Ukuqaphela Ukuncintisana Okucindezelayo Nezimpikiswano, kusukela ku-Animal Models kuya ku-Endophenotypes: Ukubukeza Okulandelanayo (i-2010)

UNaomi A Fineberg,^1,2,3,* UMarc N Potenza,⁴ USamuel R Chamberlain,^1,3 UHeather A Berlin,⁵ Lara Menzies,³ Antoine Bechara,⁶ UBarbara J Sahakian,³ UTrevor W Robbins,⁷ U-Edward T Bullmore,^3,8 futhi Eric Hollander⁹

Ulwazi lomlobi ► Isihloko se-Article ► Ulwazi lobunikazi nelayisense ►

abstract

ISINGENISO

Ngenkathi ukusebenza okunezimpawu zokuphoqelela noma zokuphoqelela kunganikela ikakhulukazi ekusungulweni nasekukhuthazeleni futhi ngokuvamile ekuziphatheni komuntu okuguquguqukayo, umthethonqubo ongahlelekile wokuziphatha okungacabangi noma okuphoqelelayo ungahlotshaniswa nemiphumela emibi futhi ube nomsebenzi ekukhuleni kokuphazamiseka kwengqondo. Ukungabi nomdlandla kungachazwa ngokuthi 'ukuthambekela ekubhekaneni nokusabela okusheshayo, okungahlelwanga kuzisusa zangaphakathi noma zangaphandle ngokuncipha kwemiphumela emibi yalokhu kuphendula kumuntu ongathatheki noma kwabanye' (IChamberlain neSahakian, 2007; I-Potenza, i-2007b). Ngokuphikisanayo, ukucindezelwa kufanekisela ukuthambekela kokwenza okuphindaphindayo ngendlela enomkhuba noma enomqondo ovimbayo ukuvikela imiphumela emibi ebonakalayo, okuholela ekonakaleni kokusebenza (I-WHO, 1992; UHollander noCohen, 1996; Chamberlain et al, I-2006b). Lezi zakhi zombili zingabukwa njengeziphikiswa ngokweqile, noma ngenye indlela, ngokufana, kulokho ngakunye okusho ukungasebenzi kokulawulwa kokuphoqelelwa (UStein noHollander, 1995). Ngamunye angabandakanya ukuguqulwa ngaphakathi kwezinqubo eziningi ze-neural, kufaka phakathi ukunakwa, ukuqonda, kanye nokuxhumanisa izimpendulo zemoto noma zokuqonda.

Amamodeli we-Neuroanatomical abonisa ukuba khona kwamasekethe we-cortico-striatal ahlukene kepha axhumanayo kodwa ahlukaniswayo, ahlelwe ngokuhlukile ngama-neurotransmitters (Amarobbins, 2007; I-Brewer nePotenza, 2008). Kumjikelezo ophoqelelayo, ingxenye ethintekayo ye-striatal (i-caudate nucleus) ingashayela ekuziphatheni okucindezelayo kanye nengxenye eyandulelayo (i-orbitofrontal cortex, OFC) inganikeza amandla okuzibamba. Ngokufanayo, kwisekethe engaphoqeleli, isakhi sendiza (i-ventral striatum / nucleus accumbens igobolondo) singashayela isimilo esixakile kanye nengxenye yangaphambili (i-anterior cingulate / i-ventromedial preortal cortex, i-VMPFC) ingahle ibe namandla okulawula i-inhibitory. Ngakho-ke, kule modeli, kukhona okungenani izifunda ezimbili ze-striatal neural circ (eyodwa ephoqelelayo neyodwa ephoqelela) eqhuba lezi zimo, kanye nezigaba ezihambisanayo ezimbili ezihambisanayo ezibuyisela lokhu kuziphatha. I-Hyperacaction engxenyeni ye-striatal noma ukuhlukunyezwa (ukucatshangelwa kwe-hypoactivity) ezingxenyeni zangaphambi kwalokho kungahle kube nomphumela wokwanda kokuthambekela kokuzenzisa kokuziphatha okungaziphathi noma okuphoqayo, kuya ngengxenye engaphansi ehlukunyeziwe. Okunye ukuhlukumezeka okungenzeka kungaphakathi kwamasekethe we-cortico-striatal (isib. Okuhlobene nokuncipha kokuqalisa kwe-striatal ukuze uthole imivuzo) nakho kungaba nomthelela ekuziphatheni okubonakala kungaphoqi noma okuphoqayo ngenkathi kuhileleka ekuziphatheni okuhlobene nomvuzo. Lama-pathologies angahlolwa kusetshenziswa imisebenzi yokusebenza kwengqondo ethinta le misebenzi ethile kanye / noma ngezifundo ezisebenzayo zokulinganisa ezilinganisa umsebenzi kulezi zinhlelo ze-neural. Ukugqagqana phakathi kwalezi zinhlelo ezisebenzayo, ukuze lokho okuqala njengenkinga kwisekethe engaphoqeleli kungagcina sekuyinkinga enkingeni yesekethe ephoqeleli kanye okuphambene nalokho, kungahle kufake sandla emfanekisweni wokuphoqelela ophoqelelayo UHollander noWong (1995) (I-Brewer nePotenza, 2008).

Kunokuphazamiseka okuthile kwengqondo lapho kubonakala khona ukuthi ukuziphatha okungacabanganga nokuphoqelela, okungenani ngezizathu ze-phenotypic, ukuba yisithako esiyinhloko nesilimaza kakhulu. Lezi zinkinga ezivame ukubhebhetheka, njengamanje ezihlukaniswe ngezigaba eziningi zokuxilongwa ze-DSM-IV-TR (APA), zifaka phakathi i-obsessive-compulsive disorder (OCD), i-body dysmorphic disorder, i-Tourette's syndrome, i-trichotillomania, ukunakekelwa kokushoda kwe-hyperactivity (ADHD), ukugembula kwezifo, kanye nezidakamizwa (SAs). Okuthakazelisayo, i-autism ibonakala ngokuziphatha okuphoqelekile (njengenye yezizinda ezintathu eziyinhloko zezimpawu) kanye nokuziphatha okungahambi kahle (njengenye yezizinda zezimpawu ezihambisanayo).

