onset, spatial activity pattens would be moe coelated between same-taget conditions than between diffeent-taget conditions in bain egions encoding the odo taget. Thus fo example, if a given ROI eflected the tageted note, the pestimulus patten in esponse to condition j would coelate moe stongly to j (same taget but diffeent stimulus) than to j (diffeent taget but same stimulus). Convesely, in a egion encoding the actual odo stimulus, the patten in esponse to condition j would coelate moe stongly to j (same stimulus but diffeent taget) than to j (diffeent stimulus but same taget). In this manne, one could test a distinct contast (same taget/diffeent stimulus coelations vesus same stimulus/diffeent taget coelations) to look fo both taget-elated and stimulus-elated effects, both befoe and afte odo onset (Figue 3). These analyses wee computed fo taget uns and fo taget uns in the peand poststimulus time bins and enteed into a thee-way epeated-measues NOV with the factos taget un ( o ), patten type (taget-elated o stimulus-elated patten), and time (pe- o poststimulus onset). ecause no egion exhibited a significant effect of taget un (all p s >.), data ae shown collapsed acoss and uns (fo non-collapsed data, see Figue S1). In line with the idea that pestimulus, odo-specific pattens exist in the olfactoy system, fmri ensemble coelations between same-taget conditions wee significantly highe than Reaction time (s) incong. 3 Taget cong. mix. Inconguent (taget not pesent) stimulus stimulus stimulus Figue. ehavioal Results () Oveall detection accuacy fo the taget odo did not significantly diffe acoss and uns, although pefomance was bette with and stimuli than with the stimulus mixtue (mix.). coss-ove inteaction was obseved, in which subjects wee moe accuate on taget uns when the stimulus was (conguent condition; cong.) athe than (inconguent condition; incong.) and wee moe accuate on taget uns when the stimulus was (cong.) athe than (incong.). Eo bas denote between-subject SEM fo each compaison. () Pefomance accuacy, collapsed acoss and uns, was significantly highe when the taget was pesent in the stimulus (cong.) compaed to when the taget was not pesent (incong.). Eo bas denote between-subject SEM fo each compaison. (C) Reaction times followed a simila pofile, such that subjects wee faste fo conguent tials compaed to inconguent tials. p <.5. coelations between diffeent-taget conditions (Figue 3). In PC and OFC, thee was a significant effect of patten type (PC: F 1,11 = 3.933, p <.1; OFC: F 1,11 = , p <.4) in the taget diection, wheeby same-taget conditions wee moe coelated than diffeent-taget conditions (PC: T 11 = 5.6, p <.1; OFC: T 11 = 3.67, p <.3). In PC, thee was also a significant patten type-by-time inteaction (F 1,11 = 5.79, p <.35) in which the same-taget (compaed to diffeent-taget) coelations wee lage in the pestimulus bin than in the poststimulus bin (pe: T 11 = 6.3, p <.1; post: T 11 = 1.99, p <.7). Thee was no such inteaction in OFC (p =.3). Neithe MDT no PPC exhibited a significant main effect of patten type o time (p s >.1). fmri Pattens in PPC Evolve fom Pestimulus Taget Repesentations to Poststimulus Odo Repesentations lthough PPC exhibited no main effect of patten type (eithe in the taget diection o the stimulus diection), thee was a significant patten type-by-time inteaction (F 1,11 =.7, p <.1). Follow-up t tests evealed a double dissociation, such that same-taget conditions wee moe coelated than diffeenttaget conditions befoe stimulus onset (T 11 =.6, p <.), but same-stimulus conditions wee moe coelated than diffeentstimulus conditions afte stimulus onset (T 11 = 5.45, p <.1) (Figue 3). To diectly visualize how the infomational content of the fmri signal changes ove time and acoss diffeent egions, we plotted the mean coelations between same-taget conditions (e.g., j to j) and between same-stimulus conditions (e.g., j to j) sepaately fo each time point in the tial (Figue 4). Within PC and OFC, taget-specific pattens emeged ealy in the pestimulus peiod, and in the case of PC, this effect significantly pesisted fo seveal seconds into the poststimulus peiod. In contast, taget-specific pattens in PPC wee identified pio to odo onset, but these gave way to stimulus-specific pattens late in the tial. 18 Neuon 7, , Octobe 6, 11 ª11 Elsevie Inc.

