Self-Regulation of Regional Cortical Activity Using Real-Time fmri: The Right Inferior Frontal Gyrus and Linguistic Processing

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1 Human Bain Mapping 30: (2009) Self-Regulation of Regional Cotical Activity Using Real-Time fmri: The Right Infeio Fontal Gyus and Linguistic Pocessing Giuseppina Rota, 1,2 * Ranganatha Sitaam, 2 Ralf Veit, 2,3 Michael Eb, 4 Nikolaus Weiskopf, 2,5 Gzegoz Dogil, 1 and Niels Bibaume 2,6 1 Institute fo Natual Language Pocessing, Univesity of Stuttgat, Stuttgat, Gemany 2 Institute fo Medical Psychology and Behavioual Neuobiology, Univesity of Tübingen, Tübingen, Gemany 3 Max Planck Institute fo Biological Cybenetics, Tübingen, Gemany 4 Section of Expeimental MR of the CNS, Depatment of Neuoadiology, Univesity of Tübingen, Tübingen, Gemany 5 Wellcome Tust Cente fo Neuoimaging, Institute of Neuology, Univesity College London, United Kingdom 6 Human Cotical Physiology Section, National Institutes of Health (NIH), NINDS, Bethesda, Mayland Abstact: Neuofeedback of functional magnetic esonance imaging (fmri) can be used to acquie selective contol ove activation in cicumscibed bain aeas, potentially inducing behavioal changes, depending on the functional ole of the tageted cotical sites. In the pesent study, we used fmri-neuofeedback to tain subjects to enhance egional activation in the ight infeio fontal gyus (IFG) to influence speech pocessing and to modulate language-elated pefomance. Seven subjects undewent eal-time fmri-neuofeedback taining and succeeded in achieving voluntay egulation of thei ight Bodmann s aea (BA) 45. To examine shot-tem behavioal impact, two linguistic tasks wee caied out immediately befoe and afte the taining. A significant impovement of accuacy was obseved fo the identification of emotional posodic intonations but not fo syntactic pocessing. This evidence suppots a ole fo the ight IFG in the pocessing of emotional infomation and evaluation of affective salience. The pesent study confims the efficacy of fmri-biofeedback fo noninvasive self-egulation of cicumscibed bain activity. Hum Bain Mapp 30: , VC 2008 Wiley-Liss, Inc. Key wods: opeant conditioning; self-egulation; eal-time functional magnetic esonance imaging; ight infeio fontal gyus; posody Contact gant sponsos: Gaduietenkolleg Spachliche Repäsentationen und ihe Intepetation (Univesity of Stuttgat); Deutsche Foschungsgemeinschaft (DFG), Gemany; and National Institutes of Health (NIH, NINDS), USA. *Coespondence to: Giuseppina Rota, Univesity of Stuttgat, Institute of Natual Language Pocessing, Azenbegstasse 12, 70174, Stuttgat, Gemany. giuseppina.ota@uni-tuebingen.de Received fo publication 28 Januay 2008; Revised 16 May 2008; Accepted 16 May 2008 DOI: /hbm Published online 25 July 2008 in Wiley InteScience (www. intescience.wiley.com). INTRODUCTION Recently, neuofeedback based on functional magnetic esonance imaging (fmri) has emeged as a pomising paadigm in cognitive neuoscience (Sitaam et al., 2007; Weiskopf et al., 2007). Since the 1960s, eseaches have applied biofeedback techniques using electophysiological ecodings (EEG). Evidence demonstating that humans can achieve contol ove diffeent components of the EEG using opeant conditioning paadigms has been collected, and a numbe of clinical applications epoted (Bibaume et al., 1999; Egne and Guzelie, 2003; Hammond, 2005; Mooe, 2000; Pop-Jodanova et al., 2005; Schenk et al., VC 2008 Wiley-Liss, Inc.