Ngokwesiko, ukuphazanyiswa okucindezelayo nokungacabangi kubhekwe emaphethelweni ahlukile wesilinganiso esisodwa; okwangaphambili kuqhutshwa yisifiso sokugwema ukulimala kanti okwakamuva ngokuziphatha okufuna umvuzo. Kodwa-ke, ubufakazi obuguqulwayo obuvela ezifundweni zokuhumusha buveza ukuthi ukuthambekela okwabiwe ekubhekaneni nokukhubazeka kokuziphatha, okungenzeka kubangelwe ukwehluleka kokulawulwa okuphezulu kwe-'top-down 'kwamasekethe we-fronto-striatal, noma kungenjalo kusuka ekusebenzeni ngokweqile ngaphakathi kwamasekethe we-striatal, kungaqinisa kakhulu ukungahambi kahle nokucindezela . Ngakho-ke, kunokuba kube nokuphikisana kwe-polar, ukuphoqeleka nokungafisi kungabonisa izinto ezibalulekile ezi-orthogonal ezinomthelela ngamunye kumazinga ahlukahlukene kulezi zinkinga.

Uningi lwalezi zinkinga luvame ukwenzeka ndawonye, ​​kungaba ngaphakathi komuntu oyedwa noma ukuhlangana kwemindeni, okusho ukuthi kungenzeka izindlela ezabiwe ze-pathophysiological (Hollander et al, I-2007b). Ngaphezu kwalokho, kunobufakazi bokunqwabelana ekuphenduleni kokulashwa kulo lonke ukuphazamiseka okuthile. Ngokuvamile i-OCD iphendula kuma-serotonin reuptake inhibitors (ama-SRI; ama-clomipramine kanye nama-SRI akhethiweyo, ama-SSRIs) kanye nama-SSRIs ahlanganiswe nama-antipsychotic agents (Fineberg et al, 2005). Ama-Antipsychotic amele ukwelashwa komugqa wokuqala kwe-Tourette's syndrome, ngakho-ke, kuyathakazelisa ukuthi ukuhlangana kwabo nama-SSRI kukhombisa ukusebenza ngempumelelo okukhulu kwi-OCD ehlobene nokufundisa (Bloch et al, 2006). Ukuphoqelela okuhambisana nokuphazamiseka kwe-autistic nakho kungaphendula ku-SSRI yedosi ephansi nakuma-antipsychotic (Kolevzon et al, 2006). I-Trichotillomania ingaphendula kuma-SRI naku-antipsychotic, kepha ukuqinisekiswa ezifundweni ezilawulwayo kuyadingeka (Chamberlain et al, 2007d). I-ADHD, ngakolunye uhlangothi, iphendula kuma-inaditors we-Noradrenergic reuptake inhibitors kanye ne-dopaminergic agents (isb. Amphetamine), ukugembula kwe-pathological, kanye nokuphazamiseka kokusebenzisa kabi izidakamizwa nakho kungahlanganyela impendulo yokwelashwa kwabaphikisi be-opiate (I-Brewer et al, 2008).

Ukunikezwa kwesizathu nomphumela, kusetshenziswa idatha yomtholampilo kuphela, kungaxakeka ngobuningi bezizinda zezimpawu ezihambisanayo ezenzeka ngaphakathi kokuphazamiseka kwengqondo okuyinkimbinkimbi. Ngempela, leli qembu lezinkinga libhekene ne-phenotypic heterogeneity enkulu kanye nokugqagqana. Isibonelo, ezinye izimo ezine-autism azibonisi zimpawu ze-ADHD noma zokuziphatha okuphoqelelayo, ezinye zikhombisa i-ADHD, ezinye i-OCD, kanti ezinye zikhombisa izindlela zokuphindaphinda zezimoto ezingafani ne-OCD. Ucwaningo lokuhumusha luphenya ngombono wezinqubo eziyisisekelo, futhi ngaleyo ndlela lungakwazi ukukhomba iminikelo ye-neural eqhuba izici ezithile zokuphazamiseka kwengqondo. Ama-endophenotypes ayalinganiswa, ayizici ezihlelekile, atholakala endaweni ephakathi nendawo phakathi kwe-phenotype yomtholampilo kanye ne-genotype yokuthola izifo. 'Ama-phenotypes aphakathi' anjalo acatshangelwa ukuthi ahlobene ngqo nengozi yofuzo yokuphazamiseka kwengqondo kwe-polygenic kunokuziphatha okuvezwe emtholampilo (UGottesman noGould, 2003; IChamberlain neMenzies, 2009). Izinhlobo ze-Endophenotypic zesifo zingasiza ekucaciseni ukuqonda kwethu isisekelo sofuzo sokuphazamiseka kobuchopho okuyinkimbinkimbi futhi ngaleyo ndlela sokwazisa ukuhlukaniswa kwezifo. Njengamanje, ukuphazamiseka okuphoqayo nokuphoqayo kuhlukaniswa phakathi kwezigaba ezihlukile ze-DSM-IV. Njengoba i-American Psychiatric Association icubungula ukuhlukaniswa kabusha kwe-OCD, ukuphazamiseka kokukhathazeka kanye nokuphazamiseka kokulawula okungamthelela (ama-ICD) ekubuyekezweni okulandelayo kwe-DSM-V (Fineberg et al, I-2007a), kusenesikhathi ukubukeza izindlela ezisetshenziswayo zalokhu kuphazamiseka.

Kulesi sibuyekezo esilandisayo, sibheka izindlela ze-neural ne-neuropsychological ezihambisana nezenzo eziphoqayo neziphoqayo kanye negalelo labo ezibonelweni zokuphazamiseka okuphoqayo nokuphoqayo. Siqoqa okutholakele kusuka kuhla olubanzi lwedatha eyengeziwe, enezifundo ezishicilelwe ezisanda kushicilelwa, nokucwaninga kokushicilelwa okungakashicilelwa, ucwaningo lwe-endophenotypic, nokuhlolwa kwempilo yokwelashwa, kubandakanya umsebenzi oqhubekayo ovela emayunithi ethu e-United Kingdom nase-United States. Ukuhlaziywa kwethu kugxila ekufuneni ukulinganisa, ukuhlukaniswa kokusebenza okuhle, okuqhekeka kwe-cortico-striatal neural kusuka ku-OFC kuya ku-medial striatum (i-caudate nucleus), okuhlongozwayo ukuqhuba umsebenzi ophoqelelayo, nokusuka kwi-anterior cingulate / VMPFC to the ventral striatum (nucleus accumbens igobolondo), okuhlongozwayo ukushayela umsebenzi ongafanele, nenkulumo-mpikiswano phakathi kwabo (Amarobbins, 2007; I-Brewer nePotenza, 2008) (Umfanekiso we-1).

  

Umfanekiso we-1

Ukuphoqelela kanye nokungahambi kahle: Izinqubo ze-neural zommeleli ezifaka isandla ekuphazamiseni kwengqondo. Noma ukuphazamiseka okuphoqayo nokuphoqayo kungabhekwa njengokuphikisana ne-polar, ukwehluleka kokulawulwa kwe-cortical striatal neural circuits kungagxila zombili ...