4 Coelation () PC Coelation () Taget patten-type effects: OFC PRE PRE Same taget/diff. stim. Same stim./diff. taget Same taget/diff. stim. Same stim./diff. taget POST POST Taget patten-type effects: Same taget/diff. stim. Same stim./diff. taget PPC MDT Pestimulus Pattens in PPC Take the Fom of ehavioally Relevant Odo Templates lthough the above data povide obust evidence fo olfactoy pedictive pattens, diect confimation that these codes ae peceptual templates o seach images of the actual odo equies that the seach patten fo a given odo (pio to stimulus onset) coelates with the actual evoked patten fo that odo (following stimulus onset). To test this idea, we hypothesized that if the obseved seach patten did in fact esemble the actual patten in esponse to that specific odo, then the pestimulus and poststimulus activity pattens in PPC would be moe coelated in tials in which the stimulus matched the taget than when the stimulus did not match the taget. In ageement with this hypothesis, we found highe coelations between pe- and post- Coelation () Coelation () PRE PRE Same taget/diff. stim. Same stim./diff. taget POST POST Figue 3. Odo-Specific Pedictive Codes in the Olfactoy System () We made use of a single compaison (same taget/ diffeent stimulus vesus same stimulus/diffeent taget) to look fo both taget-elated effects (geen) and stimuluselated effects (blue). These compaisons wee computed fo all taget uns (j compaed to j vesus j; j compaed to j vesus j) and fo all taget uns (j compaed to j vesus j; j compaed to j vesus j), both befoe and afte odo onset. () Taget- and stimulus-elated effects wee computed by testing whethe multivoxel coelations between sametaget/diffeent-stimulus conditions (geen bas) diffeed fom diffeent-taget/same-stimulus conditions (blue bas). Same-taget coelations significantly exceeded diffeenttaget coelations in PC and OFC both befoe and afte stimulus aival. In PPC, same-taget conditions wee moe coelated than diffeent-taget conditions befoe stimulus onset, but same-stimulus conditions wee moe coelated than diffeent-stimulus conditions afte stimulus onset. p <.5. Eo bas denote between-subject SEM fo each compaison. stimulus pattens in PPC fo taget/stimulus matching (vesus nonmatching) tials (Figue 5) (T 11 = 1.8, p <.4; binomial test, p <.3). Thus the pestimulus patten obseved in PPC does in fact appea to be quite liteally an odo template, that is, a stimulus-specific peceptual signatue of the anticipated odo in the absence of any stimulus. We next easoned that if pestimulus odo templates exist, they should help augment olfactoy peception. To this end, we egessed the stength of template fomation (as indexed by the magnitude of the pe-odo coelation between same-taget conditions) against pefomance accuacy on the olfactoy seach task, on a subject-wise basis. Put diffeently, we tested the hypothesis that subjects who geneated moe obust odo-taget templates would be able to identify the taget odo moe accuately. In ageement with this pediction, the magnitude of the pestimulus effect in PPC was significantly coelated with task accuacy (Figue 6) (R =.64, p =.). Futhemoe, the degee to which same-taget coelations exceeded diffeent-taget coelations also coelated with task accuacy (R =.66, p =.1). y compaison, pestimulus ensemble pattens in PC and OFC had no demonstable elationship to behavio (p s >.7), indicating that the availability of pedictive codes fo guiding olfactoy peceptual decisions specifically esides in PPC. Univaiate fmri Index of Pediction Eo in MDT Recent theoetical models of sensoy peception (Fiston, 5b; Rao and allad, 1999) place high impotance on hieachical pocessing and pediction eo: pedictions eflect the top-down flow in the cotical hieachy while pediction eo Neuon 7, , Octobe 6, 11 ª11 Elsevie Inc. 181

