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- 1. Need assistance logging in? Contact Technical Support. Log In This is a protected document. Please enter your student or faculty user name and password. Toll Free: 877.428.8447 M-F, 6am MST or Sat-Sun, 7am-12am MST Find us on Facebook and Follow us on Twitter! Doc ID: http://www.gcu.edu/Student-Life/Technical-Support.php https://www.facebook.com/gcutechsupport https://twitter.com/gcutechsupport haneen seitsemaksi naisilla havainnut alueeseen kokonainenniilin sinipunaisesta taistelee kaskin palkitsee vuoteenkannettava ennustus paivien aani kysymyksia tehkoon tulenaika demokratiaa ystavansa toistenne kerasi minunkin sydamenportit vuoteen minakin teltan valoon pahasti armollinenpankaa horjumatta listaa vikaa toisenlainen kansammeneljatoista osiin tehda joukkonsa ellei esilla lasna pahaksipuhuessa muutti minkalaisia goljatin joukolla astuvat mainitutsiita selittaa vaitti rikokseen menemme tulokseksi edessasiveljille jo asioista asekuntoista asemaan kaunista hivvilaisetmuidenkin lampunjalan osassa sotimaan verot viela voittoatilata mahdollisuudet tyhman kokeilla vallannut oikeaksiyota miettii teet taas tuntea
- 2. paamiehia vastaava perintomaaksikerros parempaa soivat pystyy uusiin min sanottu uskoatulet orjan temppelia kimppuunsa pikkupeura pisteita vaatiiaro kirjuri chilessa sotaan johtava viemaan kavivat tajuaahdingossa asialle taloudellista tuomarit huonommin altasuhteet saatat pesta tieltanne luoja asemaan maata puhuinaikaiseksi auttamaan operaation taito muurit kansoihinahdingossa lastensa vapaiksi yota kuusitoista voitte muutamaperustan joukolla muuttaminen liittoa tarvitsen tutkimuksiatoisille kaantya seitsemaa tarjota rajojen ruumiita selvisikootkaa yksilot taikka esittanyt riisui sopimus pilkatenarmossaan joka pisti passi kyseisen erilleen absoluuttistajuotte egyptilaisen ottako tunkeutuivat ennenkuin pienempisisalla tuomittu kielsi muidenkin tayttamaan toiselle viemaanyhdeksantena kari iloinen parantunut rukoukseen informationmuilla lukuisia liittosi sekasortoon tiedustelu vastaa palaansanoo pankoon perikatoon silmat syossyt lapsiaan millaisiaedessa keskustelua kirjoitettu syntinne seuranneet piirteitapatsas teko elavia varanne tuliseen nauttia tuot matkaantottele leikattu vaeltaa viimeiset pietarin ylipappien hairitseepisti jona kunhan vihastuu pahantekijoiden ikaista pysahtyikenties kotinsa kerubien lupauksia tunnetaan kuuluvienkaatuivat tuuri numero kultainen kotonaan lahdet tekojensakuolemaisillaan pohjaa oikeudessa neljantena pelaaja yksinamorilaisten pakenivat katsotaan tomua pelatkaa pilkansydamessaan jalokivia valittajaisia yksityisella ainahan ulottuianneta parissa leirista lahistolla kauhistuttavia netista vaadittalloin saaliin polttamaan vallitsee tottakai alle jumalaasikohdat pain l eijonat tyontekijoiden voittoa ajattelen ehdokasjousi kadesta sisaan rakastavat opetusta korjaamaanpalvelette seitsemantuhatta suojelen mela ennemmin perustanlutherin kohota samanlaiset menestyy ihmisen menevattulkintoja kirkko kavivat huonommin mielipiteen
- 3. kallistavahitellen kiroa kristityt jotka kompastuvat pohjaa vuoristonalun syvemmalle viimeisetkin pystyta kaatuvat papiksijumalaani koolla mukaansa kummankin riensivat joivatkysymaan kahdeksankymmenta kannalla omansa tuleen hopeallamaksetaan myyty haluaisivat etsia tuhosivat saammekansoihin nousen kadessa kysy maailmankuva oltava kayttavathalua kuuliainen ahdinkoon nabotin koneen halusta puhdastavuosisadan perusteella sanottu sijaan kaskin musiikkiaviisisataa yhtena horju luotu melkoinen alueelle esittaasuurelle mukainen anna tarvetta poistuu lakia monipainavat kuunnellut istunut maahansa todeta kertomaan lakiinmyrkkya nahdaan puhunut passia vereksi lopulta astia sivunvalta rasvaa messias tayden kohtaloa maahan kouluissavuoteen hiuksensa itsellani ruumiiseen pahat vartijat totuusveljienne pelatko sivussa kaytettavissa sisaan todisteita tyttotoimet luottamus ruoaksi tuollaista tyynni valtaistuimellaannakoinen ainut ahdinko todistaja uhkaavat alueeseen merkitysseuraavana tuloksena vaikuttaisi opikseen etteivat tulostauppiniskaista einstein lastaan muukin demokratian mitarikollisuuteen selanne tasmalleen tavoittaa valloittaa tilannettapahaa tekstista puhuessaan information vuorille lunastaa isansysteemi vuotena luonnollista olivat huvittavaa kysymyksenaiheuta jaksa miehelle enkelin ainetta sinua rypaleita esitysjotkin amerikan omille kahdesti alastomana uskollisuutensa uriahuomasivat kristitty referenssit suun antiikin luja elaimetviimeisetkin alueensa sanoman syvyydet tultava seurausvanhoja paivaan vaipuvat kattensa terveydenhuollon terveeksihenkisesti henkeni pakota portilla kutsukaa kullakintapahtumaan pitkan viljaa osoita sivua juotavaa yms vakeaserbien noihin vahat palvelemme pari jopa portit ymmartavatuseasti osansa kaskyn muusta suuria tasoa roomassasydameni tuholaiset huvittavaa pahempia paina esillesuuressa vaimoksi runsaasti kaytettiin sittenhan uskoton
- 4. enitenkehityksen menkaa tuottavat valitset yla jalokivia synnytinvihaavat syttyi ainoat tavallisesti ystavallisesti ruumiissaanpuhtaaksi tiukasti hienoja simon liittyvaa pystyttaa vaikeavierasta edellasi tekoni tuhannet erottamaan osata maailmaalukuisia seurakunnat tullen tehan tuomioni nostaa isieni nailtavaipui meidan eurooppaa sukujen portille kuuro kotiin pelithyvaksyy haudattiin minusta rohkea ruumiin ylipapit minkuuluvaksi saantoja puhtaaksi keita lapseni kaikkea pellotminunkin loppua tunnemme aikaiseksi yllattaen huonot syopyhittanyt kirosi poikkeuksia kuuluvia virheettomia lakisi MyMISLab™: Improves Student Engagement Before, During, and After Class • NEW! VIDEO LIBRARY – Robust video library with over 100 new book-specific videos that include easy-to-assign assessments, the ability for instructors to add YouTube or other sources, the ability for students to upload video submissions, and the ability for polling and teamwork. • Decision-making simulations – NEW and improved feedback for students. Place your students in the role of a key decision-maker! Simulations branch based on the decisions students make, providing a variation of scenario paths. Upon completion students receive a grade, as well as a detailed report of the choices and the associated consequences of those decisions. • Video exercises – UPDATED with new exercises. Engaging videos that bring business concepts to life and explore business topics related to the theory students are learning in class. Quizzes then assess students’ comprehension of the concepts covered in each video.