Sisebenzisa le datha, sizama ukulungisa imibuzo ebalulekile kufaka phakathi lokhu: (i) kungakanani ukucindezelwa kanye nokuphoqelelwa kufaka isandla kulokhu kuphazamiseka, (ii) kuncike kangakanani ekuxhumaneni noma ekuhlukaniseni i-neural circry, (iii) yini i-monoaminergic yokulamula izindlela, (iv) ingabe izici zokuziphatha ezingaphoqeleli noma eziphoqelelayo zinanoma yiliphi inani eliqhubekayo lokuphathwa okuhlobene nokwelashwa kwezokwelapha, futhi (v) sikhona yini isilinganiselo sobunye obuhlanganisa yonke le mininingwane? Siphinde futhi sibheke namathemba ocwaningo lwesikhathi esizayo esikholelwa ukuthi lungathuthukisa kakhulu insimu.

IModeli ZOKUGUQUKA ZOKUFUNDAZA NOKUZIPHATHA

Ukuhlolwa kwe-neurocognitive okuhlosiwe kubamba amandla okucacisa izindlela ama-ejenti we-pharmacological akhipha imiphumela yawo emihle yomtholampilo nokubikezela imiphumela yemitholampilo (Chamberlain et al, 2007e; I-Brewer nePotenza, 2008). Kusetshenziswa imisebenzi ebucayi kanye ne-domain eqondene nesizinda sezinzwa, ukuphoqelelwa kanye nokuphoqelelwa kungahlukaniswa kube yizizinda ezihlukanisiwe nezinobungozi ze-neurobiologically kubantu bomuntu nasezilwaneni zokuhlola, ngezici ezithile ezibandakanya izingxenye ezihlukanisayo zepharry-striatal circry (Winstanley et al, 2006).

Imininingwane iveza ukuthi ukufakwa kungasuselwa kunqubo eyodwa noma eziningi ezihlukile ze-neurocognitive. Lokhu kufaka phakathi ukuthambekela kokukhishwa kwe-pre-potent motor disinhibition, okulinganiswa isikhathi sokumiswa kwesiginali (i-SSRT) msebenzi (U-Aron noPoldrack, 2005), ixhumeke ebantwini ngokusebenzisa kusebenze i-cortex ephansi yangakwesokudla (i-RIF) nokuxhumeka kwayo kwe-subcortical (URubia et al, 2003) futhi kwaguqulwa kumagundane nakubantu yi-norepinephrine (Chamberlain et al, 2006c, 2007a; Cottrell et al, 2008), kepha hhayi i-serotonin (Clark et al, 2005; Chamberlain et al, 2006d). Enye into efaka ubunzima ekubambezeleni ukwaneliseka nokukhetha imivuzo emincane esheshayo yize kunemiphumela emibi yesikhathi eside, kulinganiswa ngokwenza izinqumo noma imisebenzi yokugembula efana neCambridge Ginji Task (CANTAB), eqondiswe ngokujikeleza kwe-orbitofrontal nokujikeleza okuhlobene kwe-cortical ngaphansi kokushintshwa kwe-serotonergic modulation (Rogers et al, I-1999b), kanye nokujikeleza kwe-subcortical under dopaminergic kanye ne-serotonergic control (Winstanley et al, 2006). Ingxenye yesithathu iqukethe amasampula wolwazi anganele ngaphambi kokwenza isinqumo, esilinganiswa ngemisebenzi yamasampula wolwazi njenge-Reflection Task (Clark et al, 2006) futhi kungenzeka i-5-Choice seri Reaction Time Task (5-CSRTT) (Amarobbins, 2002) (Ithebula 1).

  

Ithebula 1

Ukuhlukaniselana Ukudlula Kunye Nokuphoqelela Ngokuya Ngezizinda Ze-Neurocognitive: Imisebenzi kanye ne-Neural / Neurochemical Correlates

Ukuphoqeka, mhlawumbe, akuqondakali kahle. Ukwehluleka ku (i) ekufundeni okuguqukayo (ie amandla wokuvumelanisa nokuziphatha ngemuva kwempendulo engemihle, kulinganiswa ngemisebenzi ethile yokufunda eguqukayo) kanye (ii) nokuguquguquka kokunaka kokuqondisa, kungahle kube negalelo ekwaziseni (Izinsuku et al, 1996; Clarke et al, 2005). Zombili lezi zinselelo zibonisa izindlela zokungakwazi ukuguquguquka kwengqondo, kodwa ngayinye ibonakala inamasekhethi ahlukile we-neural.

Ukufundwa okuphindayo kukhubazeka izilonda ku-OFC (kepha hhayi i-dortolateral preortal cortex, DLPFC) kuzo zonke izinhlobo (Izinsuku et al, 1996; Berlin et al, 2004; Hornak et al, 2004; I-Boulougouris et al, 2007). Ebantwini, i-OFC isebenza ngokukhetha ngesikhathi sokufunda okuguqukayo (IHampshire no-Owen, 2006). Ngokuphikisanayo, izilonda eziya ku-PFC yamuva zilimaza ukuguquguquka kokushintshwa kozinti (Izinsuku et al, 1996), futhi ekusebenzeni kwabantu ukusebenza komsebenzi kuhlobene nokwenza kusebenze kokukhethwa kwecortex yangaphakathi yenhlangano eyedlule (VLPFC) (IHampshire no-Owen, 2006) (Ithebula 1).

Manje kunobufakazi obukhulu obuxhumanisa ukufunda okuguqukayo nezinqubo ze-5-HT, kufaka phakathi namagundane (Masaki et al, 2006; I-Boulougouris et al, 2008; I-Lapiz-Bluhm et al, 2009), iziqu ezingezona ezomuntu (Clarke et al, 2004, 2005; Walker et al, 2009), nabantuPark et al, 1994; Rogers et al, I-1999a; Evers et al, 2005) kususelwa emakhemikhali ekhemisi, emithanjeni nasekudleni, kanye nasebufakazini bokusungula izakhi zofuzo kwezinkawu ze-rhesus (Izquierdo et al, 2007). Ngokuvamile, ukunciphisa i-serotonin yobuchopho, ikakhulukazi ezifundeni ezithile njenge-OFC (isib Clarke et al, 2004), kuphazamisa ukufunda ukuguquguquka. Ukulawulwa oku-systemic kwe-5-HT-2A antagonist kuye kwaboniswa futhi kukhubaza ukufunda emuva kwesikhala (I-Boulougouris et al, 2008). Isiphikisi se-5-HT6 receptor siphinde saboniswa ukuthi sikhuthaze ukufundwa okuguqukayo nokushintshwa kokunaka kumagundane (Hatcher et al, 2005). Kodwa-ke, kube nokuhluleka okuthile ukuthola imiphumela yokufunda okuphindayo, imvamisa ngemuva kokudangala kwe-tryptophan, kubantuI-Talbot et al, 2006) namagundane (i-van der Plasse ne-Feenstra, i-2008), kanye nokuntuleka kwe-serotonin transporter kumagundane nakho akubonakali kuthinta ukubuyiselwa kwesikhala okulula (IHomberg et al, 2007).

