5 Nture Publishing Group http://www.nture.com/ntureneuroscience Structurl nd functionl symmetry of lterl Heschl s gyrus reflects pitch perception preference Peter Schneider, Vness Sluming,, Neil Roberts, Michel Scherg, Riner Goebel, Hns J Specht 5, HGünter Dosch 5, Stefn Bleeck 6, Christoph Stippich & André Rupp The reltive pitch of hrmonic complex sounds, such s instrumentl sounds, my be perceived by decoding either the fundmentl pitch (f ) or the spectrl pitch (f SP ) of the stimuli. We clssified lrge cohort of subjects including symphony orchestr musicins to be either f or, depending on the dominnt perceptul mode. In subgroup of 87 subjects, MRI (mgnetic resonnce imging) nd mgnetoencephlogrphy studies demonstrted strong neurl bsis for both types of pitch perception irrespective of musicl ptitude. Compred with f listeners, possessed pronounced rightwrd, rther thn leftwrd, symmetry of gry mtter volume nd P5m ctivity within the pitch-sensitive lterl Heschl s gyrus. Our dt link reltive hemispheric lterliztion with perceptul stimulus properties, wheres the bsolute size of the Heschl s gyrus depends on musicl ptitude. Pitch perception is n essentil prerequisite for understnding music nd speech intontion. Although there is common greement tht the perceived pitch of hrmonic complex tones like instrumentl sounds or vowels in the singing voice is closely relted to the fundmentl frequency (f ) of the sound spectrum, lrge individul differences in pitch nd timbre perception chllenge this one-to-one reltionship,. In prticulr, if f is not physiclly present, pitch is perceived either s the missing f or s spectrl pitch (f SP ), corresponding to the dominnt perceptul mode (historiclly referred to s synthetic versus nlytic pitch perception, ). At the corticl level, both frequency processing nd pitch perception hve been found to correlte with neurl ctivity chnges in the uditory cortex, relted to different processing stges of hierrchiclly orgnized uditory subres 5. Physicl stimulus properties such s periodicity 6, temporl regulrity 7,8 nd frequency spectrum 9 re encoded in both subcorticl nd corticl structures of the uditory scending pthwy. In primry uditory cortex, sound frequency is represented in mirror-symmetric tonotopic frequency mps 9, by sptiotemporl integrtion.themorecomplexthestimulind the processing tsks, rnging from pitch perception to melody 7, timbre or tonlity processing, the more lterl nd nterior re the min peks of ctivtion in Heschl s gyrus (HG) nd nterior suprtemporl gyrus () 6. Furthermore, the representtion of pitch s perceptul, rther thn physicl, stimulus property ws found to correlte with neurl ctivity chnges in the non-primry uditory cortex 5. Consistent with this finding, numerous functionl imging studies point to the existence of pitch processing center immeditely nterolterl to primry uditory cortex within the lterl Heschl s gyrus (lhg), subserving the processing of fixed pitch 6,pitch chrom 7, pitch slience 5,pitchdirection 8, pitch sequences 9 nd lively pitch. Both reltive hemispheric symmetries 6 nd the bsolute mgnitude of the neurl uditory cortex substrte 7 re importnt in enbling understnding of how brin structure mps with the observed functionl speciliztion. In prticulr, recent functionl imging studies show reltive left-hemispheric speciliztion for rpid temporl processing,5, wheres right uditory cortex shows stronger sensitivity for spectrl processing nd slower temporl processing mode 5. Motivted by these findings of symmetry nd strong mutul correltions between erly uditory evoked ctivity, ntomicl size nd behviorl predisposition in the nteromedil portion of HG 7,we hypothesize here tht f versus f SP perception my serve s predictor reflecting both functionl nd structurl spects of the pitch-sensitive res in lhg. The min purpose of this study ws to investigte (i) individul psychometric differences in f nd f SP perception in reltion to musicl ptitude, (ii) the neurl bsis for type of pitch perception by using MRI nd mgnetoencephlogrphy (MEG) nd (iii) the influence of reltive hemispheric lterliztion versus bsolute mgnitude of both gry mtter volume structurlly nd uditory evoked ctivity functionlly. Deprtment of Neurology, University Hospitl Heidelberg, INF, D-69 Heidelberg, Germny. School of Helth Sciences, Division of Medicl Imging, University of Liverpool, Johnston Building, The Qudrngle Brownlow Hill, Liverpool L69 GB, UK. Mgnetic Resonnce nd Imge Anlysis Reserch Centre (MARIARC), University of Liverpool, Pembroke Plce, PO Box 7, Liverpool, L69 BX, UK. Deprtment of Cognitive Neuroscience, Fculty of Psychology, Universiteit Mstricht, Postbus 66, 6MD Mstricht, The Netherlnds. 5 Deprtment of Physics, University of Heidelberg, Philosophenweg, D-69 Heidelberg, Germny. 6 Institute of Sound nd Vibrtion Reserch, University of Southmpton, University Rod Highfield, Southmpton S7 BJ, UK. Correspondence should be ddressed to P.S. (Peter.Schneider@med.uni-heidelberg.de). Published online August 5; doi:.8/nn5 NATURE NEUROSCIENCE VOLUME 8 [ NUMBER 9 [ SEPTEMBER 5