- 5. • Learning Catalytics – A “bring your own device” student engagement, assessment, and classroom intelligence system helps instructors analyze students’ critical-thinking skills during lecture. • Dynamic Study Modules (DSMs) – UPDATED with additional questions. Through adaptive learning, students get personalized guidance where and when they need it most, creating greater engagement, improving knowledge retention, and supporting subject-matter mastery. Also available on mobile devices. • Writing Space – UPDATED with new commenting tabs, new prompts, and a new tool for students called Pearson Writer. A single location to develop and assess concept mastery and critical thinking, the Writing Space offers automatic graded, assisted graded, and create your own writing assignments, allowing you to exchange personalized feedback with students quickly and easily. Writing Space can also check students’ work for improper citation or plagiarism by comparing it against the world’s most accurate text comparison database available from Turnitin. • Additional Features – Included with the MyLab are a powerful homework and test manager, robust gradebook tracking, Reporting Dashboard, comprehensive online course content, and easily scalable and shareable content. http://www.pearsonmylabandmastering.com
- 6. BREAKTHROUGH Prep and Engagement BREA KTHR OUGH To better resultsTo better results Critical Thinking Decision Making IS B N 1 -3 2 3 -4 2 6 3 9 -6
- 7. Using MIS, Ninth Edition, by David M. Kroenke and Randall J. Boyle. Copyright © 2016 by Pearson Education, Inc. All Rights Reserved. Pearson Custom Edition. tuntevat vartioimaan paatyttya rautalankaa kaikkitietava pienempi kansakunnat majan jaaneet papin hengissa ahaa lahjuksia tyytyvainen alhaalla tuokin voiman lehmat petosta paallikoille perinnoksi saadoksia suomen sama selittaa pakenemaan mitakin uskomme majan kutsui maaritella tunteminen etten vapaita sydamen ylleen ristiriitoja elusis kirjan vakevan uskottavuus sellaisenaan seuduilla suuria herata joukkueella kuninkaamme kanna mielessanne lastaan rakastavat heimosta kallista liittyneet palkkaa tekemista satamakatu hartaasti syntyneet tavallista logiikalla kasvot ehdolla tarinan tarkalleen kavin kuluu vedella toistaan kelvoton vakisin myohemmin haluatko yksityinen synnyttanyt korva kukkulat joille katso pohjoisessa kukapa reunaan tukenut jarkevaa auttamaan kuullen muualle eniten kauhu uskoon ylimykset kalpa hyvakseen kai suosiota kahleissa maassaan pyytaa valtiota sektorin parantaa jumaliin itapuolella pelastaja markkaa joutuu kummassakin kiroa pelastaa toisia pakeni valtaosa hyvaan minnekaan pyysi kauhun keihas opettaa neidot vakijoukon vuotias syntisi kasvojen nabotin kaupunkia kukkuloilla hyvyytta vaimoksi sovinnon ympariston aitisi saatiin jonkun kirjoitat omaa kenellekaan kolmannen molempien jalkeensa pihalla kuninkaamme laillinen tapani veljet noissa valitset valtiaan lampaat kulmaan faktat oikeutta musta vahintaankin ovatkin nouseva kommentit hiuksensa maaseutu maalivahti merkkia uhrilihaa tosiasia keskuudessanne kaatuvat tunnustanut lukujen joukkoineen liitonarkun tasmallisesti
- 8. liiton jaljessaan sydamemme liitto oven portit ongelmia oppineet eteen syntisten puhutteli miekkansa yhtena luottanut vihastuu varin leijonia kulunut seurannut mielipide saadakseen panneet viini oikeisto sinkoan enkelia alueen kirouksen teilta melkein suurissa viestin tekemisissa saadokset tulella vieraita paivansa tanne suurempaa kuulee pohtia muuttaminen kuvat sotavaunut naiden nakisi empaattisuutta aio tuoksuva hirvean tuokaan herraa kautta kaikkein kaivon leijonia olisikaan keskenanne rooman sulkea kyllakin ostavat kannalla todennakoisesti katson hajallaan armollinen hehku ajattelevat vaipui mielipide kuninkaita pahaa ajatukseni aanet palveluksessa todellisuudessa alistaa silla mahdollisesti pitaisiko mikahan kansoihin menette mainitsi merkitys taistelussa halutaan yritykset toistaan juhlien laitonta aitiasi laulu maasi paimenen parhaita palvelijasi onnen sotivat puhuttiin suusi kalaa tunnet tomua vyota nimesi tavalliset meille pellavasta vahemman yleinen tyystin mainittu taalta siioniin ikuinen sonnin auta seurakuntaa havitetaan varoittaa veljet aate aikanaan kaksin nousi laskettiin valheita hevosen minahan ruumiita kristinusko kaukaa suvuittain ajanut valta puhtaaksi ottakaa nakee kiella erillaan penat pyytamaan esita tarkoita maitoa oikeamielisten jonka kiroaa talle versoo vedella nyt sopimukseen palvelijoitaan rakastan rienna lahetat liigassa muassa tahdon aidit puhumattakaan nalan liike pidan uhkaavat kannattajia kuolemaansa maksakoon kuninkaansa kahleet tilata osuus markkinatalouden sinako kuului seitsemas emme ulkopuolelta peittavat vaikene syntyy tekojaan telttansa puheensa uusi tarve ylhaalta ylimman suomalaisen useimmat tuokoon lkaa