5 Coelatioin () ST() - SS() PC PPC OFC Same-taget diffeent-stimulus Same-stimulus diffeent-taget Taget > stimulus Stimulus > taget PC PPC OFC Coelation between pe and post ().6. Taget and stimulus matching Taget and stimulus non-matching Non-matching value Figue 5. Pedictive Odo Templates in PPC Resemble the Stimulus Response to the Taget Smell () In PPC, pestimulus taget-specific ensemble pattens moe closely esembled poststimulus odo pattens when the taget matched the stimulus (e.g., j vesus j) compaed to when it did not (e.g., j vesus j). Subject-aveaged coelations fo matching and nonmatching conditions, aveaged acoss both and tagets, ae shown (means ± SEM). Eo bas denote between-subject SEM fo each compaison. () scatteplot of matching vesus nonmatching conditions in PPC indicates that the pestimulus taget template was moe highly coelated to matching (vesus nonmatching) poststimulus odo epesentations fo 1/1 subjects. Matching value Figue 4. The Tempoal Evolution of Pedictive Codes and Stimulus Repesentations Diffes acoss Olfactoy Cotical Regions () In all thee egions, coelations incease pio to stimulus aival fo sametaget conditions (blue lines) and emain elevated ove same-stimulus conditions (ed lines) in PC and OFC. In contast, the coelation time couse in PPC exhibits two peaks: an ealy peak fo same-taget conditions and then a late peak fo same-stimulus conditions, eflecting the obseved double dissociation between patten type (taget vesus stimulus) and time (pe vesus post) in this egion. Each plotted point epesents the mean ove two consecutive TRs. lack stas indicate time points at which same-taget coelations exceed same-stimulus coelations; black diamonds indicate time points at which same-stimulus coelations exceed same-taget coelations (at p <.5). Eo bas denote between-subject SEM fo each compaison. () Fo bette visualization of these effects, the coelation diffeence between the blue and ed lines in panel was plotted fo each egion at each time-point (ST(), same-taget -value; and SS(), same-stimulus -value). shift in patten coding fom taget to stimulus is appaent in PPC at the cossing of the x axis. Red stas, significant taget-elated effect; ed diamonds, significant stimuluselated effect; p <.5. eflects the bottom-up flow of affeent sensoy infomation. Inteestingly, findings fom univaiate fmri analyses commonly show that an expected (vesus unexpected) pecept elicits lowe mean activity in sensoy-elated egions, a diffeential effect that has been attibuted to pediction eo signaling (Summefield and Egne, 9). Theefoe, we conducted a complementay univaiate imaging analysis to look fo evidence of eo signaling in ou data (Figue 7). fmri activation in MDT was significantly educed in esponse to expected tials compaed to unexpected tials (T 11 =.41, p <.3), suggesting this egion may paticipate in geneating a pediction eo signal. y compaison, thee wee no significant diffeences in PC, PPC, o OFC (p s >.). DISCUSSION The vast majoity of natual, eal-wold odos ae encounteed in the pesence of othe competing smells. Thus, on any given inhalation, the olfactoy system faces the challenge of disambiguating salient odo objects fom othe odos pesent in the backgound (Linste et al., 7). On top of this challenge, human olfactoy peception is both tempoally and spatially impoveished (Sela and Sobel, 1), implying that attentional captue may be insoluble fo the olfactoy system (Laing and Glemaec, 199). y utilizing fmri multivaiate analyses in conjunction with an odo seach task, we wee able to show that odospecific ensemble pattens emege pio to odo stimulation and (in PPC) eliably pedict subsequent behavioal pefomance. These findings povide obust evidence fo object-based attentional mechanisms that diectly impact on odo peception. Sepaation of the fmri time seies into pe- and poststimulus bins enabled us to identify ensemble pattens of activity both befoe and afte odo aival. efoe the sniff and in the absence of odo, olfactoy ensemble codes in PC and OFC wee specific fo the attended odo taget, athe than being a geneal effect of attention, indicating that subjects can geneate featue-specific infomation about an odo pio to its eceipt. fte odo onset, taget-elated pattens in PC and OFC pesisted fo up to seveal