5 Nture Publishing Group http://www.nture.com/ntureneuroscience Figure Psychometric testing nd grouping. () Experimentl design: prticipnts were required to stte the dominnt direction of pitch shift between tone pirs. Solid lines represent the hrmonics of the test tones nd dshed lines the hrmonics which re not physiclly present, such s the missing fundmentl, indicted s number. (b) Bimodl distribution of fundmentl (f ) nd spectrl pitch (f SP ) listeners. (c,d) Perceptul chnges s function of the coustic vribles. The dependence on frequency (f ) nd lowest order of hrmonics re depicted in seprte curves for stimuli composed of N ¼, nd djcent hrmonics. n indictes the order of hrmonics in complex tone; tht is, n integer multiple of the fundmentl frequency (f SP ¼ n f ). N is the number of physiclly present hrmonics (on the left of ech curve). RESULTS Psychometric testing nd grouping A psychometric pitch test ws designed on the bsis of stndrd methodology, for prmetric rnge tht ws extended with respect to the typicl pitch rnge of musicl instruments. The test required prticipnts to stte the dominnt direction of pitch shift between items in ech of totl of pirs of complex tones with systemtic vrition of frequency (f), order of hrmonics (n) (tht is, multiple integer of the fundmentl frequency (f SP ¼ n f )) nd number (N) of present hrmonics. The stimuli were such tht the perceived direction of the shift in pitch between the two tones ws dependent upon whether they re decoded in f or f SP pitch (Fig. ). Accordingly, for ech individul psychometric symmetry coefficient ws derived by recording the number of occsions of f listening versus f SP listening nd computing n index of pitch perception preference d p ¼ (f f SP ) /(f + f SP ). Anlysis of the psychometric dt of lrge smple of 7 musicins including symphony orchestr musicins 8 nd 8 nonmusicins showed tht d p demonstrted brod bimodl distribution (Fig. b), which llowed for dichotomous clssifiction of ll subjects s belonging to one of two behviorl groups, either f listeners (d p o ) or (d p ). The overll strong seprtion ws most pronounced in the lower (Fig. c, spectrl frequencies o,5 Hz, F,9 ¼ 7., P o.) s compred with the higher spectrl frequency rnge. Furthermore, the tendency to bse direction of pitch judgments on the implied f incresed systemticlly with incresing number (N) of components (Fig. c, F,88 ¼ 98.5, P o.) nd with decresing order (n) of hrmonic number (Fig. d, F,88 ¼ 5.8, P o.). The seprtion of f nd ws such tht twocomponent stimulus (N ¼ ) hd even stronger fundmentl pitch chrcter for f listeners s four-component stimulus (N ¼ ) hd for. Neurl bsis of pitch perception MRI of brin structure nd functionl MEG of neurl ctivity in response to hrmonic complex tones were performed in subgroup of f nd 5 nd demonstrted strong neurl bsis for type of pitch perception. The individul surfces of ll 87 left nd right uditory cortices were segmented nd reconstructed three dimensionlly from the T-weighted MRI slices (Fig. ). The pronounced oblique crescent-shped gyrl entity in nterior uditory cortex, including HG in its mediolterl extent nd nterolterlly, ws lwys identified by detection of the first complete Heschl s sulcus (chs) s posterior boundry of HG nd the first trnsverse sulcus (FTS) s the nterior boundry (Fig. b d, red). HG my include incomplete duplictions by sulcus intermedius (SI) 9 indenting loclly its crown or medil Heschl s sulcus (mhs), not reching the lterl end. We next clculted the gry mtter volume long the medil-lterl-nterior progression of this nterior gyrus (Fig. b, dshed lines), by mrking the corresponding gry vlues successively c.5.5 5 n 5 ms N Pitch test Tone Tone f SP f f listeners 6 5 Complex tones b 5 5.5..79..9. Averge spectrl frequency (khz) f listeners < >.5.5 Index of pitch perception preference in cross-sectionl slices perpendiculr to the orienttion of HG nd. Overll, the gry mtter volume incresed successively from to(fig. e,f). When compring the volumes of the left nd the right hemispheres, we found chrcteristic symmetry exclusively within the lterl spect of HG irrespective of musicl ptitude. The f listeners demonstrted pronounced leftwrd symmetry (Fig. e), wheres demonstrted pronounced rightwrd symmetry (Fig. f). The symmetry strted t the lterl border of, peked within the lterl edge of HG nd ws bsent in. This structurl symmetry ws prlleled by corresponding functionl symmetry. In prticulr, we performed n MEG study in which subjects were instructed to listen pssively to hrmonic complex tones covering the lrge prmetric rnge of the pitch test. Auditory evoked fields were recorded continuously over both hemispheres. The source ctivity ws clculted from the sensor distribution by modeling one equivlent dipole in ech hemisphere. When fitted to the secondry P5m response peking 5 ms fter tone onset (P5m), the dipoles loclized in the lterl portion of HG in most cses. Figure g,h shows the group-verged source wveforms for professionls nd non-musicins. P5m mgnitude ws lrger in the left hemisphere for f listeners (professionls: fctor. ±., F, ¼ 6., P o.; non-musicins: fctor.5 ±., F,9 ¼.5, P o.) nd in the right hemisphere for (professionls: fctor. ±., F,9 ¼., P o.; non-musicins: fctor.6 ±., F,9 ¼ 7.7, P o.). No significnt hemispheric symmetry ws observed for the erly Pm (ref. 7) nd the pitch-sensitive Nm response,. Morphometry of uditory cortex subregions Bsed on this specific connection of structurl nd functionl symmetry in reltion to pitch perception, we identified objective criteri to define lhg. After normliztion, grnd-verge uditory cortex d.5.5 N f listeners 7 Lowest hrmonic number n VOLUME 8 [ NUMBER 9 [ SEPTEMBER 5 NATURE NEUROSCIENCE