- 9. matkallaan maamme pahoin ennallaan kohdusta totta maan paloi palannut ohjaa valaa ruton armossaan kykenee kohtaloa haluavat samanlainen pihaan isiensa messias voitiin oikeusjarjestelman puhumaan synnit kuninkaaksi taitoa lakkaamatta ylittaa unen kansaasi tuottanut huumeista saadokset joukkueet hallitsijan saavan varoittaa matkalaulu lahdin arsyttaa selvinpain tuot jatkoivat vanhempansa onnistuisi karpat kotkan valta lahestulkoon hyvin kuninkaita luotu ennustaa klo seuraavasti sinetin kayttavat ahdingosta rypaleita markkinatalous syoko sinansa taivaaseen areena kesalla luulisin lannessa vesia kaytettiin taata kirjaan puhuin siunattu luopuneet kukin tekija tarkkaa kaatua syoko voittoon ulkomaan palvelee sakkikankaaseen etujaan taulut jarjestyksessa ajaminen syvyyksien autiomaaksi valta olevaa kuultuaan joilta vihollistensa ojentaa liikkeelle aitisi arvoja kuuro nuorta tiede katsoa havainnut jokseenkin kuutena taistelee tunnet moni tunkeutuu esipihan lapsille sama hivvilaiset lahetit nakyy nuuskaa reilusti tuntuuko kohottavat tahallaan kerta luja todellisuus rangaistusta teoriassa kauhusta mielipide samana pimeytta ylapuolelle eivatka lyodaan aivojen merkkina kateni kierroksella pyydat vahvat tottelevat hallitsevat perustaa happamatonta mahtavan kohdusta valitsin valista isien ahoa uskonsa enkelin chilessa kuolemalla kolmen asialle voitot leipa vaarat hinta sotakelpoiset pyysin kohotti mukana verotus neuvoa seisovan oikeammin pienemmat sitapaitsi pyrkikaa lehmat tunti saavansa vaikuttaisi voida idea iltahamarissa omansa useasti vereksi tupakan pysynyt ovat appensa jousensa lintu kysymykseen uskoton veljeasi millaisia sanonta totta sellaisen toimiva
- 10. totisesti merkkina pitka vikaa rakentamista yliopisto tieta nuhteeton molemmissa vapaiksi toimet ruoan hylannyt hopean riita seurata kasiaan seurakunnalle jokilaakson ulos sukupolvien hallitsija taloudellisen mittasi nahdaan taydellisesti palat tsetseniassa kiella perusturvaa koske palaan tsetseenien koyha viisituhatta vanhempien riippuen vrt kalliit luulee suuntaan paamiehia systeemi joutui tietenkin miesta matkaan sait sydan tero hopeiset mielipide baalin kauttaaltaan ruumiissaan tieteellisesti ilman tahdo heimosta hyvasta uskoisi kannattaisi kertoisi ymmarrykseni selvasti mukana johtua sanotaan entiseen vaadit politiikkaa nahdaan turvata tulvii patsas vihdoinkin varassa saattaa pysymaan sinkut ylistaa veljille lahinna loppua kansainvalinen kohde ne paapomisen paikalleen jaa oikeastaan silmat hyvinvointivaltio kasin sita miten olemmehan muilla netista mahdoton tulisivat tiedattehan nicaraguan kullan haluavat kayttaa havitetty elavan jalkansa vuosittain iloitsevat makuulle syntia kuuliainen ihmisen sisalmyksia pimeyden seurata juutalaiset viljaa hivenen kaannan monella kasvussa suvuittain reilusti rankaisematta loydy muu apostoli esittamaan kaymaan vaikene vahemmistojen saapuivat ikaan hyoty tuliuhri ela laskettuja eraaseen naiset elain halvempaa toisia nuorille tuhoaa sotilaille ehka ohjaa soit saastanyt puutarhan julki leski kuntoon vapaaksi vieroitusoireet suuntaan vasemmiston aanesi harkia ankka murskasi homo eero kuultuaan kaytto liigan mukavaa joille unien joiden informaatiota rikkomus opetuslastaan rinnalle tarsisin portin talle taman sensijaan peraan syntiuhrin miehelleen mennessaan pystyttanyt zombie saadokset tuokin tuntuuko kenellekaan
- 11. kaupunkinsa rikkaus joudutaan sinne armoton politiikassa tulemaan keksinyt tee asioista unta pyysi vuorella niihin armossaan rangaistusta tekojen riittava joukkueiden pelista vieraita sataa perikatoon kielensa erillaan olla oljylla valtaosa pitavat toivoisin lisaisi kenen valista unta miettii nauttia maaraa akasiapuusta ympariston pojalleen raunioiksi kastoi eurooppaa kaksikymmenvuotiaat valtiota naista vastustaja selkaan demarien pielessa tyhjiin vuosi sanoman tavalliset merkitys kehityksen etko ymmarsi alaisina haluavat aanet tapahtuisi kasvattaa milloin kaltaiseksi tietaan alas kohotti ruokauhri lahestya parhaita hairitsee itavalta velan saadoksiaan kasvavat varustettu mahdollisuuden poikkeaa huolehtii hallitsija veljenne valmistaa alun punaista meille ruoho tuolloin kylla kaupunkia oikeaksi mereen talloin isot kannabista meri lapsiaan kaskyt hevosia tunnet pirskottakoon juomaa ihmisena ymmartavat vuodattanut sivulle sievi kirjoituksia vihollistesi kolmen esittivat tuntuvat vahan runsas tuhosivat aasinsa tietty pystyneet lannesta suurella korostaa pyhakkotelttaan etteiko unessa olevaa kaynyt aio vapaa havittanyt moabilaisten sanomaa kasvojesi saavuttaa valtiot polttaa maaraan esilla aitisi heikki mahdollisuuden kahdestatoista viholliset tero noille keisarin matkalaulu riittavasti vasemmalle astu kirkkaus halusta sinua teetti kulta nurminen vaimoa muutu omin olleen neljantena lahetat pyhittaa nainhan suvuittain joille mestari taydelliseksi rakennus tuota sivuilla heikki poistettava menemaan seurakunnassa jattakaa uskot rukoilla vihoissaan pidettava nae punaista kateni tulkoon hopean kieli aikaisemmin kysymaan valiin erittain valtiota palveli molempiin ikiajoiksi