2 Rota et al. 2005; Scott et al., 2005; Thompson and Thompson, 1998). Fo instance, self-egulation of slow cotical potentials (SCPs) has been used to suppess epileptic seizues (Kotchoubey et al., 2001) and has been effectively applied to teat clinical impaiments such as the attention deficithypeactivity disode (Fox et al., 2005; Fuchs et al., 2003; Stehl et al., 2006). By means of fmri-biofeedback, humans can lean to contol changes of thei blood oxygen level-dependent (BOLD) signal in cicumscibed bain aeas (Caia et al., 2007; Posse et al., 2003; Weiskopf et al., 2003; Yoo and Jolesz, 2002). This technique is pomising as it could be employed to investigate the functional ole of bain aeas of inteest and to induce desiable behavioal effects associated with the contolled cotical sites (Weiskopf et al., 2004). While numeous pieces of evidence have been collected on the applicability and efficacy of EEG-biofeedback, up to now only little eseach has been conducted using fmri (fo a eview, see Bibaume, 2006). Nevetheless, it has been shown that it is possible to constuct systems that convey individual mental stategies into commands to opeate computes o electomechanical hadwae. Yoo and co-wokes (2004) developed a bain-compute inteface (BCI) based on fmri, which allowed subjects to navigate though a 2D maze, solely by thei thought pocesses. In the pesent study, we employed fmri-neuofeedback to investigate whethe healthy pesons can lean to self-egulate the BOLD esponse in the ight IFG (BA 45) and whethe a voluntay incease of the signal in this egion would modulate specific aspects of language pocessing. Evidence has been collected in favo of a cental ole of Boca s aea in syntactic and semantic pocessing (Fiedeici and Kotz, 2003; Heim, 2005). While the significance of the left IFG has been highlighted by numeous studies on language pocessing, the ole of its contalateal sites still needs to be claified. Clinical evidence has suggested that impaiments of the left fonto-tempoal netwok might induce contalateal aeas to take ove functions peviously caied out by the homologues left-sided bain stuctues (Chapman et al., 2003; Fenandez et al., 2004; Thulbon et al., 1999; Weille et al., 1995). Some studies have indicated the ecuitment of the ight hemisphee duing pocessing of emotional posody (Fiedeici and Alte, 2004; Kotz et al., 2003). Intigued by these findings, and encouaged by esults peviously epoted (Caia et al., 2007; Weiskopf et al., 2004), we used fmri-neuofeedback to tain subjects to contol the level of activation ecoded in the ight IFG. We instucted the subjects to up-egulate this bain egion while identifying emotional posody and pefoming gammaticality judgments immediately befoe and afte the leaning-phase (i.e., the feedback taining). We tested shot-tem behavioal effects of up-egulation upon posodic and syntactic pocessing by compaing the accuacy levels and eaction times pe- and post-taining. On the basis of pevious evidence (Fiedeici and Alte, 2004; Kotz et al., 2003), we hypothesized that an impovement of pefomance would be obseved in vebal-emotional but not in syntactic pocessing. The following two hypotheses wee tested: 1. By means of eal-time fmri taining, paticipants can lean to contol the level of activation in thei ight IFG and voluntaily egulate it. 2. Successful up-egulation of this bain site facilitates the identification of vebal affective infomation. MATERIALS AND METHODS Paticipants Twelve matched males, Geman native speakes (aged yeas, mean age 5 27), ight handed accoding to the Edinbugh Handedness Inventoy (Oldfield, 1971), paticipated in this study. Seven of them wee tained to acquie contol ove the BOLD signal in the ight IFG by means of eal-time fmri feedback. The emaining five wee ecuited as contol subjects. They eceived the same instuctions and undewent the same taining as the expeimental goup, but they could ely on sham-feedback infomation only. None of the subjects had a neuological o psychiatic histoy, heaing impaiment, o was on medication. Each of them had nomal o coected-to-nomal vision. Each paticipant gave witten infomed consent and was paid fo his paticipation in the expeiment. This study was appoved by the Ethics Committee of the Medical Faculty of the Univesity of Tübingen, Gemany. Expeimental Pocedue and Data Analysis The fmri-neuofeedback system employed was based on a 3-T whole body scanne with a standad 8-channel head coil (TIM Tio, Siemens, Elangen, Gemany in combination with the Tubo Bain Voyage softwae Bain Innovation, Maasticht, The Nethelands; Goebel, 2001) and in-house witten scipts unning on Matlab 6.5 (The Math Woks, Natick, MA, USA). Duing the expeiment, paticipants wee lying supine in the scanne. To minimize movement, thei head was fixed within the head coil by means of foam ubbes. Echo-plana images (EPIs) sensitive to the BOLD esponse coveing 16 axial slices wee acquied using an echo-plana imaging sequence (EPI; TR s, matix size, voxel size mm 3, slice gap 5 1 mm, effective echo time (TE) 5 30 ms, flip angle 5 708, bandwidth khz/pixel, slice thickness 5 5 mm). The fist 10 volumes of each session wee excluded fom statistical analysis to allow fo T1- equilibation effects. A T1-weighted stuctual scan of the whole bain was obtained fo each subject and seved as anatomical efeence (MPRage, matix size , 1606