I-5-HT2 RECEPTOR SUBTYPES KUNGENXA YOKUQHAQESHA IZIKHALAZO

Ukuphindaphindwa kwe-5-HT receptors kukhonjelwe lapho ama-ligands athile esakhiwa khona. Ubufakazi obandulelayo obuvela ezifundweni zezilwane nezebuntu buveza umsebenzi we-5-HT2 receptors in behaviour behaviour. Amagundane eTransgenic aswele i-5-HT2C receptors athuthukisa amaphethini wokuziphatha ophoqelelayo akha imodeli ebonakalayo ye-OCD (I-Chou-Green et al, 2003). Kodwa-ke, kukhona ukungaboni kahle okubonakalayo kwedatha etholakala kulokhu kulungiswa kofuzo nenye idatha, okungenzeka ngenxa yezinqubo zokuphoqelela ezingezicacisiwe ezisetshenzisiwe lapho kulungiswa i-transgenic, njengoba idatha yakamuva yamakhemikhali ikhombisa ukutholwa okuphambene kokuthi i-5-HT2C activation receptor ihlotshaniswa nokuphoqelelwa okwandayo. Ngakho-ke, kumodeli wokulinganisa we-T-maze alternation alternation of OCD, Ama-Tsaltas et al (2005) ithole ukuthi ukuphathwa kwe-m-chlorophenylpiperazine (mCPP), i-agonist exubekile ye-serotonin enemiphumela emibi ye-agonist ye-5-HT2C, yanda ukuphikelela noma ukuphoqelela ukuphendula, kanti ukuzimelela okungamahlalakhona nge-SSRI (fluoxetine), kepha hhayi i-benzodiazepine noma i-desipramine, kuyichithile imiphumela ye-mCPP. Inselelo nge-5-HT1B receptor agonist naratriptan ayizange ibe nomphumela wokuphoqeka ngaphakathi kwalesi simodeli, iphakamisa umsebenzi othile we-5-HT2C receptor, ongalawulwa phansi ngokwelashwa kwe-SSRI okungapheli. Ezigulini ze-OCD, inselelo enkulu yemithi ebangelwa yikhemikhali ine-mCPP ekhulayo ye-OCD dalili (Hollander et al, I-1991b). Lo mphumela waphinda wabonwa ngokusobala nge-fluoxetine (Hollander et al, I-1991a) kanye ne-clomipramine (I-Zohar et al, 1988). Ngaphezu kwalokho, kuyahambisana nalokhu okutholakele, I-Boulougouris et al (2008) uthole ukuthi umphikisi we-5-HT2C receptor antimondon ithuthukise ukufunda emuva. Ngakolunye uhlangothi, kusebenze ukuphakanyiswa kwama-receptors e-5-HT2A ngaphambili ukuze kuxhaswe umphumela we-SSRIs (EWestenberg et al, 2007). I-antipsychotic yesizukulwane sesibili ingakhulisa ukuziphatha okuphoqayo ezigulini ezine-schizophrenia, futhi kuye kwahlongozwa ukuthi lokhu kwenzeka ngokusebenzisa amandla aphikisayo e-5-HT2A (I-Poyurovsky et al, 2008), noma i-dopamine (DA) i-receptor antagonism imele enye indlela engenzeka. Ngaphezu kwalokho, ama-antipsychotic esizukulwane sesibili nesokuqala akhombisa ukusebenza kahle kwezokwelapha lapho kuhlangene nama-SSRI ku-OCD (UFineberg noGale, 2005), mhlawumbe ngokwandisa umsebenzi we-DA ngaphakathi kwe-cortex yangaphambili (mhlawumbeUkuphika et al, 2004).

UKUHLUKANIPHA KWEZOBUCHWEPHESHE KOKUFANELEKILE NOKUZIPHATHA; AMAHLATHI WOKUTHOLA

Kumamodeli wezilwane, ukwahlukaniswa okuthakazelayo phakathi kwemiphumela ye-5-HT2A ne-5-HT2C receptor antagonists on izinyathelo of impulsivity kanye nokuphoqelela kuye kwabonwa. Kwi-5-CSRTT, ukuphathwa okuhleliwe kwe-5-HT2C receptor antagonist (SB24284) kukwenze kwenyanyisa ukufakwa okuthuthukile okuvame ukubonwa ngemuva kokuncipha komhlaba kwe-5-HT okhiqizwe yi-intracerebroventricular ukuphathwa kwe-5,7-dihydroxytrypt; ukuthuthuka okufanayo okuhlobene ne-SB24284 ekuqhutshweni kwabonwa kubonwe kumagundane asebenzisana ne-sham (Winstanley et al, 2004). Ngokuphambene, ukuphathwa okuhleliwe komphikisi okhethiweyo we-5-HT2A receptor antagonist (M100907) kwakuba nezenzo eziphikisanayo, kulungisa ukufakwa zombili kumagundane asebenza ngokuxaka kanye nama-5-HT. Le mithelela ehlukile ye-5-HT2A ne-5-HT2C antagonists yalingiswa ngokufakwa kwezidakamizwa kuma-nucleus accumbens, kepha hhayi i-mPFC, ezilwaneni eziqinile (Cottrell et al, 2008). Kodwa-ke, ngokuhlukahluka kwe-5-CSRTT, bekunokwenzeka ukuthola ukuncipha okubalulekile kokuxoshwa ngemuva kokufakwa kwe-intra-mPFC kwe-5-HT2A receptor antagonist. Ukutholwa kokugcina bekuhambisana nokubona ukuthi, kubantu abaningi abasebenza ngamagundane kaLister, ngokuvamile kwakuyizilwane eziphoqelela kakhulu ezazinokugxila okukhulu kwe-5-HT ku-mPFC, okubonisa ukuthi ukungafani ngakunye nokucaciswa kwesifunda kubalulekile ekucabangeni kokuqonda ubudlelwano phakathi kwe-5-HT kanye ne-disinhibition yokuziphatha.