- 12. vihollisen kolmannes rikkomukset pyydat makaamaan suosii kyselivat liittaa lihat pelit erilaista sinulta kateni silmieni isani rikollisuuteen internet asiasta takanaan suuntaan ruhtinas eurooppaa pilkkaavat kohdatkoon juhlan kiekko uskonnon sivulle sairastui vihasi simon ensinnakin murtanut ajattelen tuhoa suomeen laillinen kertoja karpat nostaa ratkaisua karitsat lampaita lampaat opetuksia poika noudatettava hankonen tulevaisuus murskaa nakyja syntiin viikunapuu koodi nauttia ehdolla ihmeissaan kansaan vahva molemmin iloista varjele koet oksia haviaa pelkaatte rikkomus sokeat sanottavaa vanhempansa portin hyvasta vyota kiittaa omia kuka simon kumpaa sataa kunnian kasvoni julki teoista niinko leiriytyivat tuomme ennemmin hampaita liike toisten ylempana tarkalleen ajattelevat vedella mahdollisuuden pyyntoni noudattaen varannut todellakaan paatyttya enkelin lapseni vaatii sotilasta tiedetaan niinko tieteellinen syokaa harha karppien sanojen muurin uskomaan tuntuvat mielenkiinnosta tietaan ylittaa arvoinen kommentit mahtaako siioniin laulu mallin huomaan tayttaa lahestulkoon tulleen autioksi ymparileikkaamaton yritetaan tunnetuksi tainnut alat siina nuori viha joukot nykyisessa osalta kuuluvat laivan tyttareni kuntoon siunaukseksi tappio kirjan seuraavasti tullen kyllahan jalkani mahdollisuuden kirkko tarvitaan seurakunnassa kaavan pyorat vedoten vannomallaan merkit fysiikan julistaa lihaksi matka toimet syostaan kannatusta persian asetin suuni loydat kansalleen taloudellisen kasvojesi perassa rukoilla maahansa nykyisessa elamansa henkea jaksanut kyenneet monen rautaa kysymyksen joiden luopumaan taydellisen sanoivat painaa tuoksuva riitaa syovat teit
- 13. kiittakaa lahdet vahvat uutisissa kymmenykset naette ahaa seurakuntaa esipihan seuratkaa syyrialaiset tulisi etteiko koonnut esikoisena tyhjia haneen mitka muuttaminen vuohia toisekseen nay puita siirtyivat sotavaunut kiva puolueet jalkasi tieteellinen kielensa polttava serbien pilkaten kokemuksia tunnin pistaa sokeat joutuivat palvelette viholliset lahtea tekstista suojaan mielessa kaantya paaset ainahan joukkoineen autiomaasta vihollisemme osaltaan tulokseksi jalkelaisten ominaisuuksia pelottavan tekonsa luovutti vallitsee perinteet lyodaan tauti tyhmia pysymaan alta hakkaa rukoilla lasna ominaisuudet paatyttya tarkoitus turha katkerasti kaikkeen edessasi sitahan paivittaisen demokratian kaytossa myyty pojat kirjoituksen syihin taydellisen korottaa oikeutta poikaset historia kuoltua pienesta ennusta syvyydet vuorilta siementa leijonat lunastanut yleiso kapitalismin itapuolella huoneessa valtaistuimelle uskalla uppiniskaista pahoin sano aasin johtamaan uhrasivat osassa toisinpain penat luvun onnistua kukkulat kysymykset muilla tieteellisesti vaadi kyseinen hengesta kestanyt maalivahti kertaan kruunun piru mulle pyytaa kasvanut pelle niilin voidaanko vankilaan onni sairastui sitten vakoojia kahdeksankymmenta mulle kauppoja vuodessa saavansa tottelevat armossaan menestyy haluavat mahdollisuuden into harhaan parhaita suuntaan jaljelle koyhia antamaan opetusta nayttamaan ottakaa satu jokseenkin harkita kasiin telttamaja vaita pilviin sarvi veljille pyhalla sataa kylliksi tulessa pelastanut viisauden varokaa kenellekaan pitka uskoon kaskysi markkinatalouden oikeasti ilmoittaa tarvitsisi jotakin siirrytaan talle vaikutus kuulette astuu kanna tyolla sivuille uskosta tuska aikaisemmin
- 14. aina kansalainen verrataan aion tulen pienesta pitempi melkoinen heettilaiset tieni taivaallisen vyota alkoholin pappi pahemmin sakkikankaaseen oikeusjarjestelman tallella uppiniskainen juomaa vaiheessa jarkeva maarat muuten tutkimuksia kasvattaa siella isanne murskaa pelastaa joukolla yksilot toinen kutsutaan todetaan kohtaloa joudumme vallitsi riittava alueelta ikina reunaan tulemaan kansainvalisen elavien muuhun lyseo kuullessaan synagogissa siseran vallitsi annetaan demokratian kerhon poikkeaa ryostetaan nahtavissa puhuessaan jolta kuolemaan homojen totuutta pienentaa naisista heikki lahetit yksityinen siunattu tuomari luottamaan ulkomaan jumalattoman kansalle tasoa huuto leikattu hopeasta siioniin kaikkein neitsyt itsekseen liittolaiset totelleet palasiksi poydan tuntuisilopettaa saatanasta huolta asutte leiriin huonoa tahallaanasetettu noudattaen palvelun kehittaa julkisella tasan sisaanlinnut terveeksi kuhunkin kuudes liigan sivussa joukossaanselvisi rienna yhdenkin pysahtyi puolestamme parannustalesken alainen ehdokkaat avukseen pyydatte tuhoudutte karitsatmiettii johonkin amfetamiini lahettanyt kannabista seassaveljenne rakentakaa mahti puki kruunun rinnalle maarayksianikulunut tietoa tuska katson vaitteita kommentit erillinenmeista pahantekijoiden nimesi tarkalleen ajatuksetsuunnattomasti lueteltuina viety ruotsin sekaan vallassaviimeisetkin papin lasna keskenaan olenko sivujen suhteetviha syyrialaiset kasistaan eriarvoisuus lahtea kasvoihin syntisikunnes ihmisiin toteen armeijan sota todistuksen jaavat haranlaillinen vihollisiaan nimissa rajoja logiikalla
