Prefrontal modulation of visual processing in humans

Transcription

1 rticles Prefrontl modultion of visul processing in humns Frncisco Brceló 1,2, Shugo Suwzono 2,3 nd Roert T. Knight 2 1 Deprtment of Psychoiology, Fculty of Psychology, Complutense University, Somosgus 28223, Mdrid, Spin 2 Deprtment of Psychology, University of Cliforni t Berkeley, 3210 Tolmn Hll, Berkeley, Cliforni , USA 3 Deprtment of Integrted Neuroscience, Brin Reserch Institute, Niigt University, Jpn Correspondence should e ddressed to R.T.K. (rtknight@socrtes.erkeley.edu) Single neuron, evoked potentil nd metolic techniques show tht ttention influences visul processing in extrstrite cortex. We provide ntomicl, electrophysiologicl nd ehviorl evidence tht prefrontl cortex regultes neuronl ctivity in extrstrite cortex during visul discrimintion. Event-relted potentils (ERPs) were recorded during visul detection tsk in ptients with dmge in dorsolterl prefrontl cortex. Prefrontl dmge reduced neuronl ctivity in extrstrite cortex of the lesioned hemisphere. These electrophysiologicl normlities, eginning 125 fter stimultion nd lsting for nother 500, were ccompnied y ehviorl deficits in detection ility in the contrlesionl hemifield. The results provide evidence for intrhemispheric prefrontl modultion of visul processing. Attention llows us to del efficiently with the myrid of closely spced nd timed environmentl events. Visul ttention involves modultion of the excitility of extrstrite neurons through descending projections from hierrchiclly ordered rin structures Single-cell recordings 12 14, lesion studies 15,16 (Rossi et l., Soc. Neurosci. Astr., 25, 6.1, 1999) nd lood-flow dt indicte tht prefrontl cortex modultes extrstrite processing. Neuroimging studies provide sptil informtion regrding rin regions engged during visul processing, ut the temporl dynmics of prefrontl extrstrite interctions re not well defined in humns Noninvsive sclp recordings of event-relted potentils re extensively used to investigte modultion of ctivity of visul pthwys in humns 1 6. Attended visul stimuli evoke distinct ERP signtures. Attention enhnces mplitudes of erly positive P1 ( ) nd negtive N1 ( ) rin potentils, which originte from ventrl nd dorsl extrstrite pthwys 6, Homologs of these erly humn ERP components re linked to incresed firing of V4 neurons in monkeys 6, In contrst, negtive N2 ( ) potentil, which is mximl over posterior inferior temporl sclp, is evoked only y detected trgets in strem of ttended visul stimuli nd is relted to post-discrimintion processes 3,5,30. Dipole source nlyses propose N2 genertors in the inferior temporl cortex 5,30. Here we ssessed ERPs nd ehviorl performnce in ptients with prefrontl dmge engged in difficult i-field visul-discrimintion tsk. ERPs were recorded from ten ptients with unilterl focl lesions in the dorsolterl prefrontl cortex nd ten ge-mtched controls. Sujects detected inverted tringles (trgets) emedded in rpid trins of upright tringles (stndrds) rndomly presented to the ipsilesionl nd contrlesionl visul fields. Prefrontl dmge decresed neurl responses recorded from ipsilesionl extrstrite cortex for oth visul stndrds nd trgets. Electrophysiologicl deficits consisted of diminished erly extrstrite responses to ll stimuli (125 ) together with prominent reductions of post-selection trget-relted neuronl ctivity ( ) in inferior temporl res of the lesioned hemisphere. These electrophysiologicl deficits in extrstrite processing were ccompnied y deficits in detection in the contrlesionl visul field. RESULTS Behvior correctly reported 93.9% of trgets s compred with n overll 82.3% correct rte in ptients (F 1,18 = 7.5, p < 2). There ws n interction etween group nd field of presenttion, with prefrontl ptients showing trget detection deficit in the contrlesionl field (for miss rte, F 1,18 = 7.6, p < 1; Fig. 1). Overll men response times were not slower in ptients versus controls, lthough trend ws oserved (579 ± 61 nd 531 ± 49, respectively; F 1,18 = 3.65, p < 7). An interction etween group nd visul field reveled tht the ptients rection times