5 Nture Publishing Group http://www.nture.com/ntureneuroscience e Volume of -mm slices (cm ) g Dipole mplitude (nam).8.6.. 5 mp of ll 87 brins ws clculted from the individul lndmrks of FTS, chs nd posterior border of plnum temporle (PT) 5.Thetop view of this mp is depicted in Figure. Despite lrge individul differences in shpe nd progression of HG, the grnd verge over ll 87 right nd left uditory cortices demonstrted completely symmetric orgniztion with respect to ngultion, extent nd trnsition from HG to. However, the PT clerly showed the expected leftwrd symmetry. Secondly, functionl ctivtion peks in reltion to pitch perception 8,5 7,9,,,6 were plotted on this verged uditory cortex mp (Fig., mgnified HG). The min ctivtion peks concerning pitch perception re ll confined to the lterl portion of HG (x-rnge: ± 5 to ± 65; y-rnge: to ). Melody-specific L ctivtion 7,,6, origintes more nterior 5 (y ) in. Our own findings on lterliztion (Fig. e,f), the current knowledge of primry uditory cortex extent 6,9,7 f listeners 7 Direction of HG/ (mm) f listeners 5 Time (ms) P5m 5 nd the functionl seprtion of djcent pitch-sensitive res 7 were used s criteri to define objective boundries of lhg: (i) line perpendiculr to the progression of HG t the mediolterl two-thirds to seprte the region of nd lhg; (ii) line t y ¼ to seprte the region AC b Anterior Posterior f Volume of -mm slices (cm ) h Dipole mplitude (nam).8.6.. c FTS SI mhs 7 Direction of HG/ (mm) d 5 Time (ms) chs P5m y (mm) Figure Neurl bsis of fundmentl nd spectrl pitch perception. () D reconstruction of n individul uditory cortex nd uditory evoked ctivity (blue nd red dipoles). (b d) The top view of three individul D surfce reconstructions of right uditory cortex shows the pronounced gyrl entity including HG nd (colored red), bordered nteriorly by the first trnsverse sulcus (FTS) nd posteriorly by the first complete Heschl s sulcus (chs). HG my include sulcus intermedius (SI), indenting loclly the crown of HG, or medil Heschl s sulcus (mhs), not reching the lterl end. Gry mtter volume ws successively clculted in cross-sectionl slices long the medil-lterl-nterior progression. (e,f) Fundmentl pitch listeners demonstrted pronounced leftwrd symmetry of gry mtter volume nd spectrl pitch listeners rightwrd symmetry, peking within the lterl one-third of HG. (g,h) Functionl symmetry of the uditory evoked P5m source ctivity of lhg in response to hrmonic complex tones. P5m mgnitude ws reltively lrger in the left hemisphere for f listeners nd vice vers for, irrespective of musicl ptitude., professionl musicin; non, non-musicin, in ll figures. of lhg (y o, highlighted) nd (y, colored in Fig. ). By strict ppliction of these boundry definitions, the gry mtter volumes of, lhg, nd PT were clculted. Only lhg demonstrted strong leftwrd symmetry in f listeners nd rightwrd symmetry in (Tble ). The individul uditory cortex morphology of professionl musicins, eight mteur musicins nd eight non-musicins (Fig. ) illustrtes (i) the lrge individul differences with respect to ngultion nd progression of HG, (ii) the differences in structurl left-right symmetry of lhg in reltion to pitch perception nd (iii) the structurl enlrgement of the entire nterior crescent-shped gyrus in musicins s compred with nonmusicins. The frequency of duplictions or sulci depends on hemisphere nd on perceptul preference (Tble ). Structurl, functionl nd perceptul symmetry Corresponding to the definition of perceptul symmetry, the structurl nd functionl symmetry of lhg ws mesured in terms of structurl symmetry index d s ¼ (R lhg L lhg )/(R lhg +L lhg ) nd functionl P5m symmetry index d f ¼ (R P5m L P5m )/(R P5m + L P5m ). The correltion of d s versus d p ws clculted seprtely by systemticlly including or excluding HG duplictions: (i) ll duplictions including complete posterior duplictions (PDs) were included PD PT FTS SI, mhs chs x (mm) 6 5 5 6 L PT p R R Tonlity Melody condition 7 Spectrl vs. temporl vrition Melody vs. fixed pitch 6 Pitch chrom 7 Spectrl vrition Fixed pitch vs. noise 6 Pitch chnge 9 Pitch slience 5 P5m hrmonic complex tones Lively vs. fixed pitch Temporl regulrity 8 Pitch onset response 6 Figure Averged lndmrks of 87 uditory cortices (top view, stndrd stereotxic coordintes ; line width of the dshed lndmrks corresponds to verged s.e.m.). The crescent-shped nterior gyrus including HG nd nterior suprtemporl gyrus () showed completely symmetric shpe nd progression with respect to ngultion, extent, duplictions nd curvture. A complete posterior dupliction (PD) ws considered to be prt of the plnum temporle (PT). The min ctivtion peks of functionl imging studies re plotted on the mgnified mp. Blck open circles indicte the verged locliztion of the uditory evoked P5m response in lhg mesured by MEG. Pitch-specific ctivtion loclized in lhg, melody-specific ctivtion more nterior in. In key t right, superscript numbers refer to references. NATURE NEUROSCIENCE VOLUME 8 [ NUMBER 9 [ SEPTEMBER 5