seconds, iespective of the actual identity of the deliveed odo. These findings indicate that the ensemble activity in PC and OFC moe closely esemble what is being sought-out athe that what is being deliveed to the nose. That much of the olfactoy system smells what it expects athe than what it sniffs is closely eflected in ou behavioal data (Figue ). Stimulus-specific expectations induced coesponding esponse biases duing odo sampling: subjects misclassified a given stimulus moe often when peceded by an inconguent taget cue, fo example, mistaking odo fo odo when seaching fo. Similaly, eaction times wee slowe when subjects expected one odo but eceived anothe. y compaison, in PPC, taget-elated ensemble codes befoe odo onset gave way to stimulus-specific codes afte odo onset, wheeby activity pattens moe closely esembled what was 18 Neuon 7, , Octobe 6, 11 ª11 Elsevie Inc.

6 Task accuacy (%) = Same taget Same taget - same stimulus deliveed athe than what was being expected (Figues 3 and 4). This esponse pofile implies that PPC plays a highly dynamic ole at the inteface between sensation, expectation, and peception. Insofa as the pe-stimulus taget pattens (e.g., odo taget) and the poststimulus odo pattens (e.g., odo stimulus) shaed significant patten ovelap in PPC (Figue 5), ou findings diectly show that pedictive templates o seach images ae epesented hee. That the obustness of pedictive coding in PPC facilitated odo peception in a stimulus-specific manne (compae to Figue 6) futhe undescoes the key involvement of this bain aea in geneating spatially distibuted templates with liteal functional coespondence to the actual odo pattens, in accodance with longstanding anatomical and computational models of piifom function (Feeman and Schneide, 198; Habely, 1; Hasselmo et al., 199; Ojima et al., 1984; Wilson and Stevenson, 3). Cuiously, the elevance of pesisting taget pattens in PC and OFC to odo peception is unclea given that these pattens (unlike those in PPC) did not coelate with behavio. It is impotant to note that the subjects in ou study pefomed elatively slowly on this task, taking between 3 and 4 s on aveage to make a decision. Theefoe, it is plausible that within this postsniff time fame, an ongoing tace in PC may have helped optimize the attentional seach, without itself coelating diectly with peceptual pefomance. Ultimately, how these pestimulus codes in PC and OFC influence odo peception emains unesolved. Human psychophysical and neuoimaging studies inceasingly indicate that olfactoy peception benefits fom odo imagey and cognitive modulation. Fo example, imagination of a specific smell altes sniffing behavio, enhances odo detection accuacy, and elicits fmri activations in anteio (fontal) piifom cotex and posteio OFC (ensafi et al., 7; ensafi et al., 3; Djodjevic et al., 4; Djodjevic et al., 5). Similaly, contextual pesentation of nonolfactoy semantic infomation, such as pictues o wod labels, modifies both odo peception and OFC esponse pofiles in a stimulus-specific manne (de aujo et al., 5; Gottfied and Dolan, 3; Hez and von Task accuacy (%) =.66 Figue 6. Featue-Specific Pestimulus Pattens ugment Olfactoy Peception () The stength of patten coelation between same-taget conditions in PPC pedicted identification accuacy on the odo seach task. () The extent to which PPC ensemble ovelap was geate fo same-taget conditions than fo diffeent-taget conditions was also positively coelated with pefomance, on a subject-by-subject basis. Note that each dot epesents one subject. Clef, 1; Hez, 3). The fomation of olfactoy pedictive templates in PC, PPC, and OFC that pecede and in some cases pesist beyond onset of the stimulus, as shown hee, epesents a plausible unifying neual mechanism to explain the widespead modulatoy effects of imagey and context on how an odo is peceived. Recent theoetical pespectives make the case that pedicting the appeaance of paticula stimulus featues (i.e., pedictive coding ) is mechanistically distinct fom pioitizing detection of expected featues