Imiphumela yokushintshwa kwe-5-HT emaphakathi ekuphatheni okungahambi kahle ime ngokuqhathanisa nezenzo zabo emsebenzini wokunaka ngayinye se ku-5-CSRTT. Amaphepha ambalwa abonile ukuthi akukho miphumela noma ukuthuthukiswa kwangempela kokunaka kokunakwa lapho ukuziphatha okuphoqayo kuthuthukiswa (Harrison et al, 1997) noma ngemuva kokwelashwa nge-systemic noma i-intra-PFC 5-HT2A receptor antagonists efana ne-ketanserin noma i-M100907 (Passetti et al, 2003; Winstanley et al, 2003) kanye ne-5-HT1A receptor agonist 8-OHDPAT (Winstanley et al, 2003). Lokhu okutholakele kuhambisana nomqondo wokuthi ukulawula okungathinteki kokuziphatha okuxakile nomsebenzi wokunaka kuhlanganiswe kuphela kulesi simo sokuhlola futhi kusikisela ukuthi ngeke kube nobudlelwano obulula phakathi kwalaba bantu kuma-syndromes afana ne-ADHD.

Into eyengeziwe yobunzima iyaziswa lapho kucatshangelwa amathonya ale mishanguzo efanayo ngezinyathelo zokuphoqelelwa. Kusetshenziswa isivivinyo sokubuyela emuva esilula esijwayelekile esizwelayo kwizilonda ze-OFC (I-Boulougouris et al, 2007), kutholakale ukuthi i-5-HT2C receptor antagonism (ekhiqizwa ukuphathwa kwe-systemic) lula ukufunda emuva. I-M1000907 ibinomphumela ophambene wokuyiphazamisa (Ama-Tsaltas et al, 2005). Qaphela ukuthi ngokuya ngokuxolelwa, lokhu kuphambene nalokho okwatholakala ngezinyathelo zokuxoshwa. Izithuthukisi ezifanayo zokufunda ukubuyela emuva ngemuva kokulashwa ngesiphikisi se-5-HT2C nazo zatholakala ngemuva kokufakwa kwe-OFC (Boulougouris, Glennon, Robbins, imiphumela engashicilelwe) (Ithebula 2).

  

Ithebula 2

Imiphumela Ehlukile ye-5-HT2C ne-5-HT2A Receptor Antagonists on Rat Models of Impulsivity and Compulsivity

Akunandaba nokucaciswa okucacile komshini, le datha ngamakhemikhali ihlukanisa lezi zindlela zokuziphoqelela nokuphoqelela, kuphakamisa ukuthi abakwazi hinge inqubo evamile yokuziphatha kokuvimbela. Ukuhlukaniswa akunakuchazwa kalula ngokuya ngokwehlukana kwezinhlobo zezidalwa, izidakamizwa, noma umthamo womphikisi we-receptor osetshenzisiwe noma uhlobo lokugqugquzela olusetshenzisiwe; kumele zincike emsebenzini-njengoba zombili lezi zidingo zidinga ukuvimbela impendulo ukuze zisebenze kahle. Ngakho-ke, siphethe ngokuthi kunesinye isici sezinqubo ezenziwa ngumsebenzi, ezihlukanisa. Le miphumela isho nokuthi ukuphoqelelwa nokuphoqelelwa kuhlukaniswe ngokuqinile futhi kwenziwa ijoka, ukuxhasa ukuxhasa imodeli yokuguquguquka engaphoqelekile (yokuphoqelela).IHollander neWong, 1995). Baphinde baphakamise ukuthi ukufakwa ngamandla nokuphoqeka kungahlukaniswa ngokukhetha ama-5-HT2 ama-receptor ligands nokuthinta ezinhlelweni ezintsha zomtholampilo zalawa ma-ejenti. Kodwa-ke, kuzodingeka ukuthi kuxazululwe ukuthi le datha ihlangana kanjani nokuthola okungaguquki kokuthola ukuthi ukuncipha kwe-5-HT ku-OFC kukhubaza ukubuyiselwa kokuthile kokufundwa kwezinkawu ze-marmoset (Clarke et al, 2004, 2005; I-Yucel et al, 2007). Ngaphezu kwalokho, kubonakala sengathi kungenzeka ukuthi le miphumela ebonakala iphikisiwe iqondiswa ngemigudu ehlukile ye-neural: esimweni sokuphoqelela, ngokusebenzisa ukuqagela okuvela ku-infralimbic VMPFC (indawo ye-25), indawo egcwele ngokucebile i-5-HT2A receptors futhi ifakwe umfutho ngokuqinile kumvumelwano umthetho, obheke egobolondweni le-nucleus accumbens (I-Vertes, 2004) futhi, esimweni sokuphoqelelwa, ekuxhumaneni phakathi kwe-OFC ne-caudate nucleus (noma i-dorsomedial striatum ku-rat) (Schilman et al, 2008).

UKUHLOLA IZIVIVINYO EZIQHAWULAYO ​​NEZIQINISEKILE ZISEBENZISA IMISEBENZI ESEZULULA

Ukuphazamiseka okuphoqayo nokuphoqayo kuvame ukubandakanya ikhono elincishisiwe lokunciphisa noma ukuvimbela imicabango noma isimilo esiphindaphindayo. Ngakho-ke, izinkinga zokucindezela noma zokuvimbela ukusebenza okungafanele zingasusa zombili izimpawu eziphoqelelayo neziphoqayo (Chamberlain et al, 2005; Stein et al, 2006). I-ADHD ukuphazamiseka kokuqala kokuqala kubonakala ngokungazicabangeli kahle, ngezenzo ezingenampilo kanye nokulimazeka okuqinile ekuvinjelweni kwezimoto njengoba kulinganiswa ngemisebenzi efana ne-SSRT (I-Aron et al, 2003; I-Lijffijt et al, 2005). Ukuphathwa kwama-ejenti akhulisa ukuqonda njenge-atomoxetine ne-methylphenidate kuthuthukisa izimpawu futhi kuntula ukusilela kwe-SSRT kubantu abadala abane-ADHD, ngokungenzeka basebenze ngokwanda kwe-noradrenergic (noma i-dopaminergic) neurotransmission (Chamberlain et al, I-2007a).