3 Self-Regulation of IFG Activation with tfmri Figue 1. An example of visual feedback displayed to the subjects duing taining. (a) Feedback povided duing baseline blocks. The beginning of each baseline block was signaled by the symbol 1. (b) Feedback pesented duing activation blocks. The beginning of each activation block was signaled by the symbol :. [Colo figue can be viewed in the online issue, which is available at patitions, 1 mm 3 isotopic voxels, TR ms, TE ms, flip angle 5 88). We chose the pas tiangulais of the ight IFG as the taget egion of inteest (ROI taget) fo the expeimental goup and selected it individually by means of a functional localize un (details ae given in the following section). The ROI taget was selected as a squae egion (6 3 6 voxels, mm) centeed on the aea of activation. Offline statistical analysis indicated that the ROI placement was accuate and was epoduced acoss taining sessions within subjects with 1 2 voxels of displacement (mean eo voxels). The mean location acoss subjects in MNI (Monteal Neuological Institute templates; Collins et al., 1994) coodinates fo the cente of the selected ROI taget was x 5 51, y 5 18, z 5 6. We used a lage efeence slice (ROI contol) as contol aea to cancel out global changes of activity and effects due to task-unspecific activation. Duing taining, the mean BOLD signal was extacted fom the ROIs. The diffeential BOLD esponse [(ROItaget 2 ROIcontol) activation blocks 2 (ROI taget 2 ROI contol) baseline blocks] was tansfomed into the visual feedback of vaying gaduations of a themomete (see Fig. 1) and pesented in eal-time to the subjects with video pojection. As the time inteval between the acquisition of new fmri data and the pesentation of its feedback was sufficiently shot (about 1.5 s), subjects could monito in eal-time the efficacy of thei self-egulation. At the end of each taining session, subjects wee vebally asked to epot the cognitive stategies used fo both activation and baseline blocks. The functional data wee pocessed in eal-time with the Tubo Bain Voyage softwae (Bain Innovation, Maasticht, The Nethelands; Goebel, 2001). Pe-pocessing of the EPI data included 3D motion coection and dift emoval (fo a detailed desciption of the neuofeedback system in use in the pesent study, please efe to Weiskopf et al., 2003). Offline data analysis was pefomed using SPM2 (Wellcome Tust Cente fo Neuoimaging, Queens Squae, London, UK) within the famewok of the Geneal Pecentage of signal change ecoded in the ight IFG (MNI 5 51, 18, 6) acoss taining sessions fo expeimental and contol goups. Bas show means and eo bas indicate mean standad eo (SE). A significant incease of the BOLD signal in the ight IFG ( , N 5 4 taining sessions, P onetailed, egession analysis) acoss sessions was detected fo the Figue 2. expeimental goup only and suggests a leaning effect. Diffeential activation in the ROI taget fo session 4 vesus session 1 was obseved fo the expeimental goup only (two-tailed paied t test, N 5 7, P < 0.05). [Colo figue can be viewed in the online issue, which is available at

4 Rota et al. Linea Model (GLM; Fiston et al., 1995). Bain Voyage QX 1.9 (Bain Innovation, Maasticht, The Nethelands) was used fo ROI analysis. Pe-pocessing compised motion coection and nomalization of the EPIs using the MNI templates povided by the Monteal Neuological Institute. The nomalized functional images wee smoothed with a Gaussian kenel with a full width at half maximum (FWHM) of 12 mm. Fist level fixed-effects analyses wee computed fo evey subject. Hemodynamic esponse amplitudes wee estimated using standad egessos, constucted by convolving a boxca function epesenting the block duation, with a canonical hemodynamic esponse function using standad SPM2 paametes. Covaiates deived fom motion paametes wee included in the GLM (Fiston et al., 1996) to suppess potential moto atefacts. A goup fixed-effects analysis was pefomed on all the sessions sepaately fo both expeimental and contol goups (N 5 7 and N 5 5, FWE coected, P < 0.001). Moeove, the incease of signal duing activation blocks vesus baseline blocks was analyzed fo the ROI taget by means of a goup andom effects analysis (ROI analysis, ROI 5 ight BA 45, N 5 7, P < 0.05, FDR coected) pefomed session by session on the expeimental goup. Leaning effects wee investigated by testing whethe the BOLD signal inceased in the ROItaget acoss sessions. Fo both goups, sessions wee numbeed consecutively (i.e., fom 1 