5 Nture Publishing Group http://www.nture.com/ntureneuroscience Tble Gry mtter volume of uditory cortex subregions (r ¼.7, P o.); (ii) right nd left PD s were excluded; tht is, chs ws lwys the posterior boundry (r ¼.77, P o.); (iii) only left PDs were excluded, (r ¼.8, P o.); (iv) ll duplictions posterior to chs nd mhs were excluded (r ¼.7, P o.); or (v) ll duplictions posterior to chs, mhs nd SI were excluded; tht is, the nterior HG 7 ws considered (r ¼.8, P o.). Overll, the correltion remined strongly robust irrespective of inclusion or exclusion of duplictions. However, with respect to symmetric definition of boundries, the effect ws most pronounced if chs ws lwys the posterior boundry (cse, Fig. 5). The sctter plot of P5m symmetry (d f ) versus pitch perception symmetry (d p ) demonstrted gin robust effect (r ¼.6, P o., Fig. 5b). As consequence, structurl nd functionl symmetry of lhg ws strongly linked (r ¼.55, P o.). However, if bsolute mgnitude of the neurl substrte ws considered insted of the reltive hemispheric symmetries, the correltion dropped L to insignificnce (P5m dipole mplitude versus gry mtter volume of lhg: r ¼., n.s.). Influence of musicl bility With respect to the bsolute mgnitude of the neurl lhg substrte, lrge group-specific differences were found, corroborting nd extending erlier findings 7. The crescentshped nterior convolution of uditory cortex including, lhg nd, colored in red (right hemisphere) nd in blue (left hemisphere, Figs. b d nd ), demonstrted strongly enlrged gry mtter volume in professionl musicins s compred with nonmusicins (Tble ). The gry mtter volume correlted significntly with musicl ptitude s mesured by the Advnced Mesure of Music Audition (AMMA) test 7, (lhg: r ¼.7, P o.). Furthermore, the uditory evoked P5m response showed fivefold lrger mgnitude in professionls s compred with non-musicins (Fig. e,f;professionl: 5. ±.9 nam, non-musicin: 5. ±. nam, fctor.7 ±.8, F,85 ¼ 5., P o.) nd correlted with the intensity of musicl prctice during the lst ten yers (r ¼.8, P o.). No significnt f prof () f SP prof () f non () f SP non () vs. non Left hemisphere L. ±.7.6 ±.6.7 ±.5.7 ±.6 *** lhg L (highlighted).9 ±.***.67 ±.9. ±.6**.87 ±. *** L 5. ±. 5. ±..8 ±.6.7 ±. *** PT L. ±.*.8 ±.8**.6 ±..59 ±.* n.s. Right hemisphere R.5 ±.7.7 ±.6.6 ±..79 ±.7 *** lhg R (highlighted).6 ±.. ±.**.7 ±.. ±.9** *** R 5.9 ±..55 ±..9 ±.6.5 ±. *** PT R. ±..65 ±.6.6 ±.9.58 ±.5 n.s. *P o.5, **P o., ***P o. ANOVA, left versus right hemisphere (designting the dominnt hemisphere), vs. non, overll significnce of professionls versus non-musicins)., medil Heschl s gyrus; lhg, lterl Heschl s gyrus;, nterior suprtemporl gyrus; PT, plnum temporle. Vlues: men (cm ) ± s.e.m., stndrd stereotctic voxel size 9., professionl musicin., non-musicin; n.s., not significnt. f listeners, musicins correltion ws found between ny musicl bility prmeters nd neurl (d f, d s )orperceptul(d p ) symmetries. As consequence, the correltions shown in Figure 5,b remined strong for the non-musicins (d s versus d p : r ¼.75, P o.; d f versus d p : r ¼.67, P o.). DISCUSSION Appliction of n uditory judgment tsk tht is known to produce lrge perceptul differences cross individuls, in the investigtion of lrge smple of musicins nd non-musicins enbled systemtic ctegoriztion in f nd. The f listeners tended to bse direction of pitch chnge judgments on the implied fundmentl frequency, wheres the performed the pitch chnge f listeners, non-musicins, musicins, non-musicins Figure Individul HG morphology. f listeners demonstrte lrger left lhg nd lrger right lhg in most cses (lhg highlighted, red nd blue rrows). The occurrence of sulci nd duplictions (SI, sterisks; mhs, + symbols; PD, blck open circles) depends on hemisphere nd pitch perception preference. essionl musicins nd mteurs (A) showed greter gry mtter volume of the entire nterior convolution including HG nd (colored structure) thn non-musicins (bottom). R VOLUME 8 [ NUMBER 9 [ SEPTEMBER 5 NATURE NEUROSCIENCE
5 Nture Publishing Group http://www.nture.com/ntureneuroscience Tble Frequency of HG duplictions nd sulci SI mhs PD Single HG f listener () Only right HG 6 5 Only left HG 6 6 Left nd right HG 9 Without f SP listener (5) Only right HG 9 9 6 Only left HG 6 Left nd right HG 6 Without 9 7 9 SI, sulcus intermedius; mhs medil Heschl s sulcus; PD, complete posterior dupliction. The frequency of HG duplictions or sulci (given by the number of observed cses from ll 87 subjects) depends on hemisphere nd on perceptul preference. In prticulr, for ll 9 cses where either in the left or in the right hemisphere SI ws present, the frequency differed significntly for s compred to f listeners (w () ¼.9, P o.). judgment on the bsis of the spectrl envelope rther thn fundmentl frequency. By using MRI nd MEG we found strong neurl bsis of both types of pitch perception, which corroborted the functionl speciliztion of left uditory cortex for rpid temporl,5 nd the right hemisphere for spectrl processing. The pitch test llowed systemtic nlysis of the influence of coustic stimulus properties on pitch perception. First, the seprtion of f nd ws much stronger within spectrl frequency rnge below,5 Hz nd decresed towrds the higher frequencies. This my be reflected in the psychometric dominnce principle, stting tht the center of hrmonic order which is dominnt for pitch perception decreses from n ¼ 5(f ¼ Hz) to n ¼ (f ¼, Hz). Second, the generl increse of f dominnce with decresing n nd incresing N (Fig. c,d) corrobortes the current knowledge of fundmentl pitch sliency,,. However, our dt emphsize tht pitch perception depends on both spectrl envelope nd fundmentl frequency informtion with different weighting nd cnnot be explined by simple one-to-one reltionship between perceived