Dopamine, nthawi, ndi kukhudzidwa kwa anthu (2010)

J Neurosci. 2010 Jun 30;30(26):8888-96. onetsani: 10.1523 / JNEUROSCI.6028-09.2010.

Pine A1, Shiner T, Seymour B, Dolan RJ.

Zambiri za wolemba

Kudalirika

Disopoto dopamine neurotransication imakhudzidwa pakulimbikitsa kukakamiza kudutsa machitidwe osiyanasiyana ndi zovuta monga kuphatikiza, kusuta njuga, kukakamiza chidwi / kusokonezeka, ndi vuto la dopamine dysregulation. Pomwe malingaliro omwe adalipo a dopamine amagogomezera njira zochokera pakulandila mphotho zoperekera kapena zoziziritsa kukhosi, samapereka akaunti yokwanira ya pathological hypersensitivity ku kuchepa kwakanthawi komwe kumakhala kachitidwe kofunika kamene kamawonedwe mu zovuta izi. Apa timapereka umboni kuti gawo la dopamine pakuwongolera ubale womwe ulipo pakati pa mphoto zamtsogolo ndi kufunika kwawo kogwirizana kungathe kutsitsa kusiyana uku. Pogwiritsa ntchito njira yosankhira patali, tikuwonetsa kuti ntchito yopanga ma dopamine mopitilira muyeso imawonjezera kukhudzika pakukulitsa kufooka kopitilira muyeso wa phindu la mphotho (kuchotsera kwakanthawi) ndi kuyimira kwofananira kwa neural mu striatum. Izi zimabweretsa mkhalidwe wochepetsa kwambiri kwakanthawi kwakanthawi, wachibale, posachedwa, mphotho. Chifukwa chake zomwe tapeza zikuwonetsa njira yomwe dopamine imakhudzira kusankha kwa anthu komwe kumayambitsa kusintha kwa mayendedwe okhudzana ndi dopamine.

Introduction

Kuwonongeka kwa kudziletsa komanso kusakhudzidwa komwe kumayenderana ndi kugwiritsidwa ntchito kwa dopamine kumawonetsedwa ndi zovuta monga kukodzetsa, chidwi-deficit / hyperacaction disorder (ADHD), ndi dopamine dysregulation syndrome (Winstanley et al., 2006; Dagher ndi Robbins, 2009; O'Sullivan et al., 2009). Omalizawa, dopamine m'malo mwa chithandizo cha matenda a Parkinson (PD) imapangitsa odwala ena kukhala okakamira, omwe amadzionetsera ngati kutchova juga mopitilira muyeso, kugula, kudya, ndi zina zomwe sizingachitike mtsogolo. Komabe, chidwi chachikulu chazomwe zimakhazikika pamakhalidwe amenewa chimakhala ndi njira zingapo zopangira zisankho zomwe zitha kusiyanitsidwa ndi ma neurobiologically ndi pharmacologically (Evenden, 1999; Ho et al., 1999; Winstanley et al., 2004a, 2006; Dalley et al., 2008). Izi zikuphatikiza kusowa poyankha mayankho okonzekera ma mota, kuchuluka kwa mphotho zokhudzana ndi kutayika, kulephera kuchepa pang'onopang'ono pakuyangana kwamalingaliro, komanso kufunafuna kosankha zing'onozing'ono - zochulukirapo pambuyo pake.

Mwakutero, zoperewera zomwe tatchulazi zitha kukhala zokhudzana ndi zovuta za dopaminergic kudzera munjira yomwe dopamine idakhazikitsa pakuphunzira mphotho (Fotokozerani, 2004; Frank et al., 2007; Dagher ndi Robbins, 2009). Komabe, kufunikira kwakanthawi (kapena kusankha) - kukonda pang'ono - mphotho zokulirapo - pambuyo pake, chifukwa chakuchotsa kwambiri mphotho yamtsogolo (Ainslie, 1975; Evenden, 1999; Ho et al., 1999; Cardinal ndi al., 2004- - nkovuta kwambiri kuwerengera pankhani ya kuphunzira, ngakhale imakhalabe chinthu chofunikira kwambiri pakudzipangitsa kukhala dopaminergic impulsivity. Zowonadi, mayeso a labotale zosankha zapakati pa ziwonetserozi zimawonetsa kuti osokoneza bongo komanso gulu laling'ono la odwala omwe ali ndi vuto la ADHD amawoneka kuti ali ndi ziwopsezo zazitali zosakhalitsa, okonda mphotho zazing'ono -Sagvolden ndi Sergeant, 1998; Bickel ndi Marsch, 2001; Solanto et al., 2001; Winstanley et al., 2006; Bickel et al., 2007). Izi zikuyambitsa funso loti dopamine ali ndi gawo linalake pakuwerengera momwe kuyandikira kwa mphotho kumagwirizirana ndi mtengo wake wothandizidwa (mwachitsanzo, kuchotsera kwakanthawi), pokhapokha pakukhazikitsa kwake kopindulitsa kuphunzira.

Kufufuza ngati dopamine imasintha kutengera kudulira kofunikira nthawi, tinapereka dopamine precursor l-dopa, dopamine antagonist haloperidol, ndi placebo kwa odzipereka athanzi omwe akuchita ntchito yosankha pakati. Ntchitoyi idafunikira anthu kuti apange zisankho zenizeni pakati pa kuchuluka kwa ndalama, kupatula nthawi yosinthika, makamaka kuphatikiza kusankha pakati pa zazing'ono-posachedwa poyerekeza zokulirapo - mphotho yayikulu. Kusankha kotereku kumadziwika bwino ndi mitundu yomwe imakhala ndi zotsika za nthawi komanso zotsitsa zomwe zimapangitsa kuti chiwonjezero chambiri (kuchepetsedwa kothandizidwa)Pine et al., 2009). Chifukwa chake, kuchotsera kapena phindu lokhalo lokhala ndi mphotho yomwe yachedwa kumatsimikizika chifukwa cha kuchotsera (nambala pakati pa zero ndi imodzi) ndikugwiritsa ntchito mphothoyo. Ngati dopamine imasinthira kusankha kwa munthu pantchitoyi, itha kuwonetsa kusintha kwa kuchotsera kapena kugwiritsika ntchito / kuwona (onani Zipangizo ndi Njira) - kusiyana komwe tidatha kuwunika pano pamachitidwe ndi minyewa, pogwiritsa ntchito kujambula kwamagnetic resonance imaging (fMRI). Kuphatikiza apo, tidayesa ngati dopamine ili ndi vuto lililonse pamlingo wakuchepetsa komwe kumayambitsidwa ndi kusamvana posankha (Frank et al., 2007; Pochon et al., 2008) kusiyanitsa dziko lonse lapansi ndi zomwe zimapangitsa kuti anthu azichita zinthu mosafunikira.