as a esult of thei task elevance (i.e., featue-based attention ) (Summefield and Egne, 9). In the visual system fo example, both pocesses will lead to behavioal gains in stimulus ecognition, but will exet opposing effects on neual activity in egions epesenting the stimulus (Summefield and Egne, 9). lthough ou expeimental design cannot fomally distinguish between pedictive coding and featuebased attention pe se, the mean fmri signal decease in MDT afte delivey of expected vesus unexpected odo stimuli (compae to Figue 7) is compatible with pedictive coding models and highlights a potential impotant ole fo this egion in geneating a pediction eo signal. s a egion that eceives both topdown infomation fom OFC and bottom-up input fom PPC (Ray and Pice, 199), MDT is ideally positioned to compute an eo signal by diectly compaing pedictions with inputs. Its ecipocal connectivity with PC, PPC, and OFC also means that MDT would be able to communicate this eo signal to these othe egions fo puposes of updating these pedictions. Moe boadly, ou imaging data dovetail nicely with studies on anticipatoy attention in the visual and auditoy systems (Esteman and Yantis, 1; Kastne et al., 1999; Kuma and Sedley, 11; Luck et al., 1997; Peelen et al., 9; Ress et al., ; Summefield et al., 6) and imply that the bain geneates pedictive codes of the suounding envionment, no matte the modality. In showing that the epesentational content of pedictive codes in PPC coesponds to the activity patten elicited by the actual expected stimulus, ou data extend ealie findings confiming mean signal changes in sensoy-elevant egions. Ou esults geneally daw out the physiological distinctions between the olfactoy and visual systems, in that odo seach maps in PPC ae only two synapses downsteam fom the nasal peiphey, wheeas seach maps in the visual modality ae found much futhe along in the pocessing hieachy (Peelen et al., 9; Stokes et al., 9; Summefield et al., 6). Nevetheless, the functional similaities between these two modalities lend futhe suppot to the notion of piifom cotex as a highe-ode associative bain aea, akin to visual associative aeas in the infeio tempoal lobe. On a final clinical note, ou data offe an intiguing potential explanation fo the ealy olfactoy dysfunction commonly descibed in patients with schizophenia. Deficits in odo identification ae one of the ealiest symptoms to appea in schizophenic patients, and the extent of peceptual impaiment pedicts pooe functional outcome (Good et al., 1; Stevenson et al., 11). Given that the positive symptoms of schizophenia may be the esult of a disuption in pedictive coding mechanisms (Fletche and Fith, 9), ou data may seve to unite olfactoy findings in schizophenic patients with geneal models of the mechanisms undelying this disease. Neuon 7, , Octobe 6, 11 ª11 Elsevie Inc. 183

7 1 Neuon PC PPC fmri activity (% signal change) fmri activity (% signal change) OFC Peak % change Peak % change fmri activity (% signal change) fmri activity (% signal change) MDT Peak % change.8 Peak % change Expected stimulus ( and ) Unexpected stimulus ( and ) Figue 7. Univaiate fmri nalysis Reveals that the Mean Level of Odo-Evoked ctivity in MDT Is Reduced in Response to an Expected o Pedictable Stimulus The goup-aveaged mean pecent signal change is plotted ove time within each ROI. In MDT, unexpected conditions elicited a highe esponse magnitude than did expected conditions. Eo bas denote between-subject SEM fo each compaison. EXPERIMENTL PROCEDURES Subjects Thiteen subjects (six women; age ange, 19 to 3 yeas) paticipated in the fmri study. ll povided witten infomed consent to paticipate in pocedues appoved by the Nothwesten Univesity Institutional Review oad. Paticipants wee sceened fo abnomal sense of smell o taste, histoy of neuological o psychiatic disease, histoy of nasal disodes, allegic hinitis o sinusitis, o MRI counteindications. One subject was excluded fom analyses as a esult of technical poblems with the olfactomete. Odoants and Odoant Delivey Odoants