pitch nd fundmentl frequency 6,. A functionl seprtion of periodicity coding nd spectrl integrtion t the level of uditory cortex my ccount for the different pitch percepts, vrying between individuls by up to three or four octves, when the sme sound ws presented. The lrge perceptul dissimilrity in pitch perception ws prlleled by strong inter-individul structurl nd functionl vribility in uditory cortex. To visulize this pronounced vrition, which ws nticipted long time go from myelogenetic studies,wedepicted for the first time the full shpe nd progression of HG nd, forming together crescent-shped gyrl entity of the nterolterl strem in humn uditory cortex. The huge morphologicl differences with respect to ngultion, extent of HG nd its oblique trnsition towrds were superposed by conspicuous increse of gry mtter volume in musicns 7, (Fig. ). Averged over 87 subjects, the shpe ws completely symmetric, wheres some morphometric studies show symmetric verge mps 9,. However, these nd our studies re not sufficiently comprble owing to differences in smple size, definition of boundries nd extent of the region of interest. Furthermore, detiled morphometric nlysis showed tht the correltion between preference of f versus f SP perception nd neurl symmetry ws confined to lhg nd ws not present for the entire body of HG or. In prticulr, f listeners demonstrted n symmetry fvoring the left lhg in terms of both corticl gry mtter volume nd uditory evoked P5m ctivity, wheres showed the opposite symmetry. This corroborted the functionl speciliztion of lhg s pitch processing center.ourresultsimply left-hemispheric speciliztion for (missing) fundmentl pitch perception nd right hemispheric speciliztion for spectrl pitch perception, consistent with recent functionl imging study compring the neurl processing of spectrl nd temporl vrition. Furthermore, left uditory cortex is sensitive to short time scles (5 5 ms) 5, nd right uditory cortex to slower time scles ( ms) 5. The fundmentl pitch (f ) of n instrumentl sound (f 5 Hz) reflects its periodicity 6 T ¼ / f,corresponding to time segments shorter thn ms. Thus, the existence of two pitch centers my fcilitte the extrction of fundmentl pitch in left uditory cortex nd spectrl pitch in right uditory cortex. Indeed, most professionl musicins perceive simultneously both fundmentl nd spectrl pitch from n mbiguous tone, nd the subjective differences re rther reltive thn bsolute. Here, these reltive perceptul differences were found to correlte strongly to neurl symmetries, s nticipted by erlier studies on cerebrl dominnce 5. Thus, greter volume on the left my predispose one to her the f in n mbiguous tone, nd vice vers, greter volume on the right my led to dominnt perception of spectrl pitch or single hrmonics. A psychophysicl study on ptients with temporl lobe lesions demonstrtes fourfold higher thresholds for determining the direction of pitch chnges in ptients with right hemisphere lesions tht encroched on HG. This study concludes tht detecting the direction of pitch chnges my depend lrgely on the right HG 8. However, there is no conflict with our results, becuse the mgnitudes of pitch chnges used in our study were lrgely bove the f discrimintion thresholds investigted in the lesion study. Thus, the ltter my reflect in prticulr the ccurcy of pitch direction judgment reltive to the mgnitude of f discrimintion, irrespective of generl left-right hemispheric lterliztion effects in pitch perception. The direct link between structurl nd functionl symmetries reported here seems to be confined to locl mechnism within the pitch center of lterl HG, present only in smll time rnge of ms round P5m ctivity of the MEG recordings. The min ctivtion peks from comprble fmri 5,6 studies depict the ctivity within much lrger time frme of severl seconds, including other ctivities which originte prtilly from lterl HG, in prticulr the pitchsensitive N ctivity, nd the pitch onset response 6 occurring bout ms fter tone onset. Overll, functionl symmetries re not lwys observed in every tsk, subject, stimulus condition or specified δ s...5 f listeners f listeners Musicins -musicins.5.5.5.5 b δ f...5 Musicins -musicins Figure 5 Pitch perception preference nd neurl symmetries. () Correltion of pitch symmetry (d p ) versus structurl symmetry (d s ) of gry mtter in lhg. (b) Correltion of pitch symmetry (d p ) versus functionl symmetry (d f ) of P5m mgnitude. The correltions re strong irrespective of musicl ptitude. NATURE NEUROSCIENCE VOLUME 8 [ NUMBER 9 [ SEPTEMBER 5 5
5 Nture Publishing Group http://www.nture.com/ntureneuroscience processing level. In some cses or individuls the ctivtion mps relly re symmetric,6,. However, with respect to pitch- or melodyrelted tsks, the mjority of functionl imging studies,6,, showed right-sided symmetries. Multimodl functionl imging with professionl musicins my help to clrify under which conditions the observed pitch symmetries rise. Our findings demonstrte strong correltion between the reltive hemispheric lterliztion of structure nd function nd perceptul preference, s confirmed by morphometric,5,6 nd functionl imging studies 5. In contrst, bsolute mgnitudes of the neurl HG substrte depend on musicl expertise consistent with previous studies 7,,7,8. At more fundmentl level, recent post-mortem study observed chrcteristic symmetries in uditory belt res