Zida ndi njira

Tidagwiritsa ntchito fMRI pomwe maphunziro adasankha pakati pa zosankha ziwiri zopangidwa mosiyanasiyana (kuchokera pa $ 1 mpaka $ 150) ndikuchedwa (kuyambira 1 sabata mpaka 1 chaka) (Chith. 1). Mutu uliwonse udachita ntchitoyi maulendo atatu (okhudzana ndi mankhwala atatuwo). Zosankhazi nthawi zambiri zimakhala zazing'ono-posachedwa poyerekeza ndi zazikulu-zosankha zamtsogolo. Chimodzi mwazisankho zamaphunziro adasankhidwa mwachisawawa kumapeto kwa kuyeserera (mgawo lililonse loyesera) ndikulipira zenizeni (mwachitsanzo, patsiku lotsogola) posamutsa banki. Tidagwiritsa ntchito zisankho kuti tiwone momwe kuchotsera ukulu komanso nthawi. Tidayesa mtundu womwe umaphatikiza ntchito yothandiza (kutembenuza ukulu kukhala yothandiza) ndi ntchito yotsitsa ya hyperbolic. M'mawu osavuta, ntchito yogwiritsira ntchito kuchotsera (mtengo wogonjera) wa mphotho yomwe yachedwa (V) lofanana ndi D × U kumene D ndichotsitsa pakati pa 0 ndi 1 ndi U sizothandiza. D mwachizolowezi ndi ntchito yochepetsera mphoto ndipo imaphatikizira gawo la kuchotsera (K), yomwe imasankha momwe munthu amafunira zabwino zamtsogolo. U ndi (mwachizolowezi) ntchito yamphamvu ya mphotho ndipo zimatengera gawo la munthu (r) yomwe imatsimikiza kugwiraku / kuwonekera kwa ntchitoyo, kapena kuchuluka kwa kuchepa kwa zinthu zogwiritsika ntchito chifukwa cha phindu ndipo chifukwa chake mtengo wamtengo wapatali wachibale wokulirapo. Chachikulu K or r, munthu angathe kusankha njira posachedwa ndiye chifukwa chake iye ndiye woyenerayo (Ho et al., 1999; Pine et al., 2009). Malinga ndi chiphunzitso chothandiza, kusankha kumatsimikizidwa ndi mfundo yakugwiritsa ntchito pomwe angasankhe ndi ntchito yotsika yayikulu kwambiri.

Chithunzi 1 

Ntchito yopanga. Mituyi idapatsidwa zosankha zingapo za 220 zosankha, nthawi zambiri pakati pa zazing'ono- posachedwa komanso zokulirapo, pambuyo pake, zomwe zimasiyana kuchokera pa $ 1- £ 150 ndikuchepetsedwa ndi masabata a 1-52. Zindikirani ...

ophunzira

Anthu khumi ndi anayi akumanzere, odzipereka athanzi adaphatikizidwa pachiyeso (amuna a 6; akazi a 8; zaka zosafunikira, 21; osiyanasiyana, 18-30). Amaphunzirawa anapangidwadi kupatula omwe anali ndi mbiri yakale ya matenda amitsempha kapena matenda amisala. Maphunziro onse adapereka chidziwitso chokwanira ndipo kafukufukuyo adavomerezedwa ndi komiti ya University College London. Phunziro limodzi lidachoka mu phunziroli litatha gawo loyamba ndipo silinaphatikizidwe pazotsatira. Wina sanamalize gawo lomaliza (placebo) mu scanner, koma zomwe amachita mu magawo awiri onse ndi zina mwa masamba awiri zidaphatikizidwa pazotsatira.

Ndondomeko ndi kufotokoza kwa ntchito

Phunziro lililonse limayesedwa katatu. Pobwera pazochitika zilizonse, ophunzirawo adapatsidwa pepala lophunzitsira kuti awerenge momwe amafotokozera momwe angachitire khungu. Kenako amaliza chiwonetsero chazithunzi (Bond ndi Lader, 1974) omwe anayeza mayiko ogwirizana monga chidwi, ndipo kenako anapatsidwa envelopu yomwe inali ndi mapiritsi awiri omwe anali 1.5 mg wa haloperidol kapena placebo. Ola limodzi ndi theka mutatha kumwa mapiritsi oyamba, maphunziro anapatsidwa envulopu ina yokhala ndi mapiritsi awiri omwe mwina ndi Madopar (okhala ndi 150 mg wa l-dopa) kapena placebo. Mapiritsi a placebo (vitamini C kapena multivitamini) anali osiyana ndi mankhwalawo. Pazonse, phunziro lililonse limalandira mlingo umodzi wa Madopar pa gawo limodzi, mlingo umodzi wa haloperidol wina, ndipo pamitundu iwiri yonse ya mapiritsi anali placebo. Dongosolo la mtundu uliwonse wa mankhwala mogwirizana ndi gawo loyeserera linali lofanana pamaphunziro onse ndipo sizinadziwike kwa woyesayo kuti akwaniritse kapangidwe ka khungu. Kuyesedwa kunayamba 30 min pambuyo pakumeza mapiritsi achiwiri. Nthawi yake inali yoti akwaniritse kuchuluka kwa mankhwalawa a plasma pakatikati pa kuyesedwa. Pambuyo poyesa, maphunziro adamaliza muyeso wina wofanana (wofanana). Palibe magawo awiri oyesera omwe adachitika mkati mwa sabata la 1 wina ndi mnzake.

Ntchito yamakhalidwe anali ambiri monga amafotokozera Pine et al. (2009). Chiyeso chilichonse chimakhala ndi kusankha pakati pa mphotho yaying'ono- posachedwa ndi mphotho yayikulupo. Kusankhaku kudawonetsedwa motsatana, m'magawo atatu (Chith. 1). Magawo awiri oyambilira anali ndi kuwonetsa tsatanetsatane wa chosankha chilichonse, mwachitsanzo, kukula kwa mphothoyo mapaundi ndikuchedwa kuulandira mu miyezi ndi masabata. Pambuyo pofotokoza zomwe mwasankhazi, skrini yachitatu idalimbikitsa mutuwo kuti usankhe pakati pa njira 1 (njira yomwe idaperekedwa koyamba) kapena njira 2, pogwiritsa ntchito bokosi-batani, pogwiritsa ntchito dzanja lawo lamanja. Kuchedwa kwa 3 s kunatsata magawo atatu onsewo. Chisankhocho chingapangidwe pokhapokha pakuwonetsedwa ndi 3 s pazenera. Chisankho chikapangidwa, kusankha komwe kunasankhidwa kunkawonetsedwa pabuluu. Kupereka panali nthawi yokwanira, mutuwu ukhoza kusintha malingaliro ake. Panali kuchedwa kwa 1-4 s kutsatira gawo losankhidwa, lotsatiridwa ndikuwonetsedwa kwa mtanda wa 1 s.

Kuyesaku kunaphatikizapo kuyesa konse kwa 200. Njira 1 inali mphotho yaying'ono kwambiri - posachedwa mu 50% ya mayesero. Kuphatikiza apo, tidaphatikizanso kuyesa kwina kwa "X" 20, komwe zosankha zonse zinali zazikulu komanso zopezeka posachedwa kuposa zina. Mayeserowa adachitika pafupifupi m'chiyeso chilichonse ndipo amatithandiza kudziwa momwe zinthu zimayendera pantchitoyo, poganiza kuti chizolowezi chake chinali choti akonde mphotho yayikulupo posachedwa posankha izi. Phunziro lirilonse linapatsidwa zosankha zingapo mgawo uliwonse woyeserera (mwachitsanzo, mkhalidwe uliwonse wa mankhwala) kupatula maphunziro awiri oyamba omwe anapatsidwa chisankho mosiyana pa gawo lawo loyamba loyesa. Makhalidwe osankhidwa adapangidwa ndikugwiritsa ntchito kukula kwakanthawi kochulukirapo kwa $ 1 mpaka $ 150 m'magawo a $ 1 ndi kuchedwa kuyambira pa sabata la 1 mpaka chaka cha 1 m'magawo a masabata amodzi (koma adawonetsedwa ngati miyezi yambiri ndi masabata), kachiwiri ndi kugawa mwachisawawa. Izi mwatsatanetsatane za mfundo zomwe zidathandizira kukula komanso kufalikira. Kupanga zisankho pakati pa mphotho zazing'onoting'ono kapena zazikulupo - pambuyo pake, tidafotokozera kuti kusankha komwe kungakhale kokwezeka kwambiri kuyenera kuchedwedwa kuposa kocheperako, komanso mosemphana ndi mayeso akugwira. Maphunzirowa adapatsidwa gawo limodzi mwazosankha ziwiri molingana ndi mayankho omwe adayesedwa mgawo lawo loyamba. Izi zimapangidwa kuti zigwirizane ndi zisankho zomwe zaperekedwa pamlingo wofikira pamutu.