Izifundo ezigulini ze-OCD ziveze ukuthikamezeka kwe-SSRT nokusebenza kabi emisebenzini yokushintsha kwe-ED (Chamberlain et al, I-2006a, I-2007c; Menzies et al, I-2007a), okubonisa ukuthi kukhona iminikelo ephoqelekile nephoqelelayo yokuphazamiseka. Izihlobo ezingaxutshwe nezibalo zokuqala ze-OCD ezingafakwanga zabelana ngokulimazeka okufanayo kuma-SSRT nemisebenzi ye-ED (Chamberlain et al, 2007c) futhi ngaleyo ndlela zibonakale zibonisa amazinga afanayo wokushayiswa kwezimoto nokuguquguquka kwengqondo, naphezu kokuntuleka kwezimpawu ze-OCD. Ngokuphikisana ne-OCD, ukusetshenziswa kwebhethri le-neurocognitive test efanayo kubantu abane-trichotillomania kubonise ukungahambisani kahle nokukhetha ukuvinjezelwa kwezimoto, kuhambisana nokuhlukaniswa kwe-DSM-IV njenge-ICD (Chamberlain et al, I-2006b, I-2007b). I-MRI enobuchopho ku-trichotillomania engacaciswanga ikhombe ukwanda kokuxinana kwe-grey-grey in the putamen kwesokunxele kanye nezifunda eziningi ze-cortical (Chamberlain et al, I-2008b). Ukwanda kwendaba ezimpunga ezifundeni ezisabekayo kuye kwabikwa nasezifundweni zeTourette syndrome (Bohlhalter et al, 2006; I-Garraux et al, 2006) kanye ne-OCD (Menzies et al, I-2008a). Ngakolunye uhlangothi, iziguli ezine-Tourette's syndrome zitholakale zabelana ngokuguquguquka kwengqondo futhi zikhubazeka kakhulu kuneziguli ze-OCD emisebenzini yokwenza izinqumo, kepha zingakhubazekile kangako emsebenzini wokuvimbela izimoto (Amawashi et al, 2005), noma olunye ucwaningo oluphenya intsha nge-Tourette's alubutholanga ubufakazi bokukhubazeka kokufunda komvuzo uma kuqhathaniswa nezilawuli zomsebenzi wokugembula (Crawford et al, 2005). Li et al (2006) yehlulekile ukukhombisa ukusilela kokusebenza uma kuqhathaniswa nezilawuli ku-SSRT ezinganeni ezingama-30 ezine-Tourette's syndrome.

Ukwedlulela kokuphendula okuphoqayo nokuphoqayo ngaphakathi kwe-OCD kuphakamisa umbuzo wokuthi ngabe ukuzwela kuvame ukudala ukucindezelwa, futhi ngenxa yalokho ukuthi kungenzeka yini ukukhombisa ukukhuthazeka kwengqondo ngaphandle ukufutheka kwemoto. Uma kunjalo, yikuphi ukuphazamiseka okungakhombisa ukuphoqeleka 'okumsulwa'? Abantu abane-obsessive-compulsive disorder disorder ehambisana ne-OCD bakhombise ukukhubazeka okwandayo ikakhulukazi esizindeni sokushintshwa kwe-ED. Lokhu okutholwayo kuyahambisana nokwethulwa komtholampilo kokuphazamiseka okungalawulekiyo kobuntu, okubonakala ngokungaguquguquki kwengqondo ngokweqile nokuziphatha, kepha akubandakanyi izindlela eziphindaphindwayo zokuziphatha (okusho ukuthatheka noma ukuphoqelelwa). Ngakho-ke, ukuphazamiseka kobuntu ngokweqile- okuyimpoqo kungaba yisifo se-prototypic-compulsive (Fineberg et al, I-2007b). Izifundo zokuqinisekisa usebenzisa abantu abane-OCPD engeyona i-comorbid zingamukelwa.

I-NEUROCOGNITIVE ENDOPHENOTYPES, OCD KANYE YOKUQALA

Ngenkathi imisebenzi ye-neurocognitive ingasetshenziselwa ukukhomba izizinda ezithile ze-neuropsychological, i-neuroimaging ehambisanayo ingasetshenziselwa ukubona ngamehlo engxenye yezakhi zangaphansi ze-anatomical kanye nezijikelezo ze-neural ezibeka engcupheni yofuzo yokuphazamiseka. Ngokuhlanganisa amapharamitha we-Mocococitive kanye nesakhiwo se-MRI, kusetshenziswa ukuhlaziywa kwe-multivariate kwengqondo okuphelele (inqubo yesikwele esincane esinqunyelwe, UMcIntosh noLobaugh, 2004) novivinyo lokuvunyelwa kwenoveli, Menzies et al (2007a) ukhombe imiphumela yomndeni ekusebenzeni umsebenzi we-motor-inhibition task (i-SSRT) ehlotshaniswa nokuhlukahluka kumasayithi amaningi we-anatomical. Zombili iziguli ze-OCD nezihlobo zabo ezingathinteki ekuqaleni kuboniswe ukulimala kokuvinjezelwa kwemoto ephazamisekile, ekhonjwe yi-latency ende ye-SSRT kanye ne-latency ende ende kuhlotshaniswe nethamo levolthi lezinto ezi-grey ku-OFC ne-RIF cortex (izindawo ezihlotshaniswe ngokuhlangana ne-OCD ne-SSRT activation, ngokulandelana) futhi lenyuka nevolumu yento ebimpunga izindawo ze-striatum, cingulate, ne-parietal cortex. Le miphumela iphikisana nokuqalwa kokumelana kokuqala kwe-MRI endophenotype-mediation yomndeni, futhi okungenzeka ngofuzo, ingozi yokuxoshwa okuhlobene ne-OCD. Izifundo zesikhathi esizayo zingavivinya ngokunenzuzo imiphumela ethile yezakhi zofuzo ekushintshashintsheni kulezo zinto eziphakathi nendawo, njengenye indlela yokwakheka kweenhlangano zakudala, ukutholwa kwezinsolo zokuthi zingaba khona.

Imiphumela etholakele ne-SSRT, umsebenzi ongeyona isifo-okungaqondene nokushayiswa kwezimoto, iphakamisa ukuthi kungenzeka ukuthi i-endophenotype ingakhawulelwe ku-OCD, kodwa ngaphezu kwalokho ihlobene nokunye ukuphazamiseka okungaphakathi, futhi mhlawumbe ngaphandle, ukuphazamiseka okuphoqayo-okuphoqayo isibuko. Isibonelo, abantu abane-ADHD nezihlobo zabo babonakala bekhubazekile emsebenzini we-motor-inhibition (UCrosbie noSchachar, 2001), kepha akukacaci noma ngabe ukuhlanganiswa kokuhlangana kokulimazeka kwalabo abanobungozi emndenini we-ADHD kuyafana noma kwehlukile kubantu abanobungozi bomndeni we-OCD.