to 4), and the session numbes wee coelated with the pecentage of signal change detected in the ROI taget using a linea egession analysis. Moeove, taining-elated effects wee evaluated by computing an ANOVA fo epeated measues fo the pecentage of signal change in the ROI taget acoss sessions fo both goups. The whole expeiment consisted of thee types of sessions: one localize session (efe to the Functional Localize section) peceding the fist taining session, fou taining sessions (efe to the Neuofeedback taining section), and two behavioal test sessions (efe to the Behavioal tasks section). Evaluation of attentional skills and assessment of subjective emotional states wee measued with the d2 Test (Bickenkamp, 1994) and the Positive and Negative Affect Schedule (PANAS, Watson et al., 1988). The Functional Localize The paticipants pefomed a localize un befoe the beginning of the taining. A pecise localization of the ROItaget is cucial to povide subjects with effective neuofeedback-taining. To ely on both anatomical and functional efeences (Weiskopf et al., 2004), we used a linguistic task that eliably activates the pas tiangulais of the ight hemisphee (Dogil et al., 2004). This posodyunelated task allowed us to avoid the isk of a facilitation effect, which might have been induced by pefoming a simila o stictly elated task duing both the localize and the pefomance-evaluation phases. The localize session consisted of fou activation blocks, sepaated by five baseline blocks, beginning and ending with a baseline block. Evey block lasted fo 50 s. The stimuli consisted of 20 balanced Geman sentences with thee syntactic constituents pesented visually by means of video pojection. Duing each activation block, 10 sentences (5 s each) wee pesented without an intestimuli inteval. A total of 40 sentences wee pesented fo the whole localize session (total length of the session min). The subjects wee instucted to ead each sentence silently, to manipulate its wod ode and to eplace the subject noun phase (NP) with a hypeonym (fo details on this task, see Dogil et al., 2004). This task takes advantage of the fact that Geman gamma allows fo a faily boad choice with espect to the syntactic constituent that should be followed by the finite veb (Dogil et al., 2004). We instucted the subjects to stat each sentence by eplacing the initial constituent of the sting. An example of this sentence tansfomation is illustated below: De Schiftstelle wude übe seinen Roman befagt The wite was about his novel questioned. The wite was questioned about his novel Substitution Übe seinen Roman wude de Schiftstelle befagt About his novel was the wite questioned. Neuofeedback-Taining The taining consisted of fou sessions, each of which encompassed six activation blocks (50 s each) sepaated by five baseline blocks (30 s each), beginning and ending with a baseline block (length of each session min). Duing activation blocks, the subjects had to incease the level of activation in the ight IFG (BA 45). Duing baseline blocks, they wee instucted to elax by pefoming mental imagey (e.g., imagining themselves being on a beach with a vast expanse of blue wate). Fo both types of blocks, expeimental subjects eceived feedback of the diffeential BOLD signal detected in the ROI taget (BOLD signal in the ROI taget minus BOLD signal in the ROI contol). Contol subjects eceived sham feedback based on signals taken fom othe bain aeas. Aeas that wee used to extact sham-feedback included the paahippocampal place aea (PPA) and the posteio cingulate cotex. The symbols : and 1 wee pesented on the left side of the themomete to signal the beginning of each activation o baseline block, espectively (see Fig. 1). The same witten infomation explaining the methodology of fmri-neuofeedback, with examples of cognitive stategies was povided to expeimental and contol subjects. Subjects wee instucted to monito online changes of the visual feedback and lean to acquie contol ove the signal, inceasing the level of activation displayed by the themomete duing activation blocks. Fo the expeimental goup, achieving this goal implied finding suitable mental stategies that could eliably incease the level of activation in the ight pas tiangulais. 1608