wee deliveed by an MRI-compatible, eight-channel computecontolled ai-dilution olfactomete (aiflow set at 1 L/min), which pemits apid delivey of single-component odoants and binay (two-odoant) mixtues in the absence of tactile, themal, o auditoy cues, custom-built in ou lab and modified fom pio designs (Johnson and Sobel, 7). Odoant stimuli consisted of methyl-3-nonenoate () and 1-hexanol (), as well as a contol odoant, cinnamaldehyde (C) (see Expeimental Pocedues), eithe pesented individually o as binay combinations (i.e., +, +C, +C) to subjects though a nasal mask (Respionics, Muysville, P) that was comfotably affixed aound the nose. Odoants wee selected that wee elatively familia and easily disciminable fom each othe. ll mixtues wee of equal popotional concentation such that the same amount of the single compound was deliveed in mixtues as when it was deliveed alone, ai-diluted at 4% satuation (i.e., 4 l/min of neat-concentation odoant and 6 l/min of ai). Respiatoy Monitoing Sniffs wee ecoded online duing scanning via the nasal mask, by means of a pneumatotachogaph (spiomete) that elayed espiatoy-induced changes in mask pessue to an amplifie (D Instuments, Milfod, M). Expeimental Design Just pio to placing subjects into the scanne, we administeed odoants and though the olfactomete and asked subjects to vebally ate the intensity of each odo on a scale fom 1 to 1. The olfactomete flow settings wee then adjusted until intensity atings wee matched. This also allowed subjects to become familia with the two odos, which would be the designated taget smells duing the imaging expeiment. Each scanning session consisted of 6 blocks of 3 tials (11 min pe block). efoe each block, the subject was infomed of the identity of the taget odo and was given a sample of the taget. On each tial, subjects wee pompted to sniff by a visually pesented countdown ( 3,, 1, SNIFF ), at which time an odo was pesented. Subjects then esponded by pushbutton to indicate 184 Neuon 7, , Octobe 6, 11 ª11 Elsevie Inc.

8 whethe o not the tial contained the taget (Figue 1). The taget fo a given un consisted of odo, odo, o odo +. ecause a thee-level NOV of,, and + blocks indicated that behavioal pefomance was significantly lowe on the taget + blocks (F,17.6 = 5.558; p =.18), the taget + conditions wee excluded fom futhe analysis. Thus compaisons wee esticted to taget and taget conditions, whee pefomance did not diffe (F 1.,11. =.54; p = 78). lock and tial ode wee pseudoandomly balanced acoss subjects. On each tial, subjects eceived odo alone, odo alone, odo +, odo +C, o odo +C. The + stimulus condition was included so that we could look at tials in which the stimulus was identical (i.e., +), and only the attentional focus of the subject diffeed (eithe the note o the note). The +C and +C conditions wee included as catch tials to ensue that subjects could not simply adopt a stategy to answe yes evey time a mixtue was pesented. Due to time constaints, thee was not a sufficient numbe of catch tials included to pefom eliable statistical analyses of these events. Each condition type was deliveed an equal numbe of times pe taget block. Impotantly, the stimulus content was identical acoss uns; only the identity of the taget (and theefoe the attentional seach focus of the subject) diffeed acoss blocks. In this way, we wee able to look fo attention-diven sensoy-specific esponses by compaing the fmri time seies in same-taget vesus diffeent-taget conditions. Each scanning session also included a 7 th block of an odo localize task, consisting of 18 tials of an odo detection task (Li et al., 8). Results fom this scan wee used only fo voxel selection in subsequent analyses. cquisition Paametes and Defining ROIs ll fmri data wee collected on a Siemens Tio 3T MRI scanne, with a twelvechannel head coil and an integated paallel acquisition technique known as GRPP (GeneRalized utocalibating Patially Paallel cquisition) so that signal ecovey in medial tempoal and basal fontal egions was impoved (Li et al., 