t the level of the underlying microntomicl rchitecture 6. However, the exct reltion between bsolute chnges t the microntomicl nd mcrontomicl level still remins uncler nd needs further clrifiction. Use-dependent subcorticl chnges such s dendritic rboriztion chnges or interdigittion of neuronl clusters 6 my enhnce the mgnitude of synchronized postsynptic potentils s mesured by MEG in professionl musicins without chnging, however, the corticl thickness or volume of the underlying gry mtter tissue. Likewise, lrger HG gry mtter volume implies lrger neurl network per se, independent of neurl connectivity, nd my reflect greter potentil of musicl ptitude. A strong reltion between bsolute mgnitudes of structure nd function ws observed t the erly utomtic processing level in nteromedil HG 7 nd obviously disppers in secondry uditory cortex. Post-mortem studies 9, showed considerble vrition between structure nd function when compring the boundries of individul microntomicl structure nd mcrontomicl visible mgnetic resonnce lndmrks. These results suggest tht the functionl res do not correspond to res defined on the bsis of mcroscopic boundries. Nevertheless, when clculting micro- nd mcrontomicl probbility mps, the corresponding centroids of the loction were found to be lmost identicl,6,9.asconsequence, despite lrge individul vribility 9, the medil two-thirds of nterior HG were considered relibly good pproximtion of the nterolterl extent of primry uditory cortex 6,,7, s confirmed by cytorchitectonic 8, histochemicl 9 nd myelogenetic studies. Overll, we conclude tht the reltive hemispheric lterliztion of functionl nd structurl size reflects the type of pitch processing irrespective of musicl ptitude, wheres the bsolute mgnitudes of the neurl HG substrte depends on musicl expertise. Further studies my clrify whether the observed lterliztion is linked to preference for chrcteristic physicl sound properties (in prticulr, the fster temporl structure of percussive sounds versus the slower time scle of sustined sounds 5,9,5 ) therefore influencing musicl instrument preference nd musicl performnce. METHODS Subjects. A lrge smple of right hnded helthy subjects (5 professionl musicins including members of the Royl Liverpool Philhrmonic Orchestr 8, 8 grdute students in music, 66 mteur musicins nd 8 nonmusicins) were recruited for the psychometric evlution of pitch perception nd evlution of musicl ptitude. A subgroup of 87 subjects prticipted in the MRI nd MEG mesurements (out of 5 professionls, including members of the Royl Liverpool Philhrmonic Orchestr, 6 mteurs nd non-musicins, were f nd 5 ). Averged over the groups, no significnt differences in ge, sex nd hed size were observed. Experimentl procedures were pproved by the relevnt locl reserch ethics committee. Pitch test. The pitch test included different pirs of hrmonic complex tones. Ech tone pir consisted of two consecutive hrmonic complex tones (durtion 5 ms, -ms rise-fll time, interstimulus intervl 5 ms). Ech test tone comprised two, three or four djcent hrmonics, leving out the fundmentl frequency. Overll, the tone pirs were designed with six different upper component frequencies (9, 5, 9,,66,,96 nd 5,7 Hz) chosen to be equidistnt on logrithmicl frequency scle corresponding to the musicl intervl of mjor ninth, beginning with D (9 Hz) up to C8 (5,7 Hz). The upper component frequency of both tones in ech tone pir ws identicl to minimize the perception of edge pitch. Furthermore, the lowest presented hrmonic number trnsitions (n,min - n,min ) within tone pir ws one of the following four conditions: -, -, - 6or7-9. Thus, the spectrl components rnged between 6 nd 5,7 Hz nd f between 9 to,8 Hz. The mgnitude of f pitch chnges rnged between fctor of. (mjor second) to.8 (minor seventh); the f SP pitch chnges of the lowest hrmonic number rnged from fctor of. to.. Thus, the mgnitude of these pitch chnges ws considerbly lrger thn pitch discrimintion threshold 8. By using dditionlly complete hrmonic complex tones (n min ¼ ) s reference tones (conditions -, -, - nd5- ), the pitch test llowed detection of octve-shifted fundmentl pitches (for instnce, one octve bove f ). This cse occurred only significntly for three-component stimuli within the higher spectrl rnge (, Hz) nd ws not considered to be prt of f perception. However, if fundmentl pitch perception would men both f nd octve-shifted f perception, our results would not qulittively chnge. All stimuli were presented binurlly in pseudorndomized order using Hmmerfll DSP Multifce System with stimulus level of 5 db nsl to void the interfering superposition of combintion tones. Ech tone pir ws repeted once nd the next new tone pir presented fter puse of s. Subjects were instructed to select the dominnt pitch direction or to nswer ccording to the first, spontneous impression, if either both directions were perceived t the sme time or if tones lcked cler pitch. Test durtion ws min. All subjects were tested on n identicl set of stimuli. A subgroup of 7 subjects repeted the pitch test bout 6 months lter nd demonstrted strong individul re-test relibility (r ¼.96, P o.). Morphometry. The three-dimensionl (D) gry mtter surfce reconstructions of ll individul uditory cortices were clculted from T-weighted structurl MRI dt (Siemens, Symphony,.5-T) fter segmenttion using BrinVoyger softwre (Brin Innovtion). All