Kulipira kunachitika pogwiritsa ntchito lottery kuti asankhe kuyesa kamodzi pa gawo lililonse loyesa. Kuti tifotokozere kuti chilengedwe ndi chovomerezeka, tinagwiritsa ntchito njira yolipira yomwe inkaonetsetsa kuti zisankho zonse zichitike moyenera, ndi zotsatirapo zake. Chofunikira pamapangidwe awa chinali kusankha mwachisawawa pa chisankho chomwe chidapangidwa poyeserera, ndikulipira kwenikweni komwe kunasankhidwa mwanjira imeneyo. Izi zidakwaniritsidwa mwa kusinthidwa kwa banki yomwe idapangidwa panthawi yomwe idalumikizidwa, ndikupanga kuchuluka kwa zomwe zasankhidwa. Kusankhidwa kwa malipiro kunayambitsidwa pogwiritsa ntchito lottery yamanja mukamaliza kuyesa konse. Malotowa anali ndi mipira yakuwerengera ya 220, iliyonse imayimira kuyeserera kamodzi pa ntchitoyi. Mpira womwe udasankhidwa umafanana ndi mayeso omwe adalandira mphotho yoyeserera ija. Kukula ndi kuchedwa kwa chisankho chomwe mutuwo udasankha pamayeso osankhidwa adatsimikiza ndikupatsidwa pogwiritsa ntchito banki. Chifukwa chake, ngongole iliyonse yomwe adalandira idatsimikizika ndi kuphatikiza kwa lottery ndi zosankha zomwe adapanga - mphete zomwe zimatsimikizira kuti anthu onse amatenga nawo mbali ngati zenizeni. Njira yolipira idapangidwa kuti pafupifupi mutu uliwonse uzilandira $ 75 pa gawo lililonse. Palibe ndalama ina iliyonse yomwe idaperekedwa chifukwa choyeserera.

Mitu isanatengedwe mu scanner, adawonetsedwa makina a lottery ndikufotokozeredwa momwe bankayo ​​ingayigwiritsire ntchito, kuwatsimikizira kuti njira yolipira ndi kusankha ndiyowona. Pambuyo poyeserera mwachidule kwa mayeso asanu ndi limodzi, adatengedwera ku sikani momwe adachitirapo magawo awiri a mayeso a 110 lilime lililonse, lokhalokha kwa ~ 50 min.

Njira zoyeserera

Kuyerekezera kwa ntchito kunachitika pogwiritsa ntchito sikelo ya 3-tesla Motorola Allegra mutu-yekha wa MRI kuti mutenge zithunzi zowoneka bwino za T2 * -opepuka pazithunzi za EPho-planar (EPI) zokhala ndi vuto la oxygen oxygenation--BOLD. Tidagwiritsa ntchito momwe adapangitsira kuti azigwiriziza zomverera zothandiza mu orbitof mbeleal cortex (Deichmann et al., 2003). Izi zinali ndi kupendekera kosunthika mu mawonekedwe a 30 ° mpaka kumanzere kwa cingate-posterior cingulate AC-PC mzere, ndikugwiritsanso ntchito kukonzekera komwe kumatenga nthawi ya 1 ms komanso matalikidwe a −2 mT / m pakusankhidwa kwagawo malangizo. Kusinthaku kunathandizira magawo a 36 axial a makulidwe a 3 mm ndi 3 mm mu ndege kupanga kuti mutenge ndi nthawi yobwereza (TR) ya 2.34 s. Mituyi idayikidwa pakubwezeretsa mutu mkati mwa sikani kuti muchepetse kusuntha kwa mutu panthawi yomwe ikugulidwa. Zogwiritsira ntchito zoganiza zogwira ntchito zinapezeka m'magawo awiri osiyana a 610 voliyumu. Chithunzithunzi cholemedwa ndi T1 cholemetsa ndi mapangidwe amminda adapangidwanso pamutu uliwonse pambuyo pa magawo oyeserera.

Kuwunika kwamakhalidwe

Kuti tipeze kuchuluka kwathunthu kosankha mosakakamiza, tinawerengera zosankha posachedwa pamayeso a 220, pansi pamankhwala aliwonse, pamutu uliwonse. Mayesero omwe sanayankhidwe sanaperekedwe pachilichonse pamankhwala onse atatu. Mwachitsanzo, ngati mutu umodzi sunayankhe panthawi yoyesa 35 pamayesero a placebo, mayesowa sanawerengeredwe kuwerengera mumikhalidwe ina iwiri ya phunziroli. Izi zidawonetsetsa kuti kufananizaku kunapangidwa pamayeso poyeserera (momwe machitidwe omwewo amayeserera anaperekedwa gawo lirilonse loyesa) ndipo zovuta zilizonse za mankhwala pazomwezi sizinali zogwirizana ndi kuchuluka kwa zosankha zomwe zidapangidwa pamtundu uliwonse. ANOVA yochitira zinthu mobwerezabwereza idagwiritsidwa ntchito kuyang'ana kusiyana kulikonse pamitundu yonseyi pamankhwala.

Kuyerekeza kwa Paramu

Tinakhazikitsa lamulo laling'ono la softmax kuti tigawireko mwayi (PO1 mwasankhidwe 1) pachisankho chilichonse chosankha chopatsidwa phindu la chosankha (VO1 kusankha 1) potero

POi=e(VOi/β)e(VO1/β)+e(VO2/β).
(1)

VOi ikuyimira phindu la chosankha (mwachitsanzo, mphotho yomwe yachedwa) malinga ndi mtundu wa mtundu wa kusankha (onani pansipa). The β parameter ikuyimira kuchuluka kwa kusakhulupirika kwamachitidwe a mutuwo (mwachitsanzo, kuzindikira kufunika kwa njira iliyonse).

Tinagwiritsa ntchito mtundu wotsika mtengo wazosankha, zomwe tidanenanso kale (Pine et al., 2009) monga kupereka chidziwitso choyenera pazomwe mungasankhe pantchitoyi. Mtunduwu umati kuchotsera ()V) za mphotho yayikulu.M) komanso ndikuchedwa (d) itha kufotokozedwa motere:

V=D(d)⋅U(M)=1-e(-r⋅M)r(1+K⋅d),
(2)

kumene

D=11+K⋅d

ndi

U=1-e(-r⋅M)r.

D ingaganizidwe ngati chotsitsa-chinthu chodalira (pakati pa 0 ndi 1) chomwe chida chimachotsedwera mwanjira yofanana ndi hyperbolic (Mazur, 1987). Mtengo wotsitsa K amayesa chizolowezi cha munthu chotsitsa tsogolo kotero kuti munthu wokhala ndi zambiri K mwachangu amayesetsa kupeza mphotho pomwe amakhala patali. U alibe zofunikira ndipo amayendetsedwa ndi kukula kwa chosankha chilichonse ndipo r, gawo laulere lotsogolera kupindika kwa ubalewo. The kuchuluka kwa r, zimagwiranso ntchito kwambiri, ndikuti r ndi yoyipa, ntchito yothandizira ndi yodziwitsa. Chachikulu r (pamwambapa zero), kuchuluka kwakuchepetsa mphamvu zotsogola ndipo kungakhale kovuta kwambiri kukhala munthu wosankha. Dziwani kuti malinga ndi mitundu yazikhalidwe zomwe zimawerengera mtengo wosankha, zomwe siziganizira kuchotsera kwakukulu (Mazur, 1987), impulivity, yomwe ikufotokozedwa ndi kutsimikiza kusankha njira yaying'ono-posachedwa, ndi ntchito ya K chifukwa chake awiriwo akuyembekezeredwa kuti agwirizane bwino bwino. Chifukwa chake, K Nthawi zambiri anthu amati munthu amakhala ndi vuto ngati lomweli. Komabe, popeza kuchotsera kwakukula kwawonekanso kuti kuwonetse kusankha kwa nyama ndi anthu (Ho et al., 1999; Pine et al., 2009), timakonda kufananizira kusayikiridwa ndi machitidwe osankha popeza kuchotsera kwakanthawi kochepa sikungagwirizane ndi kiyi iyi.