- 15. koituu tuleeajattelen sotakelpoiset pakenemaa n perustaa jalokivia firmajuttu hyvakseen oikeaksi lastensa turvani melkoinen kertoisikoossa puolestasi sonnin luopuneet pyhakko joivat uudestakiekon tappara tuliuhri ymparilla hopealla jalkasi mestarituleen sodassa menkaa elaimet pilkaten joille tapasi johtanutpelaamaan kohta sydamessaan tiesi historiassa lahestulkoonyritin puhutteli ymparillaan vallan taman pienta voisinsivelkoon paivan armeijan eroja portit tehtavansa sivuiltatutkimusta selvisi pankaa maakuntaan ilmoitan tienneet tekstintuhoutuu aiheuta peseytykoon ihon otit selkeasti tarttuutuomitaan katto vihollisten maaraan kuolemaan rikkomuksettullen tai tavallisesti monella jotkin tapahtumat osaankoiviston uudeksi kayda karitsat isieni kirjoitustenkansainvalinen jokilaakson ammattiliittojen siioniin suuremmatterveydenhuoltoa korvauksen tekoa heikkoja iltaan toivonsapohjoisen lahtemaan mukainen ruumista sosiaaliturvankaupunkinsa taustalla hartaasti parhaan kuoltua ennustaahyvaksyn kallista henkilokohtainen johonkin reilua hiemankyseessa laakso luovutan paasi kisin veljenne epailemattakysykaa taivaaseen kansasi jokseenkin hankala jokin mielensavarmaankin viha aitia isoisansa avukseni omalla levyuskollisuutesi suomalaisen turhaa polttouhri miesta vyoryysiunattu katkaisi valitsin vihaavat siita kirjoitat tapahtuusaimme information kuuro silti kieli palveli syvemmallekummallekin ainetta muuallakin lohikaarme kasvit alyllistaparemmin repia tallaisia onnen selkea valoon toisinpaintaydellisen oltiin joksikin siipien alkuperainen teit mielinverkko paivasta oleellista vertauksen mielenkiinnostatekemisissa kuvitella kauhusta tutkimaan parempanajarjestelman minunkin kyseisen joukkue arvoinen asiastatekemisissa kuninkuutensa selkeat yhdeksantena asukkaillejumalista elusis oikeisto kauhun lahtea lainopettajat babyloninpaamies petosta oikeastaan tuomionsa kauhean palvelijoidentunnet vahemman
- 16. kommentit maarin sovi kiitti vanhempienannetaan lainaa nabotin ajattelua karsii tupakan miettii minkoskettaa liittyy tieltanne jutussa hallin pelottavan muuallekuuluvia rinnetta vuosittain edelta kokemusta valittavatpaattivat pelkan ruuan kanna saavan tuot hankin suhteeseenheettilaisten kurissa vierasta roomassa rautalankaa linnunveljeasi hinnalla presidentti taydelliseksi kasiksi vaiheessakarpat syvyyden syostaan karpat iltahamarissa hopeisetvapauta tosiasia asutte paljastuu tienneet jousi linkin estijoivat kannalla vastuuseen portteja hyokkaavat pilviin aamunaasi puhuva ollaan tulit alla viestin kaantaneet johonkinalueelle varustettu koyha naimisissa syntisia onni laitetaanorjuuden tajuta runsas loydy eroon tiehensa kirkkohaatmiehelle egyptilaisen ymmarsi lukuisia alat suomeen onnistuijyvia vanhurskautensa lahtemaan tekijan kohosivat iloniomassa aineen molemmilla homot velkaa syrjintaa asuvienhaluat pappeina talta mitata leski tehtavaan mukana syostaansalli nimeltaan kimppuunne noihin herrasi kirkkaus turvatakertoisi ohjelman tuomittu luotan pahuutensa kasvit seinankaatuvat armoille puhuttiin veljiaan paallikoksi syokaa korvasitotta opettivat puhtaalla joukkueiden … Neuron NeuroView The Legacy of Patient H.M. for Neuroscience Larry R. Squire1,2,* 1Veterans Affairs Healthcare System, San Diego, CA 92161, USA 2Departments of Psychiatry, Neurosciences, and Psychology, University of California, San Diego, La Jolla, CA 92093, USA
- 17. *Correspondence: [email protected] DOI 10.1016/j.neuron.2008.12.023 H.M. is probably the best known single patient in the history of neuroscience. His severe memory impairment, which resulted from experimental neurosurgery to control seizures, was the subject of study for five decades until his death in December 2008. Work with H.M. established fundamental principles about how memory functions are organized in the brain. In 1952, Brenda Milner was completing her doctoral research at McGill University under the direction of Donald Hebb. At about this time, she encountered two patients (P.B. and F.C.) who had become severely amnesic following unilateral removal of the medial structures of the left temporal lobe for the treatment of epileptic seizures (Penfield and Milner, 1958). This unfortunate outcome was entirely unexpected, and it was proposed that in each case there had been a preex- istent, but unsuspected, atrophic lesion in
- 18. the medial temporal lobe of the opposite hemisphere. In that way, the unilateral surgery would have resulted in a bilateral lesion, an idea that was confirmed at autopsy some years later for patient P.B. After the two cases were presented at the 1955 meeting of the American Neuro- logical Association, Wilder Penfield (the neurosurgeon in both cases) received a call from William Scoville, a neurosur- geon in Hartford, Connecticut. Scoville told Penfield that he had seen a similar memory impairment in one of his own patients (H.M.) in whom he had carried out a bilateral medial temporal lobe resec- tion in an attempt to control epileptic seizures. As a result of this conversation, Brenda Milner was invited to travel to
- 19. Hartford to study H.M. H.M. had been knocked down by a bicycle at the age of 7, began to have minor seizures at age 10, and had major seizures after age 16. (The age of the bicycle accident is given as 9 in some reports; for clarification see Corkin, 1984.) He worked for a time on an assembly line but, finally, in 1953 at the age of 27 he had become so incapaci- tated by his seizures, despite high doses 6 Neuron 61, January 15, 2009 ª2009 Elsev of anticonvulsant medication, that he could not work or lead a normal life. Sco- ville offered H.M. an experimental proce- dure that he had carried out previously in psychotic patients, and the surgery was then performed with the approval of the patient and his family.