were prolonged to contrlesionl s compred with ipsilesionl trgets (F 1,18 = 42.1, p < 001; Fig. 1). Electrophysiology Prefrontl ptients (Fig. 1) nd controls showed the norml pttern of lrger erly ERPs over temporo-occipitl regions contrlterl to the visul field of stimultion (cross groups, F 1,18 = 8.9, p < 1 for the P1 responses t contrlterl versus ipsilterl temporo-occipitl sites; F 1,18 = 45.7, p < 001 for the N1 response). However, P1 responses to stndrd stimuli were reduced in ptients s compred with controls, ut only in the hemisphere ipsilterl to prefrontl dmge (p < 5 for contrlesionl stndrds t Pi; p < 1 for oth contr- nd ipsilesionl stndrds t TOi; Fig. 2 nd 3). Contrlesionl trgets lso evoked reduced P1 responses t the ipsilesionl temporooccipitl res of ptients (p < 1; dt not shown). P1 ltencies were shortened t the temporo-occipitl electrode ipsilterl to prefrontl dmge (p < 05; 125 for ptients; 145 for nture neuroscience volume 3 no 4 pril

2 Miss r te (%) Re ction times () DISCUSSION Unilterl prefrontl lesions impired the ility to detect visul trgets presented rpidly in the visul field contrlterl to dmge. This ehviorl deficit ws ccompnied y reduced erly (125 ) nd longer-ltency ( ) neuronl ctivity generted in extrstrite regions of the lesioned hemisphere. The results provide informtion out the nture nd timing of disrupted extrstrite processing fter prefrontl dmge. Three distinct neurl mechnis seem compromised y prefrontl dmge in this difficult i-field discrimintion tsk. First, prefrontl dmge reduced stimulus-evoked P1 ctivity to stndrds nd trgets like over ipsilesionl prietl nd temporo-occipitl res. The P1 pek mesures neurl ctivity in the dorsl nd ventrl divisions of extrstrite cortex 6,25 28,34. These erly P1 differences suggest deficit in tonic prefrontl modultion of ttention to the contrlterl visul field. Our protocol required simultneous ttention to oth fields. Thus, we cnnot distinguish whether the P1 reduction susequent to prefrontl dmge my e further frcrticles Ipsi Contr Ipsi Contr F ront ls Fig. 1. Visul ttention deficits nd prefrontl lesions. () Behviorl indices of ttention. Miss rte (left) nd rection times (right) for ptients nd controls s function of the visul field of trget presenttion (Contr, contrlesionl field for ptients, right field for controls; Ipsi, ipsilesionl field for ptients, left field for controls). A miss ws defined s filure to respond following trget. The interction etween group nd visul field ws significnt for oth mesures. Verticl rs indicte s.e. () Group-verged reconstruction of the extent of prefrontl dmge. Both left nd right prefrontl lesions re reflected onto the left side for verging. Mximl lesion overlp (>67%) ws oserved in Brodmnn res 6, 8, 9 nd 46 nd encompssed portions of the middle nd superior frontl gyri. The verge tissue loss ws 41.4 cm 3 per ptient. Softwre permitted reconstruction of the lterl perspective of lesions, determintion of lesion volumes nd puttive cytorchitectonic res dmged. controls). N1 mplitude nd ltency did not differ etween groups t TOi (205 for ptients; 203 for controls). Prefrontl lesions olished the N2 component nd reduced the P3 response to trget stimuli generted in the ipsilesionl extrstrite cortex (F 1,18 = 15.1, p < 01 for N2 t TOi; F 1,18 = 7.5, p < 2 for P3 t TOi; Figs. 2 nd 3d nd e). Difference wvefor ssocited with trget-discrimintion processes were computed y sutrcting ERPs for the stndrd from the trget ERPs 5, This differentil ctivtion encompssed n erly negtivity (pek ltency, 203 t T5; Fig. 2) nd the N2 (pek ltency, 365 t T5) s well s susequent trget-relted P3 ctivity (pek ltency, 580 t Pz). The sclp topogrphy of the erly negtivity ws similr to tht of the N1 response, with mximum t temporo-occipitl sites contrlterl to stimultion (compre sclp topogrphy of N1 versus erly trget-relted negtivity; Fig. 3 nd c). To ssess prefrontl contriutions to this post-discrimintion ctivtion, we mesured difference-erp mplitudes in consecutive 50- windows from 0 to 700 post-stimulus. Grnd mens from three representtive time windows re shown (Fig. 3c e). Significnt