Ukuxhumana okungaphakathi kwesihloko phakathi kwe-cortex kunciphile ezindaweni ezivulekile ze-cortex kanye nokwenyuka kwamanani kuma-striatum resonates onobuhle be-OCD onobuhle obususelwa ezifundweni zokucabanga kokusebenza kokuqala (Baxter et al, 1987) kanye nezifundo ze-MRI ezihlelekile futhi ezisebenzayo (ukuze kubuyekezwe bheka, Menzies et al, I-2008a). Ukutholwa kokuqala ocwaningweni olulandelayo kusetshenziswa ukucabanga kokuphambanisa ngaphakathi kwamalungu omndeni we-OCD (Menzies et al, I-2008b) kukhombe ubufakazi bokuhlukunyezwa kwendaba emhlophe ezindaweni ezihlanganisiwe zobuchopho kufaka phakathi i-medial frontal front (eduzane ne-anterior cingulate cortex, ACC) nezindawo ezingakwesobunxele zeparietal (eduzane nezigcawu zeparietal cortex), ehambisana nemiphumela evela ocwaningweni lwangaphambilini olubandakanya iziguli ze-OCD (Szeszko et al, 2005). Kodwa-ke, ngokunwebisa lolu cwaningo ukuthi lufake amalungu omndeni we-OCD angatholakali, siphakamise lokhu okutholakele ngokusemandleni endophenotypes emhlophe ngangokunokwenzeka.Menzies et al, I-2008b).

Ngaphezu kokuhlukunyezwa kobuchopho obuhlelekile ezigulini ezine-OCD nezihlobo zabo, ucwaningo seluqalile ukuthola ubuqiniso bokusebenza kokujikeleza kwe-fronto-striatal kusetshenziswa ubuhlakani be-fMRI obuguqulwe le njongo. Besebenzisa i-paradigm ye-fMRI yokuqonda okuguquguqukayo, kwaboniswa ukuthi iziguli ezine-OCD kanye nezihlobo zazo zokuqala ezingakhonjwanga zazikhonjiswa ngaphansi kokuvuselelwa kwe-AUC ye-bilateral lateral ngesikhathi sokubuyiselwa kwezimpendulo; baphinde bathambekele ekubumbeni izinto ezingatheni ze-PFC ngesikhathi sokushintshana kwamazinga we-ED kumazinga enkambiso (Chamberlain et al, I-2008a).

Ngokubambisana, lokhu okutholakele kukhombisa ukuthi amasu we-neuroimaging anganikeza ngomthombo ocebile wama-endophenotypes e-candidate ye-OCD. Imiphumela iyahambisana nemibono eveza ukwehluleka kwe-top-down cortical inhibition of striatally mediated behaviour. Basikisela ukuthi ukukhanyiswa kwe-idiosyncratic obsessive kanye namasiko okuphoqelela abonisa i-OCD kuhambisana nokuthambekela okujwayelekile kokuziphatha okuqinile nokungavinjelwe okwabiwe phakathi kwamalungu omndeni angathintekile. Ngakho-ke, ubunzima 'bokuvimbela ukuqonda nokuguquguquka kwengqondo' bungaba nomthelela omkhulu ekuthuthukiseni izimpawu ze-OCD. Umsebenzi wesikhathi esizayo kufanele uhlolisise ukuthi le ndlela ingakwazi ukwenziwa ngempumelelo ngempumelelo kokunye ukuphazamiseka ku-spectrum esingaphoqelekile. Ukubaluleka komtholampilo kwama-endophenotypes we-putative kudinga uphenyo olwengeziwe ukuthola ukuthi (futhi kanjani) izihlobo ezingathintekile ezabelana ngezimpawu zemikhondo nama-OCD probands zingahlukaniswa nezilawuli ezihlobene ne-OCD. Ukuqonda okuthuthukisiwe kuyadingeka ngezindlela lapho izici zemvelo zingakhipha i-OCD kubantu abasengozini yezakhi zofuzo, nokuthi ngabe noma kanjani ukwelashwa kungasiza ukuguqula ukuqala kwesifo.

ICDS KANYE NAMAModeli WOKWENZA

Ngokuqhathanisa nokuphazamiseka okuphoqayo njenge-OCD, amanye ama-ICD, njengokugembula kwe-pathological, abonakala ngokukhetha ukwaneliseka kwesikhashana esincane ngaphandle kokuthola imiphumela emibi yesikhathi eside. Berlin et al (2008) qhathanisa abantu abasebenzisa ukugembula kwe-pathological nebhethri elikhethiwe le-neuropsychological (Berlin et al, 2008). Abantu abaphethe ukugembula okubhekwe kakhulu kwizinyathelo abazibike zona njengokuthi i-Barratt Impulsivity Scale babenomqondo wesikhathi esijwayelekile (isikhathi esimisiwe) ngokuqhathaniswa nezilawuli futhi bakhombisa ukusilela okulinganiswa nemibuzo yangaphambili yokuziphatha ethathwa njengokubonisa kuqala Ukungasebenzi kahle. Izihloko ezinokugembula kwe-pathological futhi zikhombisile ukwenza izinqumo ezingezinhle kwi-Iowa Gamble Task (Bechara et al, 1994) kanye nokusilela kokuhlela okuphezulu (isb. ekuHlanganiseni Kwendawo kanye nokugcinwa kwamasheya weCambridge yaseCANTAB), okufaka umjikelezo ophambi kwesikhathi kufaka phakathi isifunda se-OFC / VMPFC. Ngokungafani ne-OCD (Amawashi et al, 2005; Chamberlain et al, I-2006b), ukushintshanisa okusetshenziswayo bekungaphazamiseki ekugembeni kwe-pathological. Kodwa-ke, okunye ukuhlola kukhombisa ukuthi abantu abanokugembula kwe-pathological bafaka kakhulu kwizinyathelo ezithile zokuphoqelela noma zokugwema ukulimala, nokuthi izindlela zokuphoqelela kanye nokuphoqelelwa zingashintsha ngokuhamba kwesikhathi (isib, ngesikhathi sokwelashwa (Potenza, 2007a; Mhlophe et al, 2009). Lokhu okutholakele kuveza ukuthi ukuphoqelelwa kanye nokuphoqelelwa akuphikiswa ngokwezibalo futhi kwabelana ngobudlelwano obuyinkimbinkimbi, obuthile obuthile, nokuphazamiseka okuthe ngqo okukhombisa ubukhulu bokwakhiwa okukodwa ngaphezulu kokunye okungase kuguquke ngendlela enamandla yesikhashana.