5 Self-Regulation of IFG Activation with tfmri Behavioal Tasks Stimuli belonging to two behavioal tasks wee divided into two balanced sets (A and B), each of which was pefomed eithe befoe o afte the taining, in a andom but balanced way acoss subjects. Fo half of the subjects, the ode A-B was adopted and fo the othe half the ode B- A. At the end of the taining-phase, subjects wee instucted to focus on the cognitive stategies peviously successfully adopted and to continuously up-egulate BA 45 while caying out the two tasks. No feedback on bain self-egulation was povided to the subject in this phase. Identification of emotional posody was used to test shot-tem taining effect on posodic pocessing. This task consisted of fou sets of Geman sentences belonging to the Tübingen Affect Battey (Beitenstein, 1996), descibing happy, sad, angy, o neutal scenaios, fo a total of 16 samples. Each sentence was ead by a pofessional actess with sad, happy, angy, and neutal emotional intonations, poducing a total of 64 samples. The stings lasted 2 s and wee andomly pesented. The paticipants listened to a sentence at once and wee instucted to identify its emotional intonation in the shotest time possible, within a 4-s limit. Posody judgments wee pefomed by button pessing (i.e., selecting fom a fou-button device the key coesponding to the intended emotional intonation). A fixed inte-tial inteval of 12 s was chosen. At the end of the session, subjects wee debiefed, and thei ability to hea and undestand the auditoy pesented stimuli was confimed. Speeded gammaticality judgments wee used to test shot-tem taining effects on syntactic pocessing. The stimuli consisted of 48 balanced Geman sentences belonging to thee sets: ambiguous, incoect, and coect sentences. The sets of sentences wee appoximately the same length and wee andomly pesented. To contol fo eading stategies, the stings wee povided to the subjects in a segmented and successive manne, and each wod was pesented visually fo 400 ms. The subjects could view just one wod at a time and wee instucted to pefom gammaticality judgments (Meng and Bade, 2000). The citical segment fo deciding about gammatical coectness always appeaed at the end of each sting. Afte the pesentation of the last segment, a question mak signaled to the subjects that they should judge the coectness of the peceding sentence. The judgment task was caied out by button pessing (i.e., ight button fo coect and left button fo incoect sentences). Subjects wee instucted to cay out gammaticality judgment in the shotest time possible, within a 4-s limit. An intetial inteval of 12 s was chosen. A pevious fmri investigation indicated that the identification of emotional posody, as equied by the task hee adopted, elies on the activation of a bilateal cotical netwok that includes the ight IFG (Rota et al., 2008). On the othe hand, no involvement of this bain egion was obseved fo the gammaticality judgment task (Rota, unpublished doctoal dissetation). The tasks wee matched fo difficulty (Rota, unpublished doctoal dissetation). The mean expected accuacy fo the posody identification task was 73% 6 9% (mean accuacy 6 SD); the mean eaction times wee ms (mean RT 6 SD), and fo the gammaticality judgment task 70% 6 10% (mean accuacy 6 SD) and ms (mean RT 6 SD). Fo each task, we measued levels of accuacy and eaction times pe- and post-taining. Stimulus pesentation and collection of esponses wee caied out using the E- pime 1.1 softwae (Schneide et al., 2002). Statistical analysis of the behavioal data was pefomed with the statistical package SPSS 14.0 (SPSS Inc., Chicago, IL). RESULTS All expeimental subjects achieved voluntay diffeential up-egulation of the activation-level ecoded in the ROI taget, as equested by the task. A pogessive incease of the level of activation in the ight BA 45 (mean cente of activation in MNI coodinates 5 51, 18, 6) acoss taining sessions suggests a leaning effect ( ; N 5 4 sessions, P one-tailed; linea egession, see Figs. 2 and 3). A simila but not significant tend was obseved fo the contol goup ( ; N 5 4 sessions; P onetailed, linea egession). Inceased diffeential activation (calculated fo up-egulation blocks minus est) in the ROI taget acoss sessions was obseved fo the expeimental goup [epeated measues ANOVA, F(3,18) , P ] but not fo the contol goup [epeated measues ANOVA, F(3,12) , P ]. Fo the expeimental goup only, fixedeffects analyses showed an inceased level of activation fom session 1 (N 5 7, FWE coected, no activation obseved, P < 0.001) to session 4 (N 5 7, FWE coected, t , P < 0.001). Random effects analyses on the expeimental goup confimed the esults of the fixed-effects analyses by showing an inceased level of activation fo the ROI taget fom session 1 (ROI analysis, ROI 5 ight BA 45, N 5 7, no activation obseved, P < 0.05, FDR coected) to session 4 (ROI analysis, N 5 7, t , P < 0.05, FDR coected). A stable activation acoss sessions was detected in the lage efeence aea fo both goups [(expeimental goup: y (mean % SD of signal-change acoss sessions); contol goup: y (mean % SD of signal-change acoss sessions)]. Besides the ROI taget (see Fig. 3), a numbe of coactivated bain loci wee obseved (N 5 7, andom effect analysis, P < 0.03, uncoected). A small activation cluste (voxels 5 6) was found on the left Rolandic opeculum (t , MNI 5242, 6, 15) duing the fist taining session. The insula was activated bilateally (BA 13, t , MNI 5 33, 12, 12 and t , MNI 5233, 12, 12) duing the second session. The supeio fontal gyus (BA 9, t , MNI 5 57, 18, 27), the supplementay moto aea (BA 1609