brins were rotted in direction of the ntero-posterior commissurl line nd normlized by unfiltered trnsformtion in Tlirch spce. Using stndrd definitions of the ntomicl uditory cortex lndmrks 9,5,7, the sgittl MRI slices of the individul uditory cortices were segmented long the Sylvin fissure to obtin PT, HG nd. The inclusion rnge of imge gry vlues ws clculted in normlized box round left nd right uditory cortex. For gry mtter surfce reconstruction nd morphometry, the gry vlue inclusion rnge ws defined individully from the intensity histogrm of gry vlues for ech left nd right uditory cortex, by identifying (i) the hlf-mplitude side-lobe of the gry mtter pek distribution towrds cerebrl spinl fluid nd (ii) the sddle point between the gry nd white mtter pek. All gry vlue voxels inside this inclusion rnge were mrked nd used for D reconstruction nd morphometry. The non-utomted prts of this structurl nlysis (in prticulr, the identifiction of individul lndmrks from the individul D surfce reconstructions of uditory cortex) were obtined by observers who were blind to subject group nd hemisphere. HG subregions. Here we used the most obvious nd well-ccepted definition of HG 9, by identifying the first complete Heschl s sulcus (chs) s its posterior nd the crescent-shped first trnsverse sulcus (FTS) 9 s its nterior boundry. chs ws identified by virtue of hving cler lterl indenttion (Fig. d), lrge mediolterl extent nd pronounced depth, nd divided uditory cortex in two prts: (i) n nterior uditory strem including HG nd nd (ii) posterior strem including the PT. Bsed on normliztion, the pronounced crescent-shped gyrus nterior to chs ws subdivided systemticlly in, lhg nd. By using functionl nd structurl criteri (Fig. ), the y ¼ line ws found to be n pproprite borderline to seprte HG nd. Individul extrpoltion of FTS towrds the lterl end of HG, s proposed by some morphometric studies,,7, ws impossible in our smple owing to lrge individul differences with respect to ngultion nd 6 VOLUME 8 [ NUMBER 9 [ SEPTEMBER 5 NATURE NEUROSCIENCE
5 Nture Publishing Group http://www.nture.com/ntureneuroscience symmetric progression (Fig. ). The extent of ws defined by the medil two-thirds of HG long the mediolterl direction of HG, similr to the estimted extent of primry uditory cortex 6,9,. lhg ws the remining prt of the gyrus between nd. The gry mtter volume of ech specified subregion ws clculted by mrking nd counting ll included gry vlues of the individul gry mtter pek distribution (see bove). Finlly, the volume of lhg ws the difference between the volumes of HG nd. Mgnetoencephlogrphy. Using Neuromg- whole-hed MEG system, we recorded uditory evoked fields to twelve hrmonic complex sounds covering the prmetric rnge s used for the pitch test (f : nd 5 Hz, lowest number of hrmonics:, nd, complete spectrum nd three djcent hrmonics). Subjects were instructed to listen pssively to the sounds, ech of which ws presented times in pseudorndomized order. Corticl responses were verged for ech frequency using the BESA progrm (MEGIS Softwre) nd collpsed into n individul grnd verge for source nlysis (,6 verges). The source ctivity of the uditory evoked P5m response ws seprted from the erlier Pm nd lter Nm response by sptiotemporl source modeling 7, using one equivlent dipole in ech hemisphere. The fitting intervls were djusted to the individul source wveforms in time intervls round the peks defined by their hlf side lobes. Signl strength ws clculted for ech pek reltive to ms bseline. ACKNOWLEDGMENTS We thnk K. Srtor for providing the D-MRI in Heidelberg, the rdiogrphic stff t MARIARC for ssistnce with MRI dt cquisition in Liverpool nd E. Hofmnn (Music Acdemy, Bsel); D. Geller, R. Schmitt nd T. vn der Geld (University of Music nd Performing Arts, Mnnheim); C. Klein (Institute of Music Pedgogy, Hlle) nd D. Schmidt (Conservtory of Music nd Performing Arts, Stuttgrt) for ssistnce with collecting the psychometric dt. COMPETING INTERESTS STATEMENT The uthors declre tht they hve no competing finncil interests. Received 5 April; ccepted 8 July 5 Published online t http://www.nture.com/ntureneuroscience/. Smoorenburg, G.F. Pitch perception of two-frequency stimuli. J. Acoust. Soc. Am. 8, 9 9 (97).. Lguitton, V., Demny, L., Seml, C. & Liégeois-Chuvel, C. Pitch perception: difference between right-nd left-hnded listeners. Neuropsychologi 6, 7 (998).. von Helmholtz, H.L.F. On the Senstions of Tone (Longmns, London, 885).. Terhrdt, E. Pitch, consonnce nd hrmony. J. Acoust. Soc. Am. 55, 6 69 (97). 5. Wessinger, C.M. et l. Hierrchicl orgniztion of the humn uditory cortex reveled by functionl mgnetic resonnce imging. J. Cogn. Neurosci., 7 (). 6. Lngner, G. Periodicity coding in the uditory system. Her. Res. 6, 5 (99). 7. Griffiths, T.D., Büchel, C., Frckowik, R.S.J. & Ptterson, R.D. Anlysis of temporl structure in sound by the humn brin. Nt. Neurosci., 7 (998). 8. Gutschlk, A., Ptterson, R.D., Rupp, A., Uppenkmp, S. & Scherg, M. Sustined mgnetic fields revel seprte sites for sound level nd temporl regulrity in humn uditory cortex. Neuroimge 5, 7 6 (). 