Kuwerengera magawo apamwamba othekera amtundu uliwonse komanso muyezo wokwanira, kuyerekezera koyenera kwakukulu kunagwiritsidwa ntchito. Iliyonse ya magawo (kuphatikiza β) adaloledwa kuti azisiyanasiyana. Pa mutu uliwonse, kuthekera kwake kudawerengedwa mwanjira iliyonse ya 220 yomwe idasankhidwa kuchokera pazisankho za 220 (kuphatikiza mayeso a nsomba), kugwiritsa ntchito fomula yofewa ndikuyikika ndi ntchito zokulitsa ku Matlab (MathWorks). Kuyerekeza kwa chipika kuwerengeredwa pogwiritsa ntchito kuthekera kwa kusankha komwe kwasankhidwa pamayesero t (PO(t)) kuchokera Eq. 1 kotero kuti

lnL=ΣtlnPO(t).
(3)

ANOVA yochitira zinthu mobwerezabwereza idagwiritsidwa ntchito kuyesa kusiyana kulikonse pamtengo wotsika (K) ndimathandizidwe othandizira (r) pamankhwala.

Pazolinga za kulingalira ndi kuchitapo kanthu kosanthula, kuwunikira kowonjezereka kunachitika momwe zosankha zonse zamutu uliwonse zimapangidwira palimodzi (ngati zimapangidwa ndi nkhani imodzi) ndikuwonetsedwa ngati mutu wovomerezeka kuti ziyerekezere mfundo zamawu ovomerezeka (ndikugwiritsa ntchito) kachitidwe koyenera pamwambapa, Kuyerekezera kwapakati). Izi zidapangidwa kuti muchepetse phokoso lomwe limagwirizanitsidwa ndi njira yoyenera pamutu umodzi. Kuphatikiza apo, sitinkafuna kutipangitsa kuti tipeze zosiyanazo mu mtundu wathu wamawonekedwe polingalira za fMRI, pofunafuna umboni patokha pazomwe tapeza.

Kusanthula kufotokozera

Kusanthula kwazithunzi kunachitika pogwiritsa ntchito SPM5 (www.fil.ion.ucl.ac.uk/spm). Pa gawo lililonse, zithunzi zisanu zoyambirira zidatayidwa kuti zitheke chifukwa cha zotsatira za kuyanjana kwa T1. Zithunzi zomwe zidatsala zidasinthidwa kuti zikhale voliyumu yachisanu ndi chimodzi (kukonza mawonekedwe a mutu), osagwiritsa ntchito mawonekedwe, osinthika mwanjira ya Montreal Neurological Institute (MNI) template yaukazitape, ndikusinthidwa pang'onopang'ono ndi gawo limodzi la magawo atatu a Gaussian kernel ya 8 mm kwathunthu- m'lifupi pamlingo wocheperako theka (FWHM) (ndikusinthanso, chifukwa cha 3 × 3 × 3 mm voxels). Zida zamagetsi ochepera zimachotsedwa pogwiritsa ntchito fayilo ya 1 / 128 Hz-pass-pass ndikupitilira kwakanthawi kwa fMRI nthawi yakonzedwa ndikuwongolera pogwiritsa ntchito njira ya AR (1).

Mamapu osiyananso ndi mutu umodzi adapangidwa pogwiritsa ntchito modulamu yamitundu yonse malinga ndi mzere wofananira. Tinapanga kusanthula, kuwunika kusintha kochokera mu zigawo za BOLD zomwe zikugwirizana ndi mitundu yosiyanasiyana yosangalatsa: U, Dndipo V pa zosankha zonse pazamankhwala onse. Izi zidatilola kuzindikira zigawo zomwe zimakhudzidwa pakuwunika ndi kuphatikiza magawo osiyanasiyana amtengo wapatali (mu mawonekedwe a placebo) ndikuyang'ana kusiyana kulikonse pakayendetsedwe ka mankhwala.

U, Dndipo V Pakusankha kwina kulikonse (awiri pamayeso) amawerengedwa pogwiritsa ntchito ziwonetsero za chizindikiro cha ovomerezeka (K ndi r) potengera mtundu wathu wophunzitsika wazopangidwira komanso wothandizika ndi canonical hemodynamic reaction function (HRF) kumayambiriro kwa njira iliyonse. Kusintha konse kunakonzedwa ngati ndodo ndipo ma regressor onse amtundu womwewo anali a orthogonalized (m'malamulo omwe atchulidwa pamwambapa) kusanthula kwa SPM5. Kukonza zojambula zoyenda, magawo asanu ndi amodziwo adapangidwa kuti azikhala osakondwereza pakuwunika kulikonse. Powunikiranso kowonjezera, tidachotsa zovuta zilizonse zokhudzana ndi orthogonalization wa regressor mu kusanthula kwathu kwa fMRI pogwiritsa ntchito mtundu wina wa regression koma tsopano ndikuchotsa gawo la orthogonalization. Apa regressor adaloledwa kupikisanapo mosinthana kotero kuti mu mtundu woyeserera kwambiri ziwalo zonse zomwe zimagawidwa zimachotsedwa, kuwulula mbali zapadera za U, Dndipo V. Pansi pa chithunzichi, tinaonanso zosiyana zomwezo D ndi V kudutsa pama mankhwala osokoneza bongo komanso popanda kusiyana U, ngakhale kukula kwa kusiyana kunachepetsedwa.

Pa mulingo wachiwiri (kusanthula kwamagulu), zigawo zomwe zikuwonetsa kusinthidwa kwazomwe zidafotokozedwa koyambirira adazindikiritsa zotsatira za kusanthula kwakanthawi β zithunzi zochokera pamapu omwe ali ndi mutu umodzi. Tidaphatikizanso kusintha kwa mayeso a impulsivity (kusiyana kwa anthu omwe asankhidwa posachedwa) ngati covariate pochita zosiyana ndi kusiyana kwa mayeso a l-dopa ndi placebo. Tikulemba zotsatira za zigawo zomwe gulu lambiri la voxel t mtengo wolingana p <0.005 (yopanda tanthauzo), yokhala ndi tsango lokulirapo osachepera asanu. Ma Coordinates adasinthidwa kuchoka pagulu la MNI kukhala gulu la stereotaxic la Talairach ndi Tournoux (1988) (http://imaging.mrc-cbu.cam.ac.uk/imaging/MniTalairach).

Zithunzi za T1 zopangidwa zinapangidwa kuti zizigwiritsidwa ntchito pazithunzi za EPI zogwiritsidwa ntchito pamutu uliwonse ndikusinthidwa pogwiritsa ntchito zigawo zochokera pazithunzi za EPI. Anatomical kuthekera kunachitika mwa kuphimba t mamapu pamtundu wa makonzedwe oyendetsedwa pamitundu yonse komanso kutengera chithunzi cha Mai et al. (2003).