6). Imaging paametes included: TR, 1.51 s; TE, ms; slice thickness, mm; gap, 1 mm; in-plane esolution, mm; field of view, 3 mm, matix size, mm. Image acquisition was tilted at 3 to futhe educe susceptibility atifact in olfactoy aeas. total of 4 slices pe volume wee collected to ensue adequate coveage of olfactoy bain egions. In addition to the functional scans, a T1-weighted whole-bain anatomical scan at 1 mm 3 esolution was acquied fo the pupose of outlining egions of inteest (ROIs). n additional lowe-esolution anatomical scan was acquied with the same slice potocol as the functional scans, to aid with ealignment of the functional data to the high esolution whole-bain anatomical image. Data wee analyzed with mvista ( and Matlab. Fist, we defined olfactoy cotical aeas by outlining ROIs of anteio piifom cotex (PC), posteio piifom cotex (PPC), mediodosal thalamus (MDT), and obitofontal cotex (OFC) on each subject s T1-weighted anatomical scan, with efeence to a human bain atlas (Mai et al., 1997). Following ou pio techniques (Howad et al., 9), the anatomical landmak used fo delineating the caudal extent of PC fom the ostal extent of PPC was defined as the location in the coonal T1 sections whee the medial tempoal and basal fontal lobes fist join togethe. Constuction of the ROIs was pefomed befoe any futhe analysis, and in the absence of functional esults. ecause one subject s acquisition did not fully cove MDT, this paticula ROI could not be analyzed fo that subject. In a subsequent step, we set out to functionally estict the ROIs to voxels that wee activated duing the localize scan. Fist, we conveted the time seies in each ROI into pecent signal change by dividing each by its mean esponse and multiplying by 1. Then, fo each subject we calculated an activation mask to filte out voxels fo which we had no signal. We poduced images of the aveage esponse acoss all time points at each voxel. ecause voxels in gay and white matte have a significantly diffeent mean esponse than voxels in bone o ai, we wee able to filte voxels on the basis of thei mean esponse to include only voxels fo which we had signal (Zelano et al., 7). This eliminated voxels that wee in egions of high susceptibility, paticulaly nea the vental fontal and tempoal suface of cotex. Second, fo each subject we poduced a noise mask simila to the fist, which calculated the standad deviation of the esponse at each voxel. This mask also disciminated between egions of high susceptibility and bain tissue and futhe excluded voxels with high noise, such as voxels on lage blood vessels. Thid, we esticted each subject s anatomical ROI to those voxels that esponded to odo stimulation on the localize task. This was calculated by coelating the esponse at each voxel following an odoant event with a standad hemodynamic esponse function used by mvista softwae. y calculating the coelation of each voxel to an expected hemodynamic esponse function, and the statistical significance of this coelation, we wee able to poduce a statistical paametic map of the esponsiveness of each voxel to odoants. To limit the anatomical ROIs to odoant esponsive voxels, we excluded all voxels whose coelation to the hemodynamic esponse function had a statistical significance value highe than p =.1. Subsequent analysis poceeded with these functionally esticted ROIs. s indicated in Supplemental Infomation, despite diffeences in the numbes of voxels included in each ROI, thee was no evidence that the significant pattens wee moe likely to emege fo ROIs containing highe numbes of voxels (Figue S). Time Seies nalysis The single-tial fmri time-seies in each voxel of each ROI fo each condition wee fist baseline-coected by subtacting the mean fmri activity in the inteval fom thee TRs pe-sniff to one TR pe-sniff. Note that this pocedue had no effect on the spatiotempoal pofile of the esponse. We then aveaged acoss tials, and defined two intevals of inteest (time being stimulus onset) in each event-elated time seies, one extending fom 3 TR TR (pe-stimulus