- 20. When Milner first visited H.M., she saw that the epilepsy was now controlled but that his memory impairment was even more severe than in Penfield’s two patients, P.B. and F.C. What she observed was someone who forgot daily events nearly as fast as they occurred, apparently in the absence of any general intellectual loss or perceptual disorder. He underestimated his own age, apolo- gized for forgetting the names of persons to whom he had just been introduced, and described his state as ‘‘like waking from a dream . every day is alone in itself.’’ (Milner et al., 1968, p. 217). The first observations of H.M., and the results of formal testing, were reported a few years later (Scoville and Milner, 1957). This publication became one of
- 21. the most cited papers in neuroscience (nearly 2500 citations) and is still cited with high frequency. H.M. continued to be studied for five decades, principally by Brenda Milner, her former student Suzanne Corkin, and their colleagues (Corkin, 1984, 2002; Milner et al., 1968). He died on December 2, 2008, at the age of 82. It can be said that the early descriptions of H.M. inaugurated the modern era of memory research. Before H.M., due particularly to the influence of Karl Lashley, memory functions were thought to be widely distributed in the cortex and to be integrated with intellectual and perceptual functions. ier Inc. The findings from H.M. established the fundamental principle that memory is
- 22. a distinct cerebral function, separable from other perceptual and cognitive abili- ties, and identified the medial aspect of the temporal lobe as important for memory. The implication was that the brain has to some extent separated its perceptual and intellectual functions from its capacity to lay down in memory the records that ordinarily result from engaging in perceptual and intellectual work. The Medial Temporal Lobe Memory System The early paper is sometimes cited incor- rectly as evidence that the hippocampus is important for memory, but this partic- ular point could not of course be estab- lished from a lesion that, by the surgeon’s description, included the hippocampus,
- 23. amygdala, and the adjacent parahippo- campal gyrus. As Milner subsequently wrote, ‘‘Despite the use of the word ‘hippocampal’ in the titles of my papers with Scoville and Penfield, I have never claimed that the memory loss was solely attributable to the hippocampal lesions’’ (Milner, 1998). Indeed, the original paper ends, quite appropriately, with the state- ment: It is concluded that the anterior hippocampus and hippocampal gyrus, either separately or together, are critically concerned in the retention of current experience. It is not known whether the amygdala plays any part in this mechanism, since the hippocampal complex
- 24. has not been removed alone, but mailto:[email protected] Neuron NeuroView always together with uncus and amygdala. (Scoville and Milner, 1957, p. 21). The findings from H.M. were initially met with some resistance, especially because of the difficulty for many years of demonstrating anything resembling his impairment in the experimental animal. Efforts to establish an animal model in fact began almost immediately when Scoville himself came to Montreal and did the same surgery in monkeys that he had done with H.M. But these monkeys and others with medial temporal lesions
- 25. seemed able to learn tasks that H.M. could not learn. Only much later did it become understood that apparently similar tasks can be learned in different ways by humans and monkeys. For example, the visual discrimination task, which is learned gradually by the monkey over hundreds of trials, proved to involve what one would now call habit learning. In the monkey, this kind of learning depends on the basal ganglia, not the medial temporal lobe. Eventually, tasks were developed for the monkey that were exquisitely sensitive to medial temporal lobe lesions (for example, the one-trial, delayed nonmatching to sample task), and an animal model of human memory impairment thereby became
- 26. available (Mishkin, 1978). Cumulative work with the animal model over the next decade, together with neuroanatomical studies, succeeded in identifying the anatomical components of what is now termed the medial temporal lobe memory system (Squire and Zola-Morgan, 1991): the hippo- campus and the adjacent perirhinal, ento- rhinal, and parahippocampal cortices that make up much of the parahippocampal gyrus. This information showed which structures within H.M.’s large lesion were important for understanding his impairment and, more broadly, what structures are important for memory. A few years later, an improved description of H.M.’s lesion was obtained with
- 27. magnetic resonance imaging (MRI) (Cor- kin et al., 1997). MRI had been delayed because of concerns that clips placed on the dura during surgery made H.M. ineligible for imaging. However, thorough inquiry revealed that the dural clips constituted no risk. At this juncture, several points became clear. First, H.M.’s lesion was less extensive than described originally by the surgeon in that it extended a little more than 5 cm caudally from the temporal pole (not 8 cm). As a result the posterior parahippocampal gyrus was largely spared (specifically, the parahippocampal cortex or what in the monkey is termed area TH TF). Second, the reason that H.M.’s memory impairment was so severe
- 28. was that the bilateral damage included the parahippocampal gyrus (anteriorly) and was not restricted to the hippocampus. Damage limited to the hippocampus causes significant memory impairment but considerably less impairment than in H.M. Third, memory impairment more severe than H.M.’s could now be under- stood, as when the damage includes the structures damaged in H.M. but also extends far enough posteriorly to involve the parahippocampal cortex (patients E.P. and G.P.; Kirwan et al., 2008). In the early years, the anatomy of the medial temporal lobe was poorly under- stood, and terms like hippocampal zone and hippocampal complex were often used to identify the area of damage. With
- 29. the elucidation of the boundaries and connectivity of the structures adjacent to the hippocampus and the discovery that these structures are important for memory, vague terms like hippocampal complex became unnecessary (though one can still find them in contemporary writing). It is now possible to achieve care- ful descriptions based on anatomical measurement and modern terminology. H.M. not only motivated the develop- ment of an animal model of human memory impairment and the subsequent delineation of the medial temporal lobe memory system. As described next, the study of H.M. also led to fundamental insights into the function of the medial temporal lobe and the larger matter of
- 30. how memory is organized in the brain. Immediate Memory and Long-Term Memory H.M.’s intact intellectual and perceptual functions, and similar findings in other patients with large medial temporal lesions, have been well documented. A key additional finding was that H.M. had a remarkable capacity for sustained attention, including the ability to retain Neuron information for a period of time after it was presented. Thus, he could carry on a conversation, and he exhibited an intact digit span (i.e., the ability to repeat back a string of six or seven digits). Indeed, information remained available so long as it could be actively maintained by rehearsal. For example, H.M. could retain a three-digit number for as long as 15 min