Kusankha latency

Kuti tiwone momwe zotsutsana zimasinthira (zovuta pakusankha) pakusankha kwanzeru, tinawerengera zovuta zina pa zosankha za 220 powerengera kusiyana muzinthu zochepetsedwa (ΔV) mwa njira ziwiri. Kuyeza kumeneku kunawerengedwa pogwiritsira ntchito mtundu wotsika wazogwiritsira ntchito ndi ziwonetsero zofanizira (chifukwa chomwechi chomwe adagwiritsidwa ntchito pakuwunika kwa fMRI). Kuwongolera komwe kumachitika kenako kumapangidwa kuti kuwonetse ubale womwe ulipo pakati pa lingaliro lamalingaliro pazovuta zilizonse ndi muyeso wovuta. Ziwerengero zamtunduwu (βs) Kenako adagwiritsidwa ntchito ngati chiwerengero cha chidule ndipo kusanthula kwachiwiri kudachitika pogwiritsa ntchito chitsanzo chimodzi t kuyesa kufananiza βmotsutsana ndi zero. Izi zimachitika padera pagululi munthawi iliyonse. Poyesa kusiyana kulikonse pakumvana pakati pa kusamvana ndi latency pamikhalidwe ya mankhwala, timagwiritsa ntchito zitsanzo zapawiri t mayesero.

Results

Poyamba tidasanthula zomwe zimapangitsa kuti mankhwalawo azigwiritsa ntchito mwamphamvu poganizira kuchuluka kwa ang'ono-posachedwa malinga ndi zosankha zazikulu-zamtsogolo zosankhidwa, pazosankha za 220, zomwe zidapangidwa munthawi iliyonse. Izi zikuwonetsa kuwonjezeka kwakukulu kwa mitundu yosankhidwa posachedwa mumikhalidwe ya l-dopa yofanana ndi placebo (kutanthauza 136 vs 110, p = 0.013) (Gulu 1, Chith. 2). Modabwitsa, njira iyi idawonedwa mu mitu yonse momwe fanizo ili lingapangidwire. Panalibe kusiyana kwakukulu pakati pa zikhalidwe za haloperidol ndi placebo pamalingaliro awa. Zindikirani, ntchitoyo inali yophatikizana ndi magulu amodzi munthawi iliyonse.

Chithunzi 2 

Kuyerekezera kwamakhalidwe ndi kuyerekezera kwapazinthu mumikhalidwe ya placebo ndi l-dopa. a, Omwe adagwirira ntchito zomwe adasankha (220) m'magulu atatu onse azithandizo koma nthawi zambiri amasankha zazing'ono - posachedwa kuposa zazikulu ...
Gulu 1 

Chidule cha zomwe mwapeza

Tidagwiritsa ntchito kuyerekezera kuti tithe kupeza magawo oyenera (K ndi r) kwa mtundu wotsitsa wogwiritsa ntchito, pamutu uliwonse pamlingo uliwonse, kudziwa ngati zotsatira zina mwazigawozi zapakati zikuwonjezeka pakuwonekera kwanyimbo. Poyerekeza magawo amawerengera omwe amawongolera kuchotsera ndikugwiritsanso ntchito kwazomwe zachitika, zotsatira za l-dopa pamtengo wotuluka zinapezeka, sizinakhudze mgwirizano wamtokoma (Gulu 1, Chith. 2ndipo Gawo lowonjezera 1, opezeka pa www.jneurosci.org as zowonjezera). Chifukwa chake, pansi pa l-dopa, kuchotsera kwakukulu kumawonedwa pokhudzana ndi placebo (p = 0.01), zomwe zikutsogolera kuwonjezerera kwakukulu kwa mphotho zamtsogolo. Mwa fanizo, pogwiritsa ntchito gulu la ovomerezeka a gulu kupanga chiwembu chogwiritsira ntchito mankhwala aliwonse, zitha kuwoneka kuti m'malo mwa placebo pamafunika kuchedwa kwa ~ 35 masabata kuti mphotho ya £ 150 ikhale ndi mtengo wapano (wogwirizira) £ 100, komabe, pansi pa l-dopa kusinthidwa komweko kunachitika ndi kuchedwa kwa masabata a 15 okha (Chith. 2). Ziwerengero zamakono za Canonical zomwe zimagwiritsidwa ntchito pazoganiza zoganiza zinali 0.0293 ya K ndi 0.0019 r (mfundo zonse za K Amanenedwa kuwerengera nthawi zamasabata).

Malinga ndi Pine et al. (2009), kuwerengera kwapadera pamitu iliyonse (pamikhalidwe yonse) kunali kwakukulu kuposa zero, kuwulula zonse zofunikira kuchotsera kwakanthawi (p <0.001) ndi nonlinearity (concavity) zothandiza nthawi yomweyo (p <0.05). Dziwani kuti mosiyana ndi mitundu yazikhalidwe zakusankha kwamitundu yosiyanasiyana (Mazur, 1987), pomwe zosankha zimangokhala ntchito ya K, mtundu wogwiritsidwa ntchito pano ukutanthauza kuti kuchuluka kwa zosankha posachedwa kumadaliranso r chizindikiro (onani Zida ndi Njira) (Pine et al., 2009) motero K mwa iyo yokha sikuti ndiyeso yeniyeni yosankhika. Kuphatikiza apo, kulondola kwa magawo amalingaliro kumatengera kukhazikika komanso kusasinthika kwamayankho amitu. Mwachitsanzo, magawo omwe amayesedwa pamayeso a 13 a placebo anali osasangalatsa poyerekeza ndi zina zonse (Gawo lowonjezera 1, opezeka pa www.jneurosci.org as zowonjezera), kuwonetsa kuti nkhaniyi ikhoza kupanga zisankho zosagwirizana mu gawoli. Poyerekeza pamitu yonse, zindikirani kuti kuchuluka kwa zisankho zomwe zapangidwenso kumadaliranso zimadalira kusankha zomwe mwalandira (chimodzi mwazowiri).

Kuphatikiza apo, tidawunika ngati kuchepa kwakumapeto kwa zisankho kumawonekera pamene zosankha zidakhala zovuta - zotsatira zake pakuwonjezera kuyandikana kwa malingaliro osankha - komanso ngati pali kusiyana kulikonse pagulu. Tinayesanso kuyesa ubale womwe ulipo pakati pa kusankha zochita komanso kuvuta kwa kusankha kulikonse malinga ndi kusiyana kwazosinthidwa (ΔV) pakati pazosankha ziwirizi, kuwerengera pogwiritsa ntchito mitundu yanthawi yolingalira. Mu placebo (p <0.001), l-dopa (p <0.001), ndi haloperidol (p <0.001) momwe zinthu ziliri, chisankho cha maphunziro chikuwonjezeka ngati ΔV idayamba kuchepa, ndiye kuti, kusiyana kwa mtengo wogwirizira pakati pazosankha kudayamba kuchepa. Komabe, palibe kusiyana konse komwe kunawonedwa mwanjira iyi pamikhalidwe ya mankhwala. Izi zikuwonetsa kuti, mosiyana ndi zotsatira zake, kusintha kwa ma dopamine sikunatanthauze kuchuluka kwa nthawi yopatsidwa lingaliro, kapena kuthekera "kugwirira akavalo anu," ndikuwongolera lingaliro loti kusokonekera sikumanga kophatikizidwa (Evenden, 1999; Ho et al., 1999; Winstanley et al., 2004a; Dalley et al., 2008). Izi zikugwirizana ndi zomwe zidapezeka kuti zamankhwala a dopamine mu PD sizinalumikizidwe ndi kusintha kwa masankho pazosankha zina (Frank et al., 2007).