6 Rota et al. TABLE I. Activation sites unde voluntay contol as effect of the taining pocess Bain site, Bodmann s aea Coodinates, MNI z value IFG (BA 45), R 51, 18, SMA (BA 6), L 242, 26, SMA (BA 6), R 57,23, MFG, (BA 9), L 251, 9, ACC ( BA 32), R 3, 21, Ceebellum, L 26, 251, STG (BA 22), L 260, 239, Insula, L (BA 13) 242, 12, Insula, R 45, 6, The table shows bain sites diffeentially activated duing the last session as a esult of the eal-time BOLD taining. We listed fo each bain site the coesponding Bodmann s aeas and MNI coodinates. The table depicts z values fo each activated bain site obseved (andom effect analysis ove the last session of taining, N 5 7, P < 0.03, uncoected). We used the WFU PickAtlas (Tzouio-Mazoye et al., 2002) implemented in SPM to pefom anatomical labelling of bain activations. L, left hemisphee; R, ight hemisphee; BA, Bodmann s aea; IFG, infeio fontal gyus; ACC, anteio cingulate cotex; SMA, supplementay moto aea; MFG, medial fontal gyus; STG, supeio tempoal gyus. 6, t , MNI 5248, 0, 39), and the Putamen (t , MNI 5 21, 3, 23) wee activated duing the thid session. The supplementay moto aea (BA 6), the insula bilateally, the left supeio tempoal gyus (BA 22), the left middle fontal gyus (BA 9), the anteio cingulate cotex (ACC, BA 32), and the ceebellum wee activated duing the last taining session (Table I). Each of these bain sites was checked fo a monotonic incease in activation along sessions of taining. Fo none of these clustes, a significant tend was obseved. The absence of a clea monotonic incease of BOLD signal acoss sessions suppots the hypothesis that activation in these aeas does not eflect a taining-elated effect. When debiefed, subjects epoted stategies connected to speech, such as imagination of lectuing befoe a class of students, aguing scenes and debates. Othe stategies included imagined singing, imagined ecitation of poems, and ecalling old convesations with fiends. Expeimental subjects coectly identified 70% 6 13% (mean 6 SD) of the affective posodic stimuli befoe the beginning of the taining and 84% 6 15% (mean 6 SD) afte it. Statistical analysis showed a significant diffeence between the two sets of scoes (two-sided Wilcoxon signed-ank test, P ). Pe-taining RTs wee 3, ms (mean 6 SD), and post-taining RTs wee 2, ms (mean 6 SD). Statistical analyses showed no significant diffeence between the two sets of scoes (tested fo nomality, Shapio-Wilks test, two-sided paied t test, P ). With espect to the gammaticality judgment task, expeimental subjects achieved 49% 6 26% (mean 6 SD) of accuacy befoe the taining and 41% 6 29% (mean 6 SD) afte it. Statistical analysis evealed no significant diffeence between the two levels of accuacy (two-sided Wilcoxon signed-ank test, P ). Pe-taining RTs wee ms (mean 6 SD), and posttaining RTs wee ms (mean 6 SD). Statistical analyses showed no significant diffeence between the two sets of scoes (tested fo nomality, Shapio-Wilks test, two-sided paied t test, P ). Fo a summay of the esults obtained by the expeimental subjects, see Figue 4. Contol subjects identified 74% 6 14% (mean 6 SD) of the affective posodic stimuli befoe the beginning of the taining, and 78% 6 16% (mean 6 SD) afte it. No significant diffeence between the two sets of scoes was found (two-sided Wilcoxon signed-ank test, P ). Pe-taining RTs wee ms (mean 6 SD) and posttaining RTs wee ms (mean 6 SD). Statistical analyses showed no significant diffeence between the two sets of scoes (tested fo nomality, Shapio-Wilks test, two-sided paied t test, P ). With espect to the gammaticality judgment task, contol subjects coectly identified 66% 6 10% (mean 6 SD) of the stimuli befoe the taining and 56% 6 21% (mean 6 SD) of the stimuli afte the taining. Statistical analysis evealed no significant diffeence between the two sets of scoes (two-sided Wilcoxon signed-ank test, P 5 1). Pe-taining RTs wee ms (mean 6 SD) and post-taining RTs wee ms (mean 6 SD). No significant diffeence between the two sets of scoes was obseved (tested fo nomality, Shapio-Wilks test, two-sided paied t test, P ). Details ae given in Figue 5. DISCUSSION In the pesent study, we tested the hypothesis that humans can lean to volitionally incease the BOLD esponses locally in the pas tiangulais of the ight IFG. In all expeimental subjects, the level of activation esticted to the ight BA 45 inceased acoss taining sessions. This esult indicates a pogessive leaning effect and suggests that eal-time fmri-biofeedback is an effective tool fo noninvasively manipulating localized bain activity. Even though both expeimental and contol subjects wee povided with the same stategy guidelines, thei efficacy in up-egulating the ROI taget geatly diffeed. The unavailability of genuine feedback infomation made it impossible fo the contol goup to evaluate the efficacy of the ongoing egulation pocess, thus pesumably impeding the leaning pocess. The compaison of pefomances in the two tasks peand post-taining suggests that up-egulation of BA 45 coelates to a specific impovement in detecting and identifying emotional posodic intonations. This effect was not obseved fo the contol goup. The findings of the pesent study suggest that the ight IFG plays an impotant function in mediating the undestanding of a speake s emotional state and intentions. 1610