interctions were oserved mong group, hemisphere nd field of stimultion strting 200 post-stimulus, with the topogrphy of these effects chnging rpidly over time. Frontl ptients showed reduced difference-wve mplitudes fter stimultion t the ipsilesionl temporo-occipitl re (p < 5; Fig. 3c). This ipsilesionl reduction in mplitude ws significnt only when stimuli were presented to the contrlesionl visul field (F 1,18 = 5.96, p < 3; Fig. 3c). Ptients hd prominent N2 (365 ) mplitude reduction over centrl, temporo-occipitl, prietl nd occipitl res of the lesioned hemisphere (p < 01; Figs. 2 nd 3d). N2-mplitude effects were independent of the visul field of disply, occurring for stimuli presented either ipsilterl or contrlterl to prefrontl dmge. This effect ws supported y significnt min interction etween group nd hemisphere, ut not field of stimultion from fter stimulus delivery (F 1,18 = 9.96, p < 06; Fig. 3d). Topogrphicl nlyses of normlized ERP mplitudes confirmed tht different sclp voltge distriutions ccompnied the erly nd lte difference-wve effects 33. In oth groups, voltge distriution of difference wves for the erliest trget selection effects ( post-stimulus) were strongly lterlized, with mximl intensity occurring t the temporo-occipitl electrode contrlterl to stimultion (F 1,18 = 28.9; p < 01 for the liner trend; Fig. 3c). A chnge in topogrphy of the sclp voltge distriution occurred from 350 to 450 fter stimultion, resulting U-shped distriution with mximl mplitudes over temporo-occipitl sites contrlterl to stimultion (F 1,18 = 47.2, p < 01 for the qudrtic trend; Fig. 2). The initilly contrlterl N2 ecme progressively ilterlly distriuted (Fig. 3d). Frontl ptients lso showed reduced P3 responses over ipsilesionl temporo-occipitl res (F 1,18 = 4.8, p < 5; Figs. 2 nd 3e), ut not over midprietl regions. This effect could not e ttriuted to group differences in P3 pek ltency t Pz (controls, 580 ; prefrontl-lesioned, 570 ; p = 0.8). 400 nture neuroscience volume 3 no 4 pril 2000

3 l temporo-occipitl res tht lsted from 200 to 300 fter the stimulus. This time window encompssed n erly negtivity strting t the N1 pek nd lsting to N2 onset (Figs. 2 nd 3c). Erly trget-specific ctivity ( ) hd sclp distriution similr to tht for the N1 response, nd my reflect norml enhncement of the N1 genertor tht is reduced in prefrontl ptients. The findings indicte tht prefrontl lesions disrupted the ctivtion of neurl popultions in ipsilesionl inferior temporl cortex tht re specilized in the erly nlysis of oject fetures 6,7,9,27. The temporl prmeters of this trget-specific modultion re in ccord with single-neuron recordings in monkeys reveling enhnced prefrontl trget-relted ctivity 140 fter stimulus onset 13 nd top-down ctivtion of inferior temporl neurons fter trget detection 11, providing some convergence etween the monkey single-neuron nd humn ERP dt. Third, unilterl prefrontl lesions olished N2 ( ) nd P3 ( )ctivity t ipsilesionl inferior temporl res in response to trgets presented oth contr- nd ipsilesionlly. In controls, the N2 ws initilly contrlterl, with mximl mplitude occurring in inferior temporo-occipitl res 5,30. The N2 response ecme progressively evident t temporo-occipitl sites in oth hemispheres, regrdless of the visul field of stimultion 15,19,30. Becuse N2 is triggered fter trget selection, it is proposed to mesure post-selection trget-feture nlysis within inferior temporo-occipitl cortex tht requires ilterl hemispheric interction 5,6,24,30. Impirments in this longer-ltency interhemispheric interction my contriute to some of the more glol processing deficits frequently oserved following prefrontl dmge. In monkeys, prefrontl cortex projects to inferior temporl cortex 7,10,11. Single-cell studies show tht prefrontl neurons dischrge toniclly even in the sence of stimultion, possily reflecting ctive mintennce of n ttention templte in working memory 7,12,13,35. A deficit in this tonic mintennce cpcity my e reflected initilly y lowered ipsilesionl extrstrite P1 responses to ll stimuli. It is possile tht trget mtching to toniclly mintined extrstrite