Zotsatira zake zimasinthidwa ndikufanizira kusintha pazinthu zitatu zomwe zidadziwika Bond ndi Lader (1974),, kukhala tcheru, kukhutira, ndi bata, zokhudzana ndikusintha kwamawu omwe amawoneka mumkhalidwe wa placebo. Zosiyana zinapezeka m'malo a haloperidol motsutsana ndi placebo, pomwe mitu yomwe inali yocheperako pansi pa haloperidol (p <0.05).

Kuti tipeze momwe zimayendera pansi pa l-dopa poyimiridwa pamlingo wa neural, tinalemba ma regressor atatu (orthogonalized) regametric regressors, U, Dndipo V, yolumikizidwa ndikuwonetsera njira iliyonse, malinga ndi mtundu wathu, kuzidziwitso zamaganizidwe aubongo. Ma regressor adapangidwa pamutu uliwonse, pachikhalidwe chilichonse, pogwiritsa ntchito zovomerezeka zam'ndondomeko zomwe zimayesedwa pamitu yonse yamaphunziro onse, poyesa lingaliro lopanda tanthauzo loti zochitika muubongo sizimasiyana pakati pazikhalidwe.

Pakuwunika koyambirira, tinayang'ana malumikizidwe a ma regressor atatuwa mumkhalidwe wa placebo kuti tithandizire zomwe tapezapo kale (Pine et al., 2009). Zotsatira zathu (Zowonjezera, opezeka pa www.jneurosci.org as zowonjezera) anali ogwirizana ndi omwe adawonetsedwa kale, m'menemo D, Undipo V onse adadzipangira okha pazinthu zina za caudate (pakati pa zigawo zina). Izi zimathandizira mawonekedwe oyang'anira, osakanikirana pamalingaliro amtengo pomwe ophatikiza amtengo amamangiriridwa mosagwirizana kenako ndikuphatikizidwa kuti apereke mtengo womwe ukugwiritsidwa ntchito kuwongolera kusankha.

Kuwunika kovuta kwa fMRI kumangoyang'ana pakukhazikika kwakhalidwe pakusintha kwa l-dopa poyerekeza ndi machitidwe a placebo. Poyerekeza ntchito za neural za U, Dndipo V, kusiyana kwakukulu kunapezeka kwa onse awiri D ndi V, zotsatira zomwe zikufanana ndi zotsatira za machitidwe. Mwachindunji, tidawona ntchito zowonjezera m'magawo okhudzana ndi kuchotsera D l-dopa wokhudzana ndi malo a placebo (Chith. 3a ndi Zowonjezera, opezeka pa www.jneurosci.org as zowonjezera) ndipo palibe vuto lililonse la haloperidol (ndiye kuti maumboni omwe amapezeka mu placebo ndi haloperidol sanasiyane kwambiri). Madera amenewa anali ndi ma striatum, insula, subgenual cingulate, ndi lateral orbitof mbeleal cortices. Zotsatira izi zikuwonetsa kuti kuchepa kwa ntchito kwa zigawozi ngati mphotho kumayamba kuchepetsedwa (kapena kuwonjezeka pamene kukuyandikira kwakanthawi) (McClure et al., 2004; Tanaka et al., 2004; Kable ndi Glimcher, 2007; Pine et al., 2009) (onaninso Zowonjezera kwa placebo, kupezeka pa www.jneurosci.org as zowonjezera) ili chizindikiro kwambiri l l dopa lofanana ndi machitidwe a placebo, mwanjira yomwe ikufanana ndi kupeza, komwe l-dopa imakulitsa chisangalalo pamalipiro aposachedwa powonjezera kuchotsera, potero kupatsa posachedwa mphotho zokongola kwambiri pamalipiro amtsogolo. Kuphatikiza apo, monga momwe panalibe kusiyana kwakukulu pamalingaliro r gawo kudutsa mayesedwe awa, sitinawone kusiyana kwakukulu U ntchito pakati pa l-dopa ndi mayesero a placebo, kuwonetsa kuti l-dopa sizinakhudze kusinthidwa kwa ntchito ya mphotho.

Chithunzi 3 

Kusiyanaku mu zochitika za neural pakati pa l-dopa ndi machitidwe a placebo poyang'ana mtengo wamtengo wapatali ndi kuchotsera (mapu amawu a parametric ndi kuyerekezera kwapadera). a, Magawo omwe amagwirizana ndi kuchotsera (D) (mwachitsanzo, kuyandikira kwa mphotho) ...

Maphunziro apakale (Kable ndi Glimcher, 2007; Pine et al., 2009), komanso kuwunika kwa gulu la placebo lokhalo, zigawo zokhazikika, mwa zina, polemba zofunikira zothandizidwa (V). Mukayerekeza zigawo zikugwirizana ndi V, ntchito yochepetsedwa idawonedwa mu zigawo za caudate, insula, ndi zotsogola zam'mbuyo, mu l-dopa poyerekeza ndi malo a placebo (Chith. 3b ndi Zowonjezera, opezeka pa www.jneurosci.org as zowonjezera). Zotsatira zake zikuwonetsa kuti kuti ulandire mphotho ya kukula kwakukulu ndi kuchedwetsa, ntchito yochepetsedwa m'magawo okhala ndi mtengo wothandizirana (kuchotsera ntchito) idayambitsidwa ndi l-dopa. Kuchepetsa kumeneku kunalumikizidwa ndi kuchotsera kwakanthawi kwakanthawi, ndipo zidawonjezera kuwonjezeka kwa zosankha zazing'onoting'ono posachedwa (mosafunikira) pamenepa.

Chifukwa chakuti fMRI deta idagwiritsa ntchito magawo amodzi ovomerezeka (pazochitika zonse, kuyesa mfundo zopanda pake kuti zonse ndi zofanana), zotsatira izi zikugwirizana ndi zotsatira zomwe zimapangitsa kuwonjezeka kwa kuchotsera pansi pa l-dopa kumapangitsa kutsitsidwa D, zomwe zimatsogolera pakuchepetsa kofananira V , chifukwa chake, amakonda kwambiri abale pamalipiro aposachedwa. Dziwani kuti ngati dopamine idasungitsa zofunikira kuchotsera zokhazokha, munthu akhoza kulosera zotsatirapo zake, atachita zambiri mu l-dopa.

Kuyendera zotsatira zamakhalidwe (Gulu 1, Chith. 2) idawonetsa kuti kuwonjezeka kwa kutsatiridwa kwatsatiridwa l-dopa kunawonetsedwa kwakukulu pamaphunziro ena kuposa ena. Pazifukwa izi, tinayang'ana mosiyana ndi momwe zidasinthidwira powerengera kusiyana pakati pa zosankha zomwe zasankhidwa mu placebo ndi mayeso a l-dopa. Kukula kwakukulu kumeneku, kukuchulukirachulukira kwa kunyengerera (kuchotsera) komwe kumayambitsa l-dopa. Mwa kukonzanso kuchuluka ngati covariate mosiyanitsa D L-dopa minus minbo malo (Chith. 3a), tidapeza kulumikizana kwakukulu ndi zochitika mu amygdala (padziko) (Chith. 4). Chifukwa chakuti kusiyana pakati pa maphunziro pazosankha kungakhale kukhudzidwa pang'ono chifukwa chakuti maphunziro adapatsidwa gawo limodzi mwa zosankha ziwiri, ndikuwonjezera mphamvu (kuthekera kuphatikiza maphunziro ena), tidabwereza kuwunikaku, nthawi ino pogwiritsa ntchito kusiyana kwakukulu K mfundo kuchokera ku placebo kupita ku mayesero a l-dopa. Zotsatira za kusanthula uku Zowonjezera, opezeka pa www.jneurosci.org as zowonjezera) adawonetsanso kulumikizana kwamphamvu pakati pa zochitika za amygdala ndi kuchuluka kwa kuwonjezeka K kuchokera ku placebo kupita ku mayesero a l-dopa. Zotsatira izi zikuwonetsa kuti mutu uliwonse womwe ungatengeke chifukwa cha mphamvu ya l-dopa umasinthidwa ndi mayankho a amygdala pakuyandikira kwa mphotho.