7 Self-Regulation of IFG Activation with tfmri Cotical activation maps of the leaning effect obtained by the expeimental goup acoss taining sessions. Statistical paametic maps ae based on a andom effects analysis, N 5 7, P < 0.05 (uncoected fo visualization). ROI taget activation maps ae displayed on a single subject T1 template (MNI coodinate z Figue ) using a spatial mask (mask 5 ight BA 45) constucted with the WFU-PickAltas (Maldjian et al., 2004, 2003) implemented in SPM2. [Colo figue can be viewed in the online issue, which is available at So fa, the ole played by the ight hemisphee, and specifically by the ight BA 45, with espect to language pocessing has been maginally exploed. The pedominance of the left hemisphee fo a multitude of linguistic aspects has been highlighted by numeous clinical studies, stating with the pioneeing woks by Boca and Wenicke. Futhe empiical evidence has been accumulated as neuoimaging tools have been developed (fo a eview, see Démonet et al., 2005). Howeve, the puzzle posed by the ight hemisphee is fa fom being solved, and conclusions about hemispheic specializations and thei ole fo the pocessing of distinct linguistic components ae fa fom being dawn. Impotant insights have been povided by a numbe of clinical neuolinguistic studies. Musso and co-wokes (1999) used Positon Emission Tomogaphy (PET) to investigate shot-tem cotical changes coelated to ecovey fom Wenicke s aphasia. A functional eoganization of Figue 4. Up-egulation of the ight IFG: behavioal effects fo the expeimental goup. Mean levels of accuacy fo gammaticality judgments and posody identification peceding and following BOLDfeedback taining ae shown. A significant impovement was obseved fo detection of affective intonations only (two-sided Wilcoxon signed-ank test, P < 0.05). Bas show means accuacy levels, and eo bas indicate mean SE. [Colo figue can be viewed in the online issue, which is available at wiley.com.] Figue 5. Up-egulation of the ight BA 45: behavioal effects fo the contol goup. Mean levels of accuacy fo gammaticality judgments and identification of posodic intonations peceding and following BOLD-feedback taining ae shown. No significant diffeence was obseved fo gammaticality judgments (two-sided Wilcoxon signed-ank test, P 5 1) and fo identification of affective posody (two-sided Wilcoxon signed-ank test, P ). Bas show levels of means accuacy, and eo bas mean SE. [Colo figue can be viewed in the online issue, which is available at

8 Rota et al. the bain netwok and the ecuitment of contalateal bain sites wee descibed as key factos fo the estoation of lost speech abilities. Real-time fmri feedback offes the possibility of exploing whethe the language system can be sepaately modulated and whethe behavioal domain-specific effects ae tiggeed by this cognitive contol. To ou knowledge, ou study is the fist to addess these impotant topics by using BOLD biofeedback. Diveging conceptualizations exist with espect to the latealization of posodic pocessing in the bain (Gandou, 2000). Coexistence of multiple phonetic cues (such as duation and pitch) and dispaate functions (affective, linguistic, etc.) fo the speech signal makes it aduous to isolate the neuonal substate of speech posody and might be the souce of contadictoy evidence about its bain mapping. A widely suppoted conceptualization highlights the dominant engagement of the ight hemisphee in assessing emotional posody egadless of valence (Dogil, 2003; Wildgube et al., 2005). In a caefully designed expeiment, Gandou and colleagues, (2003) dissociated the neual cicuits esponsible fo the pocessing of emotional and linguistic components of posodic speech. The eseaches took advantage of the fact that in Chinese, both intonation (eithe statement o question) and emotional cues can be signaled though posody. Gandou and colleagues epoted the exclusive ecuitment of pefontal egions (including the IFG) of the ight hemisphee duing the pocessing of emotional posody. Ross (1981) examined patients affected by focal ight hemisphee damage, whose ability to compehend affective posody was impaied, and fomalized the concept of aposodic syndomes. Consistent with these obsevations, futhe clinical studies have suggested that individuals affected by ight hemisphee lesions show a moe pevasive insensitivity to emotive featues of posodic stimuli, (Pell, 2006) and a educed decoding capacity fo emotional aspects of posody (Pell, 2007). Winhuisen and