templte could trigger lter ERP components. However, given evidence otined in monkeys performing detection tsks 11, phsic fcilitory input from prefrontl cortex is proly involved in triggering post-selection ctivity in the ensuing fter trget detection. Prefrontl lesions my disrupt this lter phsic intrhemispheric re-entrnt feedck mechnism etween prefrontl nd extrstrite cortex. This signl would provide the neurl enhncement required for full post-selection nlysis of oject fetures in extrstrite cortex 35. Our evidence for tsk-specific intrhemispheric control of visul processing is in ccord with other lesion dt supporting intrhemispheric prefrontl control of uditory 36 nd motor processing 37. Visul ttention involves the tonic ctivtion of templte or representtion of the sought-fter stimulus tht cn e used to guide top-down selection of oject fetures nd sptil loctions 7. Single-cell recordings in nimls 11 14,35 nd neuroimging studies in humns 17 21,23 provide evidence tht dorsolterl prefrontl cortex is importnt for holding these temporry representtions in working memory. Within this frmework, we propose tht dmge in prefrontl extrstrite intrhemispheric network disrupts erly ctivtion nd susequent post-perceptul mtching of templtes held in working memory with incoming sensory informtion. Evidence from lesions, lthough clerly implicting dorsolterl prefrontl cortex in extrstrite processing, does not permit more fine-grined neurontomicl nlysis of the prefrontl suregions involved in tonic versus phrticles Contrlesion stndrds t TOi P1 N1 Contr lesion trgets t TOi N1 N TOi TOi P TOc TOc Ipsilesion stndrds t TOc Ipsilesion trgets t TOc Fig. 2. Erly nd lte ERPs nd voltge mps. () Group-verged ERPs to contrlesion stndrds s recorded from the ipsilesionl temporooccipitl electrode (TOi for ptients, T5 for controls), nd ERPs to ipsilesion stndrds s recorded from the contrlesionl electrode (TOc for ptients, T6 for controls). Voltge mps show the distriution of the P1 pek to contrlesionl stndrds (tht is, right stndrds for controls). The P1 pek reched mximum over the T5 electrode in the control group, ut ws significntly reduced in the ptients. () Group verges of the difference wvefor (trgets minus stndrds) evoked y contrlesionl stimultion t the ipsilesionl temporo-occipitl electrode (TOi for ptients, T5 for controls), nd evoked y ipsilesionl stimuli t the contrlesionl temporo-occipitl electrode (TOc for ptients, T6 for controls). Voltge mps show the difference wve verged over poststimultion (N2). The N2 response to contrlterl trgets oserved in controls ws sent over the ipsilesionl extrstrite re of frontl ptients. The susequent P3 ws reduced t TOi. Asterisks indicte significnt group differences in mplitude: p < 5; p < 1; p < 01. tionted into pre-stimulus (tonic) versus stimulus-locked (phsic) ttention-specific components 6,18 20,26,34. In contrst with the deficit in P1 modultion for ll contrlesionl stimuli, trget-specific ctivity recorded from extrstrite cortex within the first 200 did not differ etween ptients nd controls (Fig. 2). These results re comptile with the notion tht the post-selection nlysis of trget fetures my not hve initited t this erly processing stge. Second, with further nlysis of trget fetures, we oserved deficit in ERP responses to contrlesionl trgets over ipsilesion- nture neuroscience volume 3 no 4 pril

4 Difference wves Stndrds ERP recording nd nlysis. Brin electricl ctivity ws recorded from tin electrodes plced t 19 sclp sites (Fp1, Fpz, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1 nd O2) ccording to the system. The electro-oculogrm (EOG) ws mesured with four electrodes ttched to the left nd right cnthi of oth eyes, s well s eneth nd ove the outer edge of the left eye. Electrode impednces were kept elow 5 kω. All sites were referenced to linked mstoids. The EEG ws mplified (nd pss, Hz), digitized (256 Hz per chnnel) nd digitlly stored in PC for off-line nlysis. The verging epoch ws 1024, including 200- seline. Trils were utomticlly rejected from further nlysis on the sis of links, EMG rtifcts in the sclp chnnels (pek-to-pek mplitude, 80 ) or lterl eye movements s monitored in the horizontl EOG. The men rejection rte ws 14.8% for left hemifield-trget trils nd 14.6% for right hemifield-trget trils, with no significnt differences noted etween ptients nd controls. As ehviorl nd electrophysiologicl performnce were comprle for left- nd right-lesioned prefrontl ptients, performnce nd electrophysiologicl dt re presented for stimuli delivered in the visul field ipsilterl or contrlterl to the lesion. For exmple, TOi refers to the verged ERP dt from the T5 electrode for left prefrontl lesions comrticles Stimulus Field Contrlesionl Ipsilesionl P 1 pek (145 ) N1 pek (200 ) Mximl lesion overlp (>67% cross ptients) comprised Brodmnn s res 6, 8, 9 nd 46 (Fig. 1; refs. 38, 39). Vrile mounts of dmge in Brodmnn s res 6, 8, 9, 10, 44, 45 nd 47 occurred in individul ptients. There were three right- nd seven left-lesioned ptients. Testing took plce t lest one yer fter injury. Medicl complictions, psychitric disturnce, sustnce use, psychoctive drug tretment or other neurologicl diseses were criteri for exclusion. All ptients hd norml or corrected-to-norml visul cuity. Three ptients hd upper-motor-neuron wekness in the lims contrlterl to their lesions nd responded with their ipsilesionl lims. The verge ge of ptients ws 65.4 ± 13.5 yers (3 femle; 7 mle). Ptients were mtched y 10 controls free of neurologicl or psychitric disese for ge (66.3 ± 6.5 yers), sex nd eduction. The reserch ws pproved y the Humn Sujects Review Committees of the Mrtinez Veterns Administrtion Reserch Service nd the University of Cliforni. c d e TOi Pi P z Pc TOc Frontls Fig. 3. Sclp topogrphy of erly nd lte extrstrite responses. Sclp distriution of grnd men ERP mplitudes for prefrontl ptients nd controls t ipsilesionl nd contrlesionl temporo-occipitl (TOi/TOc), prietl (Pi/Pc) nd midprietl (Pz) res, plotted s function of the field of stimulus presenttion. (, ) Men mplitudes of erly P1 nd N1 responses to stndrds. (c e) Men difference wves (trget minus stndrd) from three time-windows fter stimultion. Chnges from 0 reflect differentil ERP responses to trgets s compred with stndrds. Note the different voltge scles for different ERP mesures. Asterisks indicte significnt group differences: p < 5; p < 1; p < 01. sic extrstrite processing. Dmge ws mximl in res 6, 8, 9 nd 46 of the middle nd superior prefrontl gyrus nd extended into other prefrontl fields in individul ptients. In summry, neuroimging studies implicte prefrontl cortex in the modultion of extrstrite responses to ttended sensory events 17 21,23. We used the temporl resolution of event-relted potentils coupled with lesion nlysis to demonstrte tht prefrontl cortex regulted visul processing in extrstrite cortex s erly s 125 milliseconds fter stimulus delivery, nd tht susequent visul processing depended on prefrontl cortex throughout the ensuing 500 milliseconds. METHODS Ptient selection. Ten ptients were selected on the sis of unilterl focl lesions to their dorsolterl prefrontl cortex s determined y computed tomogrphy (CT) or mgnetic resonnce imging (MRI) scnning. Lesions were due to single stroke (nine ptients) or crniotomy (one ptient) nd were restricted to lterl prefrontl cortex. TOi Pi P z Pc TOc Stimuli nd procedure. Sujects st in comfortle chir 1.6 m from video monitor in sound-ttenuted recording chmer. They were instructed to fixte centrl yellow crosshir nd to press utton upon detection of rndomly occurring trgets emedded in stre of tskirrelevnt stimuli delivered to oth visul hemifields. Thus, sujects were required to continuously llocte ttention cross the entire visul field. We chose this i-field ttention tsk to reduce the possiility of differentil effort or rousl tht could rise from locked design. We resoned tht if ptients hd prole in detecting contrlesionl trgets, locked hemifield design might result in reduced effort, compounding ny ehviorl deficit. Trgets were inverted tringles interspersed within trins of repetitive, upright tringles (stndrds) nd tsk-irrelevnt unique, novel, color imges such s pictures of fish or