Chithunzi 4 

Kusinthika kwa intersubject kukuwonjezeka kwa kutengeka kutsatira l-dopa. a, Mapu a Statistical parametric omwe akuwonetsa madera akuwonetsa chidwi chonse ndi kuchotsera (mu l-dopa minus malobo placebo) komanso omwe adagwirizana ndi momwe ...

Kukambirana

Malingaliro omwe alipo a dopamine amayang'ana ntchito yake pakuphunzira mphotho, pomwe dopamine imaganiziridwa kuti imayeseza cholosera cholosera chomwe chimagwiritsidwa ntchito kusintha zikhalidwe zamayiko ndi zomwe zimalola kuneneratu ndikuwongolera, motsata, pakupanga chisankho. Mitunduyi yakhala ikugwiritsidwa ntchito kufotokozera momwe kukonzekera kwa dopamine kungapangitse kukhala ndi machitidwe osafunikira komanso osokoneza bongo, pamaziko a zokumana nazo (ie, kudzera pophunzira) (Fotokozerani, 2004; Frank et al., 2007; Dagher ndi Robbins, 2009). Apa, gawo lodziwika la kufunikira linafufuzidwa momveka bwino, kutengera kulumikizana kwakanthawi yamalipiro ndi ntchito yawo, popanda kuyankha komanso kuphunzira. Pakusankha pakati, opanga zisankho ayenera kusankha pakati pa mphotho yayikulu ndi kuchedwa. Izi zimatheka pochepetsa phindu la zinthu zam'tsogolo zogwiritsira ntchito (malinga ndi kuzengereza kwawo) kuyerekeza zomwe ali nazo. Mwa izi, dopamine ikhoza kukulitsa chisankho mosakakamiza m'njira ziwiri zosiyana (Pine et al., 2009,, motere: chifukwa cha kuchuluka kwa kuchepa kwa zinthu zogwiritsika ntchito (zomwe zingachepetse mtengo wamtengo wapatali wophatikizana ndi mphotho zazing'onoting'ono), kapena kudzera kuchotsera kwapang'onopang'ono kwa mphotho zamtsogolo. Zotsatira zathu zikuwonetsa kuti dopamine imakhudza moyenera kuchotsera, popanda phindu lililonse pakugwiritsa ntchito. Kuphatikiza apo, zotsatira za machitidwe izi zidathandizidwa mosadalira ndi fMRI idatha kuti kusiyana kofunikira komwe kumapangidwa ndi l-dopa kunali kosinthira kwa mayankho a neural mu zigawo zomwe zimakhudzana ndi kuchotsera kwa mphotho ndipo, chifukwa chake, phindu lawo lonse, lopanda zotsatirapo zake zofunikira zenizeni za mphotho. Mwachidule, kafukufukuyu amapereka umboni kuti dopamine amawongolera momwe nthawi ya mphotho imaphatikizidwira pakupanga mtengo wake wamtengo wapatali. Izi zikuwonetsa kawonedwe kakapangidwe kamene dopamine imayang'anira kusankha kwa munthu ndipo, chimodzimodzi, mikhalidwe monga kusachita zinthu mwachangu.

Zotsatira zathu zimawonjezera lingaliro loti kusokonekera sikumapangidwa mophatikiza komanso kuti ma subtypes osiyanasiyana amtunduwu akhoza kusiyanitsidwa pharmacologically ndi neurobiologic (Evenden, 1999; Ho et al., 1999; Winstanley et al., 2004a; Dalley et al., 2008). Zotsatira za dopamine zinkawoneka mu chisankho chomwe chimayesedwa malinga ndi zosankha / zokonda koma sizinakhudze mayeso -Frank et al., 2007) - zimachitika ngati njira zisankhidwa bwino, zomwe zimabweretsa chisankho-Botvinick, 2007; Pochon et al., 2008komanso zokhudzana ndi kusinkhasinkha kapena kukonzekeraEvenden, 1999; Clark et al., 2006).

Palibe phunziro laumunthu lomwe lawonetsabe mphamvu ya dopamine yolimbikitsira kukhudzika kwakanthawi. Zoyeserera zam'mbuyomu zam'mimba mwa makoswe zawonetsa zosagwirizana pakusankha kwakanthawi, pomwe ena akuwonetsa kuti kukulitsa kwa dopamine kumabweretsa kuchepa kwa chisankho chosafulumira kapena kuti kuchepa kwa dopamine kumabweretsa kuwonjezeka (Richards et al., 1999; Cardinal ndi al., 2000; Wade et al., 2000; Zisumbu et al., 2003; Winstanley et al., 2003; van Gaalen et al., 2006; Bizot et al., 2007; Floresco et al., 2008), pomwe ena amawonetsa chosiyana, chodalira mlingo, kapena alibe zotsatira (Logue et al., 1992; Chothandizira ndi Thiébot, 1996; Evenden ndi Ryan, 1996; Richards et al., 1999; Cardinal ndi al., 2000; Zisumbu et al., 2003; Helms et al., 2006; Bizot et al., 2007; Floresco et al., 2008). Zina mwazomwe zimapangitsa kuti pakhale kusiyana, ngati, kuwongolera kumachitika kapena mawu osonyeza, ngati chiphaso chilipo panthawi ya kuchedwa, presynaptic motsutsana ndi postynaptic zotsatira za mankhwala, paradigm wogwiritsidwa ntchito, mankhwala ogwiritsidwa ntchito / receptor , makamaka mankhwala. Maphunziro aumunthu pazosankha zapakatikati adawona kuwonjezeka kwa kudziletsa (de Wit et al., 2002) kapena ayi (Acheson ndi de Wit, 2008; Hamidovic et al., 2008) popititsa patsogolo dopamine ntchito. Ambiri mwa maphunziro awa amakhala ovuta chifukwa chogwiritsa ntchito ma monoaminergic zolimbikitsa monga amphetamine kapena methylphenidate, omwe nthawi zambiri amaganiza kuti amachepetsa mphamvu. Maphunzirowa akhoza kusokonezedwa ndi kutulutsidwa kwapadera kwa serotonin (Kuczenski ndi Segal, 1997), zomwe zimakhudzanso mukusinthika kwa kusankha pakati. Makamaka, zawonetsedwa kuti kupititsa patsogolo ntchito ya serotonin kumatha kuchepetsa kukakamiza posankha kapena mosinthanitsa (Wogar et al., 1993; Richards ndi Seiden, 1995; Poulos et al., 1996; Ho et al., 1999; Mobini et al., 2000) ndikuti chiwonongeko cha serotonergic neurons chitha kulepheretsa zotsatira za amphetamine (Winstanley et al., 2003). Kuphatikiza apo, anthu amaganiza kuti, pamaziko a umboni waukulu, kuchuluka kwa amphetamine kumachepetsa kupezeka kwa dopamine kudzera mu zotsatira za Presynaptic, zomwe zingafotokoze zotsatira zake zodalira mlingo m'maphunziro ambiri am'mbuyomu komanso momwe amathandizira pakuwathandiza (muyezo waukulu) mu puterly hyperdopaminergic ADHD (Seeman ndi Madras, 1998, 2002; Solanto, 1998, 2002; Solanto et al., 2001; de Wit et al., 2002). l-Dopa sanagwiritsidwepo ntchito kale kuti asokoneze kusankha mopupuluma, ndipo mwina amapereka umboni wowonjezera komanso wowona wa gawo la dopamine. Ngakhale l-dopa imatha kubweretsa kuwonjezeka kwa noradrenaline ndipo magwiridwe ake enieni samamveka bwino, noradrenaline silingaganizidwe kuti itenga gawo lalikulu pakukhazikitsa chisankho pakati pa azaka zambiri (van Gaalen et al., 2006). Kuphatikiza apo, ndizotheka kuti l-dopa ikadayambitsa zotsatira zoyipa zomwe sizinatengeke ndi mamba ogwiritsa ntchito pano.