9. Formisno, E. et l. Mirror-symmetric tonotopic mps in humn primry uditory cortex. Neuron, 859 869 ().. Pntev, C., Hoke, M., Lütkenhöner, B. & Lehnerz, K. Tonotopic orgniztion of the uditorycortex:pitchversusfrequencyrepresenttion.science 6, 86 88 (989).. Seifritz, E. et l. Sptiotemporl pttern of neurl processing in the humn uditory cortex. Science 97, 76 78 ().. Griffiths, T.D. Functionl imging of pitch nlysis. Ann. NY Acd. Sci. 999, 9 ().. Jnt, P. et l. The corticl topogrphy of tonl structures underlying western music. Science 98, 67 7 ().. Hll, D. et l. Spectrl nd temporl processing in humn uditory cortex. Cereb. Cortex, 9 (). 5. Pengos, H., Melcher, J.R. & Oxenhm, A.J. A neurl representtion of pitch slience in nonprimry humn uditory cortex reveled with functionl mgnetic resonnce imging. J. Neurosci., 68 685 (). 6. Ptterson, R.D., Uppenkmp, S., Johnsrude, I.S. & Griffiths, T.D. The processing of temporl pitch nd melody informtion in uditory cortex. Neuron 6, 767 776 (). 7. Wrren, J.D., Uppenkmp, S., Ptterson, R. & Griffiths, T.D. Seprting pitch chrom nd pitch height in the humn brin. Proc. Ntl. Acd. Sci. USA, 8 (). 8. Johnsrude, I.S., Penhune, V.B. & Ztorre, R.J. Functionl specificity in the right humn uditory cortex for perceiving pitch direction. Brin, 55 6 (). 9. Wrren, J.D. & Griffiths, T.D. Distinct mechnisms for processing sptil sequences nd pitch sequences in the humn uditory brin. J. Neurosci., 5799 58 ().. Griffiths, T.D., Uppenkmp, S., Johnsrude, I., Josephs, O. & Ptterson, R.D. Encoding of the temporl regulrity of sound in the humn brinstem. Nt. Neurosci., 6 67 ().. Tervniemi, M. Lterliztion of uditory-cortex functions. Brin Res. Brin Res. Rev., 6 ().. Devlin, J.T. et l. Functionl symmetry for uditory processing in humn primry uditory cortex. J. Neurosci., 56 5 ().. Ztorre, R. & Belin, P. Spectrl nd temporl processing in humn uditory cortex. Cereb. Cortex, 96 95 ().. Ztorre, R.J., Belin, P. & Penhune, V. Structure nd function of uditory cortex: music nd speech. Trends Cogn. Sci. 6, 7 6 (). 5. Boemio, A., Fromm, S. & Poeppel, D. Hierrchicl nd symmetric temporl sensitivity in humn uditory cortices. Nt. Neurosci. 8, 89 95 (5). 6. Gluske, R.A., Schlote, W., Brtzke, H. & Singer, W. Interhemispheric symmetries of the modulr structure in humn temporl cortex. Science 89, 96 99 (). 7. Schneider, P. et l. Morphology of Heschl s gyrus reflects enhnced ctivtion in the uditory cortex of musicins. Nt. Neurosci. 5, 688 69 (). 8. Sluming, V. et l. Voxel-bsed morphometry revels incresed gry mtter density in Broc s re in mle symphony orchestr musicins. Neuroimge 7, 6 6 (). 9. Rdemcher, J. et l. Probbilistic mpping nd volume mesurement of humn primry uditory cortex. Neuroimge, 669 68 ()..Morosn, P. et l. Humn primry uditory cortex: cytochitectonic subdivisions nd mpping into sptil reference system. Neuroimge, 68 7 ().. Penhune, V.B., Ztorre, R.J., McDonld, J.D. & Evns, A.C. Interhemispheric ntomicl differences in humn primry uditory cortex: probbilistic mpping nd volume mesurement from mgnetic resonnce scns. Cereb. Cortex 6, 66 67 (996).. Leonrd, C.M., Purnik, C., Kuldu, J.M. & Lombrdino, L.J. 998. Norml vrition in the frequency nd loction of humn uditory cortex. Heschl s gyrus: where is it? Cereb. Cortex 8, 97 6 (998).. Pntev, C. et l. Incresed uditory corticl representtion in musicins. Nture 9, 8 8 (998).. Tlirch, J. & Tournoux, P. Co-plnr Stereotxic Atls of the Humn Brin (Thieme, New York, 988). 5. Westbury, C.F., Ztorre, R.J. & Evns, A.C. Quntifying vribility in the plnum temporle: probbility mp. Cereb. Cortex 9, 9 5 (999). 6. Ritter, S., Dosch, H.G., Specht, H.J. & Rupp, A. Neuromgnetic responses reflect the temporl pitch chnge of regulr intervl sounds. Neuroimge (in the press). 7. Penhune, V.B., Cismru, R., Dorsint-Pierre, R., Petitto, L. & Ztorre, R. The morphometry of uditory cortex in the congenitlly def mesured using MRI. Neuroimge, 5 5 (). 8. Glburd, A. & Snides, F. Cytorchitectonic orgniztion of the humn uditory cortex. J. Comp. Neurol. 9, 597 6 (98). 9. Wllce, M.N., Johnston, P.W. & Plmer, A.R. Histochemicl identifiction of corticl res in the uditory region of the humn brin. Exp. Brin Res., 99 58 ()..Pfeifer, R.A.Pthologie der Hörstrhlung und der corticlen Hörsphäre. in Hndbuch der Neurologie Vol. 6 (eds. Bumke, O. & Förster, O.) 5 66 (Springer, Berlin, 96)..Gordon, E.E. Introduction to Reserch nd the Psychology of Music (GIA, Chicgo, 998).. Plomp, R. Aspects of Tone Senstion (Acdemic, London, 976).. Meyer, A. The serch for morphologicl substrte in the brins of eminent persons including musicins: historicl review. in Music nd the Brin (eds. Critchley, M. & Henson, R.A.) 55 8. (Heinemnn, London, 977).. Rupp, A., Gutschlk, A., Uppenkmp, S. & Scherg, M. Middle ltency uditory-evoked fields reflect psychocoustic gp detection thresholds in humn listeners. J. Neurophysiol. 9, 9 7 (). 5. Glburd, A.M., Le My, M. & Kemper, T.L. Right-left symmetries in the brin. Structurl differences between the hemispheres my underlie cerebrl dominnce. Science 99, 85 856 (978). 6. Schlug, G., Jäncke, L., Hung, Y. & Steinmetz, H. In vivo evidence of structurl brin symmetry in musicins. Science 67, 699 7 (995). 7. Münte, T.F., Kohlmetz, C., Nger, W. & Altenmüller, E. Superior uditory sptil tuning in conductors. Nture 9, 58 (). 8. Gser, C. & Schlug, G. Brin structures differ between musicins nd non-musicins. J. Neurosci., 9 95 (). 9. Joliveu, E., Smith, J. & Wolfe, J. Tuning of vocl trct resonnce by soprnos. Nture 7, 6 (). 5. Belin, P., Ztorre, R.J. & Lfille, P. Voice-selective res in humn uditory cortex. Nture, 9 (). NATURE NEUROSCIENCE VOLUME 8 [ NUMBER 9 [ SEPTEMBER 5 7