flowers. The proility ssocited with ech stimulus type ws 20%, 70% nd 10% for trgets, stndrds nd novels, respectively. Stimuli were presented for 107 either 5 to the left or 5 to the right of the centrl crosshir. Interstimulus intervls were either 200 or 900 (Bernoulli distriution with p = ), nd 2 trgets were never presented sequentilly. All stimuli sutended 5 of visul ngle nd were mtched in luminnce. The ckground luminnce ws 0.4 foot-lmerts nd the stimuli were 5.2 footlmerts. To void ftigue, dt were gthered in 2 seprte 1-h sessions run severl dys prt; ech session consisted of 12 locks of 150 stimuli. Sujects were instructed to respond s quickly s possile to trgets in ny loction. To respond, the right hnd ws used y ll sujects ut three ptients with motor wekness, who responded with the hnd ipsilterl to the lesioned hemisphere. Behviorl performnce ws comprle etween these three ptients nd the other seven prefrontl ptients. A hit ws defined s correct detection following trget presenttion. Filure to respond in tht window ws recorded s miss. We exmined responses to visul stndrds nd trgets not preceded y novel stimuli, s prefrontl lesions modify novelty-relted neuronl processing in ll modlities. Here we lso oserved ltered novelty processing; these effects re discussed elsewhere 40, nture neuroscience volume 3 no 4 pril 2000

5 rticles ined with dt from the T6 electrode from right prefrontl lesions. Similrly, Pi equls P3 for left lesions verged with P4 electrode dt from right lesions. Ipsilesionl ERP dt were compred to left hemisphere ERP dt from controls, nd vice vers. Although no significnt differences were noted etween left- nd right-lesioned ptients, power considertions due to the size of the groups precluded definitive conclusions out hemispheric lterlity. Trget-relted men nd pek mplitudes of ERP components were mesured reltive to 200- prestimulus seline. Erly extrstrite ERPs for stndrds were mesured in windows of for the P1 nd for the N1. Trget-relted components were mesured in similr windows for the P1 nd N1 nd in windows of for the N2 nd for the trget P3. Pek ltencies for these components were mesured reltive to trget onset. For sttisticl tests of sclp topogrphy, men ERP mplitudes were sujected to series of ANOVAs with group (ptients, controls) s the etween-suject fctor nd visul hemifield (ipsilesionl, contrlesionl), hemisphere (lesioned, intct) nd electrode (centrl, temporooccipitl, prietl nd occipitl) s the repeted mesures fctors. Seprte ANOVAs crried out on ERP ctivity from electrodes F7, F3, F4 nd F8 did not revel significnt group differences t frontl res. A finer temporl nlysis of the ttention effects ws performed on the difference wvefor otined y sutrcting the stndrd ERPs from the trget ERPs 31,32. Men difference-wve mplitudes were mesured in consecutive 50- windows from 0 to 700 post-stimulus. Amplitudes were then normlized to ssess the sclp distriution of voltges independent of source strength. Vector length ws defined s the squre root of the sum of squred difference-wve mplitudes over ll loctions, clculted seprtely for ech group nd visul hemifield 33. Percentges of hits nd misses, s well s hit response times were nlyzed y ANOVA with group nd visul hemifield s independent fctors. Significnce levels re reported using the uncorrected degrees of freedom. When pproprite, we used Greenhouse-Geisser corrections to yield corrected proility vlues. ACKNOWLEDGEMENTS Supported y Fundción Complutense del Amo, Comunidd de Mdrid grnt 08.5/0012/98 nd NINDS grnt NS We thnk Cly C. Clyworth for technicl support. An erlier version of this work ws presented t the 39th Meeting of the Society for Psychophysiologicl Reserch (Grnd 1999). RECEIVED 2 NOVEMBER 1999; ACCEPTED 10 FEBRUARY Hillyrd, S. A., Mngun, G. R., Woldorff, M. G. & Luck, S. J. in The Cognitive Neurosciences (ed. Gzznig, M. S.) (MIT Press, Cmridge, Msschusetts, 1995). 2. Hillyrd, S. A. & Anllo-Vento, L. Event-relted rin potentils in the study of visul selective ttention. Proc. Ntl. Acd. Sci. USA 95, (1998). 3. Luck, S. J. 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