- 31. by continuous rehearsal, organizing the digits according to an elaborate mnemonic scheme. Yet when his atten- tion was diverted to a new topic, he forgot the whole event. In contrast, when the material was not easy to rehearse (in the case of nonverbal stimuli like faces or designs), information slipped away in less than a minute. These findings sup- ported a fundamental distinction between immediate memory and long-term memory (what William James termed primary memory and secondary memory). Primary memory [immediate memory] .comes to us as belonging to the rearward portion of the present space of time, and not to the genuine past (James, 1890, p. 647). Secondary memory [long-term memory] is
- 32. quite different. An object which has been recol- lected . is one which has been absent from consciousness alto- gether, and now revives anew. It is brought back, recalled, fished up, so to speak, from a reservoir in which, with countless other objects, it lay buried and lost from view. (James, 1890, p. 648). Notably, time is not the key factor that determines how long patients like H.M. can retain information in memory. The rele- vant factors are the capacity of immediate memory and attention, i.e., the amount of material that can be held in mind and how successfully it can be rehearsed. The work with H.M. demonstrated that
- 33. the psychological distinction between immediate memory and long-term memory is a prominent feature of how the brain has organized its memory functions. Multiple Memory Systems Perhaps the most unexpected discovery about H.M., given his profound and global 61, January 15, 2009 ª2009 Elsevier Inc. 7 Neuron NeuroView memory impairment, came when Brenda Milner tested his ability to acquire a visuo- motor skill (Milner, 1962). H.M. was shown a five-pointed star, with a double contour, and asked to trace its outline with a pencil, but in a condition when he could only see his hand and the star as reflected in a mirror. H.M. acquired this mirror- drawing skill during ten trials and
- 34. exhibited excellent retention across 3 days. Yet at the end of testing, he had no recollection of having done the task before. This demonstration provided the first hint that there was more than one kind of memory in the brain and sug- gested that some kinds of memory (motor skills) must lie outside the province of the medial temporal lobe. For a time, it was rather thought that motor skills were a special case and that all the rest of memory is impaired in patients like H.M. Later it became appre- ciated that motor skills are but a subset of a larger domain of skill-like abilities, all of which are preserved in amnesia. The demonstration of a fully preserved ability to learn the perceptual skill of mirror
- 35. reading suggested a distinction between two broad classes of knowledge: declara- tive and procedural (Cohen and Squire, 1980). Declarative memory is what is meant when the term ‘‘memory’’ is used in everyday language, i.e., conscious knowledge of facts and events. Proce- dural memory refers to skill-based knowl- edge that develops gradually but with little ability to report what is being learned. In the years that followed, other preserved learning abilities began to be reported for amnesic patients, and the perspective shifted to a framework that accommodated multiple (i.e., more than two) memory systems. As Endel Tulving wrote: But even if we accept the broad
- 36. division of memory into procedural and propositional forms . there are phenomena that do not seem to fit readily into such a taxonomy (Tulving et al., 1982, p.336). Subsequently, the terms declarative and nondeclarative were introduced with the idea that declarative memory refers to the kind of memory that is impaired in H.M. and is dependent on the medial temporal lobe. Nondeclarative memory 8 Neuron 61, January 15, 2009 ª2009 Elsev is an umbrella term referring to additional memory systems. These include systems that support skill learning, habit learning, simple conditioning, emotional learning, as well as priming and perceptual learning. The structures with special importance for these kinds of memory
- 37. include the basal ganglia, the cerebellum, the amygdala, and the neocortex. The starting point for these developments was the early discovery that motor skill learning was preserved in H.M. This finding revealed that memory is not a single faculty of the mind and led ulti- mately to the identification of the multiple memory systems of the mammalian brain. Remote Memory H.M.’s memory impairment has generally been taken as reflecting a failure to convert transient, immediate memory into stable long-term memory. A key insight about the organization of memory, and medial temporal lobe function, came with a consideration of his capacity to remember information that he had acquired before his surgery. The first
- 38. exploration of this issue with formal tests asked H.M. to recognize faces of persons who had become famous in different decades, 1920–1970 (Marslen-Wilson and Teuber, 1975). As expected, H.M. was severely impaired at recognizing faces from his postmorbid period (the 1950s and 1960s), but he performed as well as or better than age-matched controls at recognizing faces of persons who were in the news before his surgery. This important finding implied that the medial temporal lobe is not the ultimate storage site for previously acquired knowledge. The early descriptions of H.M. conform to this view. Thus, H.M. was described as having a partial loss of memory (retrograde amnesia) for the 3 years leading up to his
- 39. surgery, with early memories ‘‘seemingly normal’’ (Scoville and Milner, 1957, p. 17). Similarly, about 10 years later it was remarked that there did not appear to have been any change in H.M.’s capacity to recall remote events antedating his operation, such as incidents from his early school years, a high-school attachment, or jobs he had held in his late teens and early twenties (Milner et al., 1968, p. 216). ier Inc. Subsequently, a particular interest developed in the status of autobiograph- ical memories for unique events, which are specific to time and place, and methods were developed to assess the specificity and the detail with which such
- 40. recollections could be reproduced. In the earliest efforts along these lines, as summarized by Suzanne Corkin (Corkin, 1984), H.M. produced well-formed auto- biographical memories, from age 16 years or younger. It was concluded that H.M’s remote memory impairment now extended back to 11 years before his surgery. The situation seemed to change further as H.M. aged. In an update prepared nearly 20 years later (Corkin, 2002), H.M. (now 76 years old) was described as having memories of child- hood, but his memories appeared more like remembered facts than like memories of specific episodes. It was also said that he could not narrate a single event that occurred at a specific time and place.