bin) and anothe fom 3 TR 6 TR (post-stimulus bin). Ou ationale fo defining these bins was pincipally based on including as many pe-stimulus TRs (4 TRs, o 6 s) as was easonably possible befoe the pe-stimulus bin began to encoach on the end of the pevious tial. The post-stimulus bin was designed to span the main fmri esponse peak, which geneally occus 4-5 s afte the stimulus onset, with a 4-TR width set to ensue that the pooled vaiance ove the inteval was matched fo pe- and post- bins. We then ceated pe-stimulus and post-stimulus vectos fo each subject containing the mean activity in the two time-bins fo each voxel. Note that inceasing the post-bin width by an additional TRs did not significantly alte the main findings. To compae the diffeent conditions, we computed linea coelation coefficients (R values) between the voxel vectos fo the diffeent conditions fo each subject, esulting in a single coelation coefficient pe subject, pe ROI, and pe condition compaison. To look fo effects of taget and stimulus, we hypothesized that the ensemble patten would be moe coelated between same-taget/diffeent stimulus conditions than between diffeent-taget/same stimulus conditions in bain egions encoding the odo seach taget. Note that all same-taget conditions coincided with diffeent-stimulus conditions, and all same-stimulus conditions coincided with diffeent-taget conditions. In this way, we wee able to look fo both taget and stimulus effects in a single compaison in the pe- and poststimulus bins. In a multivaiate analysis to establish evidence fo stimulus-specific pedictive templates (Figue 5), pestimulus taget pattens wee compaed to poststimulus odo pattens in PPC. ecause a pestimulus patten could theoetically be compaed to a post-stimulus patten fom the same tial, consequently intoducing analysis confounds, we made sue that pe- and poststimulus compaisons wee always dawn fom independent tials. Fo example, if a pestimulus taget patten was deived fom the j condition, then the poststimulus odo patten fo compaison would have been deived fom the j condition (and neve fom the j condition). Regions of inteest included PC, PPC, OFC, and MDT. ecause esults did not diffe between the left and ight ROI fo each egion (p s >.), esults ae epoted collapsed acoss sides. Fo each ROI, the data wee enteed into thee-way epeated-measue NOVs with taget un (odo o odo ), patten type (taget-elated o stimulus-elated), and time (pe- o poststimulus bin) as factos. Use of a epeated-measues NOV, which is based on within-subject vaiance acoss conditions, effectively eliminated potential confounds that might aise fom between-subject vaiance. sepaate univaiate fmri analysis was also conducted in an effot to identify bain aeas involved in pediction eo coding. To this end, we computed the mean time-seies fo each ROI by aveaging acoss all voxels and tials pe condition, sepaately fo each subject. The maximum value ove a window Neuon 7, , Octobe 6, 11 ª11 Elsevie Inc. 185

9 fom 3 to 6 TRs post-sniff was then computed fo each subject fo each ROI fo each condition, and compaison between expected and unexpected conditions was achieved though paied t tests. Statistical significance citeion fo all compaisons was set at p <.5, with eithe paied t tests (compaison of two conditions) o epeated-measues NOV (compaison of thee o moe conditions), as appopiate. SUPPLEMENTL INFORMTION Supplemental Infomation includes two figues and can be found with this aticle online at doi:1.116/j.neuon CKNOWLEDGMENTS We thank Katheina Haune, Joel Mainland, and M.-Masel Mesulam fo helpful comments and Katie Phillips fo assistance in collecting data. This wok is suppoted by the National Institute on Deafness and Othe Communication Disodes gants 1R1DC114 and K8DC7653 (to J..G.) and F3DC (to C.Z). ccepted: ugust 15, 11 Published: Octobe 5, 11 REFERENCES ensafi, M., Pote, J., Pouliot, S., Mainland, J., Johnson,., Zelano, C., Young, N., emne, E., famian, D., Khan, R., and Sobel, N. (3). 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