Kulephera kwathu kupeza kuchepa kofananira kokhudzidwa ndi placebo ndikuyang'anira putative dopaminergic antagonist haloperidol ikuyenera kuwonetsa zinthu zingapo. Izi zikuphatikizapo kuchepa kwa haloperidol komanso kufalikira kwa mankhwala kapena kuchuluka kwake - kafukufuku wina akuwonetsa kuti haloperidol itha kukulitsa dopamine m'miyeso yaying'ono, chifukwa cha zotsatira za presynaptic pa D2 autoreceptor (Frank ndi O'Reilly, 2006). Kuphatikiza apo, zovuta zomwe zimachitika chifukwa cha mankhwalawa, kuphatikiza kuchepetsedwa kwa chidwi, zitha kukhala kuti zimapangitsa chidwi chazomwezi. Maphunziro owonjezerawa ayenera kugwiritsa ntchito olimbana ndi ma dopamine kuti awone ngati kuchepa kwa ntchito ya dopamine kungachepetse kutsika kwa anthu.

Dopamine amadziwika kuti amathandizira kwambiri pamakhalidwe oyambira mphotho monga njira yoyandikira ndi chimaliziro (Parkinson et al., 2002). Zotsatira zoterezi zimagwirizana ndi gawo limodzi pakupanga masisitere olimbikitsira (Berridge, 2007; Robinson ndi Berridge, 2008) ndipo ndizovuta kwambiri kuwerengera pankhani ya kuphunzira, pa se. Kulumikizana kwa mayankho osakhudzidwa komanso oyendetsedwa ndi dopamine kukugwirizana ndi lingaliro la kuvuta kwa Pavlovian, pomwe mayankho ogwirizana ndi zoyambira, zozama zamkati zimapanga chinthu chosavuta, chosinthika chokhazikitsidwa chogwirira ntchito limodzi, ndipo nthawi zina kupikisana ndi, njira zina zowongolera, monga chizolowezi- Zochita ndi zotsogozaDayan et al., 2006; Seymour et al., 2009). Makamaka, "zinthu ndi zochita za" za ku Pavlovia izi zimadalira chilengedwe komanso kuyang'ana kwakanthawi mphotho, motero, zimapereka njira imodzi yomwe dopamine ikhoza kuwongolera kuchepa kwa nthawi. Ngati njira ngati imeneyi ikuyambitsa kukhudzidwa kwa dopamine chifukwa cha ntchitoyi, ndiye kuti izi zitha kunena kuti njira yotsogola (ya Pavlovian) imagwira ntchito mozama kwambiri kuposa momwe pano, chifukwa zabwino zomwe zimagwiridwa ndi ntchito iyi ndi mphotho yachiwiri yomwe imachitika pa 1 sabata. Malongosoledwewa akuimira mosiyana ndi lingaliro la kuphatikiza kopatsa chidwi kwa dopaminergic ya kachitidwe (kozikidwa m'malo achitetezo) omwe amangokhulupirira mphoto yakanthawi yochepa chabe (McClure et al., 2004). Nkhani yotere ya duel-system imakhala yovuta kuyanjanitsa ndi maphunziro am'mbuyomu (Kable ndi Glimcher, 2007; Pine et al., 2009), zomwe zikusonyeza kuti madera olimbitsa thupi amawona phindu nthawi zonse.

Nkhani ngati imeneyi imadzutsa mafunso ofunikira okhudzana ndi chidwi cha amygdala chomwe chimatipatsa chidwi chomwe tawona mu deta yathu. Apa, ntchito za amygdala poyankha D covaried ndi momwe mkhalidwe umakhala wosakhudzidwa kutsatira l-dopa. Mu Pavlovian-- chida chosinthira (PIT), chodabwitsa chomwe chimadalira kulumikizana pakati pa amygdala ndi striatum (Cardinal ndi al., 2002; Seymour ndi Dolan, 2008), ndipo mawu ake amadziwika kuti asinthidwa ndi dopamine (Dickinson et al., 2000; Lex ndi Hauber, 2008,, zokopa za Patlovian zimawonjezera kuyankha kuti ulandire mphotho. Makamaka, kukhudzika kwanthaka kumakhudzana ndi zochitika za amygdala (Talmi et al., 2008,, kutanthauza kuti amygdala atha kusintha momwe mphotho zoyambira ndi zotsimikizika zimathandizira. Ngati ndi momwe ziliri, ndiye kuti zikulosera kuti kuwongolera kopindulitsa kwa mphotho panthawi imodzi yokha kungapangitse kukhudzidwa kwakanthawi kudzera munjira yodalira amygdala. Tikuwona umboni kuti zotupa za basolatal amygdala zimachulukitsa kusokonekera kwa makoswe (Winstanley et al., 2004b), chowonera chosiyana ndi zomwe titha kuyerekezera ndi zomwe zilipo. Mosiyana ndi izi, ntchito za amygdala zidanenedwapo kale kuti zikugwirizana ndi kukula kwa kuchotsera kwakanthawi paphunziro la fMRI (Hoffman et al., 2008). Izi zimapereka maziko a kafukufuku wamtsogolo omwe angayese mwadongosolo malonjezo olakwika awa mwa anthu.

Pomaliza, zotsatirazi zimayankhula pagulu lachipatala ndikupereka chofotokozera chifukwa chake kuwonjezeka kwamakhalidwe oyipa komanso owopsa kumawonedwa mu dopamine dysregulation syndrome, bongo, ndi ADHD, zonsezi zomwe zimagwirizanitsidwa ndi malo oopsa a dopamine kapena kapena kusefukira kwa dopamine kapena chidwi (Solanto, 1998, 2002; Seeman ndi Madras, 2002; Berridge, 2007; Robinson ndi Berridge, 2008; Dagher ndi Robbins, 2009; O'Sullivan et al., 2009). Pothandizira lingaliro ili. Voon et al. (2009) adapeza kuti mankhwala a dopamine mwa odwala PD omwe ali ndi vuto lodziletsa pakukhudzidwa adalumikizidwa ndi kuchuluka kwakanthawi kwakanthawi. Pomaliza, zotsatira zomwe zawonetsedwa pano zikuwonetsa kuthekera kwa dopamine kukulitsa kutengeka mtima mwa anthu ndikupereka chidziwitso chatsopano pantchito yake pakusinthira kusankha mopupuluma potengera kuchotsera kwakanthawi. Zotsatira izi zikuwonetsa kuti anthu atha kukhala ndi vuto lakanthawi kochulukirapo pomwe zinthu zomwe zimakulitsa zochitika za dopamine, monga mawonekedwe amphotho, amapezeka panthawi yopanga zisankho.

Zowonjezera Zowonjezera

zambiri zapamwamba

Kuvomereza

Ntchitoyi idathandizidwa ndi a Wellcome Trust Program Grant kupita ku RJD, ndipo AP idathandizidwa ndi ophunzira a Medical Research Council. Tikuthokoza K. Friston, J. Roiser, ndi V. Curran potithandizira kukonza ndi kusanthula, komanso kukambirana mozama.

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