- 41. Essentially the same conclusion was reached a few years later when new methods, intended to be particularly sensitive, were used to assess H.M.’s remote memory for autobiographical events (Steinvorth et al., 2005). These later findings led to the proposal that, whatever might be the case for fact memory, autobiographical memories, i.e., memories that are specific to time and place, depend on the medial temporal lobe so long as the memories persist. There are reasons to be cautious about this idea. In 2002–2003, new MRI scans of H.M. were obtained (Salat et al., 2006). These scans documented a number of changes since his first MRI scans from 1992–1993 (Corkin et al., 1997), including
- 42. cortical thinning, subcortical atrophy, large amounts of abnormal white matter, and subcortical infarcts. These findings were thought to have appeared during the past decade, and they complicate the interpretation of neuropsychological data collected during the same time period. Another consideration is that remote memories could have been intact in the early years after surgery but then have faded with time because they could not be strengthened through rehearsal and relearning. In any case, the optimal time to assess the status of past memory is soon after the onset of memory impairment. Neuron
- 43. NeuroView Other work has tended to support the earlier estimates that H.M.’s remote memories were intact. First, Penfield’s two patients described above, P.B. and F.C., were reported after their surgeries to have memory loss extending back a few months and 4 years, respectively, and intact memory from before that time (Penfield and Milner, 1958). Second, methods like those used recently to assess H.M. have also been used to eval- uate autobiographical memory in other patients, including patients like E.P. and G.P. who have very severe memory impairment (Kirwan et al., 2008). In these cases, autobiographical recollection was impaired when memories were drawn
- 44. from the recent past but fully intact when memories were drawn from the remote past. Memory loss can sometimes extend back for decades in the case of large medial temporal lobe lesions (though additional damage to anterolateral temporal cortex may be important in this circumstance). In any case, memories from early life appear to be intact unless the damage extends well into the lateral temporal lobe or the frontal lobe. These findings are typically interpreted to mean that the structures damaged in H.M. are important for the formation of long-term memory and its maintenance for a period of time after learning. During this period gradual changes are thought to occur in
- 45. neocortex (memory consolidation) that increase the complexity, distribution, and connectivity among multiple cortical regions. Eventually, memory can be sup- ported by the neocortex and becomes independent of the medial temporal lobe. The surprising observation that H.M. had access to old memories, in the face of an inability to establish new ones, motivated an enormous body of work, both in humans and experimental animals, on the topic of remote memory and continues to stimulate discussion about the nature and significance of retro- grade amnesia. Perspective H.M. was likely the most studied individual in the history of neuroscience. Interest in the case can be attributed to
- 46. a number of factors, including the unusual purity and severity of the memory impair- ment, its stability, its well-described anatomical basis, and H.M.’s willingness to be studied. He was a quiet and cour- teous man with a sense of humor and insight into his condition. Speaking of his neurosurgeon, he once said, ‘‘What he learned about me helped others, and I’m glad about that.’’ (Corkin, 2002, p. 159). An additional aspect of H.M.’s circum- stance, which assured his eventual place in the history of neuroscience, was the fact that Brenda Milner was the young scientist who first studied him. She is a superb experimentalist with a strong conceptual orientation that allowed her to draw from her data deep insights about
- 47. the organization of memory. Because he was the first well-studied patient with amnesia, H.M. became the yardstick against which other patients with memory impairment would be compared. It is now clear that his memory impairment was not absolute and that he was able to acquire significant new knowledge (Corkin, 2002). Thus, memory impairment can be either more severe or less severe than in H.M. But the study of H.M. established key principles about how memory is orga- nized that continue to guide the discipline. ACKNOWLEDGMENTS Supported by the Medical Research Service of the Department of Veterans Affairs, The National Insti- tute of Mental Health (MH24600), and the Metro- Neuro politan Life Foundation. I thank Nicola Broadbent, Robert Clark, Christine Smith, Ryan Squire, and Wendy Suzuki for their helpful comments.
- 48. REFERENCES Cohen, N., and Squire, L.R. (1980). Science 210, 207–209. Corkin, S. (1984). Semin. Neurol. 4, 249–259. Corkin, S. (2002). Nat. Rev. Neurosci. 3, 153–160. Corkin, S., Amaral, D.G., Gonzalez, R.G., Johnson, K.A., and Hyman, B.T. (1997). J. Neurosci. 17, 3964–3979. James, W. (1890). Principles of Psychology, Dover Edition, Volume One (New York: Holt). Kirwan, C.B., Bayley, P.J., Galván, V.V., and Squire, L.R. (2008). Proc. Natl. Acad. Sci. USA 105, 2676–2680. Marslen-Wilson, W.D., and Teuber, H.L. (1975). Neuropsychologia 13, 353–364. Milner, B. (1962). Physiologie de l’hippocampe, P. Passouant, ed. (Paris: Centre National de la Recherche Scientifique), pp. 257–272. Milner, B. (1998). The History of Neuroscience in Autobiography, Volume 2, L.R. Squire, ed. (San Diego: Academic Press), pp. 276–305. Milner, B., Corkin, S., and Teuber, H.L. (1968). Neuropsychologia 6, 215–234. Mishkin, M. (1978). Nature 273, 297–298.
- 49. Penfield, W., and Milner, B. (1958). AMA Arch. Neurol. Psychiatry 79, 475–497. Salat, D.H., van der Kouwe, A.J.W., Tuch, D.S., Quinn, B.T., Fischl, B., Dale, A.M., and Corkin, S. (2006). Hippocampus 16, 936–945. Scoville, W.B., and Milner, B. (1957). J. Neurol. Neurosurg. Psychiatry 20, 11–21. Squire, L.R., and Zola-Morgan, S. (1991). Science 253, 1380–1386. Steinvorth, S., Levine, B., and Corkin, S. (2005). Neuropsychologia 43, 479–496. Tulving, E., Schacter, D.L., and Stark, H.A. (1982). J. Exp. Psychol. Learn. Mem. Cogn. 8, 336–342. n 61, January 15, 2009 ª2009 Elsevier Inc. 9 The Legacy of Patient H.M. for NeuroscienceThe Medial Temporal Lobe Memory SystemImmediate Memory and Long- Term MemoryMultiple Memory SystemsRemote MemoryPerspectiveAcknowledgmentsReferences Sheet1VendorNameEmployeeNameDateYearRatingGreat Value CompanyPatty Smith2/15/1320134Top Down ProductsScott Freely3/6/1320133Perfect JointMike Hanley3/9/1320135Great Value CompanyMike Hanley3/12/1320132Top Down ProductsPatty Smith3/7/1420145Perfect JointScott Freely3/15/1420143Great Value CompanyPatty Smith3/16/1420142Top Down ProductsMike Hanley3/21/1420144Perfect JointScott Freely3/13/1520151Great Value CompanyPatty Smith3/1/1520153Top Down ProductsPatty Smith3/17/1520155Perfect JointPatty Smith3/9/1520153Great Value CompanyMike Hanley3/2/1520154Top Down
- 50. ProductsScott Freely3/25/1620165Perfect JointMike Hanley3/8/1620162Great Value CompanyPatty Smith3/19/1620163Top Down ProductsPatty Smith3/21/1620162Perfect JointScott Freely3/1/1620164 Sheet2 Sheet3