colleagues (2005) conducted an expeiment on post-stoke aphasic patients and utilized epetitive Tanscanial Magnetic Stimulation (TMS) to selectively suppess left and ight IFG activations duing a speech task. By analyzing the patients esponses to both conditions, the authos concluded that fo some of the poststoke aphasics examined ight IFG activation is essential to cay out esidual language functions. The findings of ou expeiment suppot this evidence and ae consistent with a numbe of studies that indicate the involvement of the ight IFG in the pocessing of posodic featues fo auditoily pesented stimuli (Fiedeici and Alte, 2004; Kotz et al., 2003). Following these lines, BOLD-biofeedback taining could potentially be used to stimulate and stengthen linguistic abilities connected to emotional pocessing. The possibility of facilitating the pocessing of emotional speech appeas to be of paticula inteest fo a numbe of clinical applications. As epoted by Hoeket and colleagues (2007), deficits in the pocessing of emotional cues conveyed by speech ae among the most pevasive distubances in psychosis. Clinical evidence suggests that schizophenia coelates with an abnomally educed ceebal blood volume (Bambilla et al., 2007), and hypofunctioning of the pefontal cotices (Snitz et al., 2005). Inteestingly, the ecognition of emotion fom posodic stimuli is also compomised in patient suffeing fom majo depession. Depessed patients ae biased in thei intepetation of neutal emotions (fo both posody and faces) and tend to attibute a negative valence to them (Kan et al., 2004). de Asis and colleagues (2001) found hypoactivation in hippocampal egions and in the dosal ACC fo patients with unipola mood disode. Pieces of evidence have suggested that a educed blood flow, paticulaly in the pefontal egions, could be the souce of executive impaiments in depession (Fossati et al., 2002; Schlosse et al., 2007). Pesumably, these bain sites could be tageted as loci of self-egulation, and neuofeedback aids could be employed to nomalize hypofunctioning cotical netwoks. To what extent eal-time fmri-biofeedback might benefit the teatment of clinical disodes such as schizophenia and depession and facilitate the impovement of cognitive and/o behavioal pefomances in healthy subjects is an impotant topic of investigation that needs to be claified by futue eseach. The compaison of the pefomances in the two tasks pe- and post-taining showed no significant diffeences fo syntactic pocessing. We egisteed low accuacy levels fo gammaticality judgments fo all subjects. Dual task pocessing (i.e., simultaneous self-egulation and pefomance of a behavioal task) might influence negatively behavioal pefomances. Weiskopf and colleagues (2004) documented this phenomenon as they investigated the effects of PPA up-egulation in a memoy task. The subjects wee tained to diffeentially up-egulate the PPA and downegulate the SMA and vice vesa. Thee was a stong intefeence effect duing PPA-up/SMAdown but not duing SMA-up/PPA-down. Contay to the expectations, the incease of activation in the PPA deceased the pefomances duing a memoy task. On the othe hand, no intefeence was obseved duing the SMA up-egulation (i.e., the stategies used to up-egulate the SMA, like moto imagey, wee not in conflict with the encoding of infomation). The gammatical task used in ou expeiment equied a high woking-memoy load: the sentences wee pesented in a fagmented and successive manne, and subjects needed to emembe each wod (fo a total of 14 wods) to judge gammaticality. Subjects engaged in the up-egulation and simultaneously pefomed this task befoe and afte taining. Most subjects used stategies fo up-egulation closely connected to speech and language pocessing. Pesumably, this gammatical task was too esoucedemanding to be pefomed togethe with egulation. The esults of this task do not allow us to daw any conclusions with espect to the effects of the IFG up-egulation 1612

9 Self-Regulation of IFG Activation with tfmri upon syntactic pocessing. Howeve, they povide impotant infomation fo futue eseach with fmri-neuofeedback. The pesent data suggest that while testing behavioal effects of bain egulation, paticula effot should be placed on choosing tasks of low complexity (i.e., that equie low woking-memoy and/o attentional load) to avoid possible intefeence effects. Testing behavioal pefomances of egulation duing sepaate sessions should be consideed as an altenative option. CONCLUSIONS The pesent study indicated that by using BOLD-neuofeedback, subjects can achieve voluntay contol ove activation in the ight IFG. A coelation between its exeted local up-egulation and the impovement of pefomance duing the detection of emotional intonations is suggested. ACKNOWLEDGMENTS We ae indebted to an anonymous eviewe fo his comments on the pevious vesion of this manuscipt. 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