Hollander et al (2007a) qhathanisa amaqembu amathathu abantu abaneminyaka yobudala kanye nabesilisa — aqondana nobulili, ahlanganisa ukugembula kwe-pathological (ukuphoqelela kakhulu) ne-OCD kanye ne-autism (ngokuyimpoqo), kusetshenziswa ibhethri lemisebenzi yokucabanga, yokuqonda, neyokusebenzelana. Ngenkathi kwenziwa imisebenzi yokuphendula (ukuvimba / ukungahambi) evame ukwenziwa komsebenzi wokujikeleza kwe-fronto-striatal, wonke amaqembu amathathu we-spectrum-disorder abonise ukusebenza kwe-fMRI okungajwayelekile ezindaweni ezi-dorsal (cognitive) kanye ne-ventral (ngokomzwelo) ye-ACC uma kuqhathaniswa nezilawuli ezinempilo . Kwakungekho mehluko wokusebenza obalulekile phakathi kwamaqembu amane. Kodwa-ke, ukuhlaziya okuphakathi kweqembu kukhombise ukwehla kwamandla kwe-dorsal ACC kuwo womathathu amaqembu eziguli ahambelana nokulawulwa okunempilo. Ngakho-ke, ngesikhathi sokuvinjelwa kokuphendula, zombili iziphazamiso eziphoqelelayo nezingaphoqeleleki bezibonakala ngokuncipha kokusebenza kwe-dorsal ACC, okungaba nomthelela ekwehlulekeni ukuvimbela ukusebenza kwezimoto ngendlela efanele kulokhu kuphazamiseka.

Lapho amaphethini wokusebenziswa komuntu ngamunye we-ventral ACC ehlanganiswa nezindlela zokuphoqelela noma zokuphoqelela, ukuvela kokungaboni ngasolinye phakathi kweqembu kuqhume. Ngaphakathi kweqembu lokugembula le-pathological, i-ventral ACC / i-ventral striatum activation ehambisana kahle nezinyathelo zomtholampilo zokuziphatha okukuphoqelela okufuna ukuthola imbuyiselo (njengoba kulinganiswa yi-TCI Impulsiveness kanye ne-Total Harm avoal, i-NEO-FFI Extraversion, Ingqikithi Yesikhathi Sokulinganisa, ne-Iowa Gancing Task ). Ngaphezu kwalokho, abagembuli abasebenza ngokukhuphuka ku-ventral ACC (indawo 25) bakhombise izikolo eziphansi zokucindezelwa emisebenzini yokuguqula ukuguquguquka (izigaba ze-ID / ED ziqediwe). Ngokuphikisanayo, eqenjini le-autistic (ukuphoqelela), umsebenzi we-ventral ACC / we-ventral striatum oxhumene nobunzima obukhulu ukuphoqa imikhuba yokunciphisa usizi (yokuqinisa), nokwanda kokusebenza ngaphakathi kwezindawo ezifanayo ze-ventral ACC (indawo ye-25) ehambisanayo nokunyusa okuphoqayo (i-ID / ED yokuguquguquka kwamaphutha aphelele) futhi inciphise ukucindezelwa emsebenzini we-Time Estimation.

Lokhu 'kuhlukaniswa kabili' kusikisela ukuthi ekugembuleni kwe-pathological kanye ne-autism, umehluko okhona kumthelela we-neuromodulation emigwaqeni ye-ventral corticostriatal ngesikhathi sokuvinjelwa kokuziphatha, okungaba ukugembula okungokwemvelo okungaholela ekuqhubekeni kokungacabangi naku-autism kuqhube ukucindezela. Kubuye kukhumbuze imininingwane evela kumagundane echazwe kwenye indawo lapha ekhombisa imiphumela ephikisayo ye-5-HT2C kanye ne-5-HT2A receptor antagonists ngokungazami ku-5-CSRTT kanye nokuphoqelela (indawo yokufunda okuguqukayo kwe-serial) (Ama-Tsaltas et al, 2005; I-Boulougouris et al, 2007) - kanye nokutholakele okuphikisanayo kukaCarlli et al-Ukuthi ukuthathwa kwesimo se-agonist ye-5-HT1A esifundeni se-infralimbic kunciphise ukusebenza kokukhuthazela (kwi-5-CSRTT) ngaphandle kokuthonyela ukuphendula okuphoqayo, nge-5-HT2A receptor antagonist has a wide effect (Chambers et al, 2004). Ngokubambisana, lokhu okutholakele kusikisela ukuthi ukujikeleza okufanayo kwe-neural kungashayela izici eziphoqayo noma zokuphoqelela zokuziphatha komuntu nokuthi i-5-HT subtypes ku-VMPFC (5-HT2A) ne-OFC (5-HT2C), kanye nokushoda kwe-dorsal ACC. ukwehluleka kokuvinjwa kokuphendula kokuphazamiseka okungapheli (ukugembula kwe-pathological) nokuphazamiseka okuphoqelekile (OCD, autism).

UKUQONDA, UKUQINISEKISA, NO-DA

Izindlela ze-DA kuhlelo lwe-mesolimbic zinomsebenzi obalulekile ekuzuzeni nasekuqiniseni (Ohlakaniphile, 2002). Ekuphazamisekeni kokulawulwa kokufakelwa, ukusebenza okwandisiwe kwe-ACC ye-ventral ngesikhathi sokuvinjwa kokuphendula kungahle kuhlobane nokuziphatha okuningayo okufuna umvuzo. Imiphumela yokuqala iphakamisa ukuthi abagembuli be-pathological abathobeki kangako ukuthola umvuzo ku-TCI umvuzo wokuthenjiswa komvuzo kunokulawula okunempilo futhi bafuna amazinga aphakeme wokukhuthaza (ukufuna okusha)Berlin et al, 2008). Kodwa-ke, ezinye izifundo zezifundo ezinokugembula kwe-pathological zithole ukwenziwa okuncishisiwe kwe-ACC, ikakhulukazi engxenyeni yayo yangaphakathi, ngesikhathi sesifundazwe sokuhlola nokuhlolwa kokulawula ukuqonda (amandla et al, I-2003a, I-2003b). Ngokuphathelene nokuphazamiseka okuphoqayo, ukuhlangana okuhle phakathi kokukhiqizwa kwe-ACC kwe-ventral ngesikhathi sokukhiqizwa kokuphendula kanye nokwanda kokucindezelwa ezigabeni ze-ID / ED kanye namaphutha ephelele angashintshwa kungabonisa ukwanda komsebenzi we-dopaminergic kusuka ekusweleni okuhlobene, ngokuhambisana nemodeli ye-mesolimbic ye-OCD (UJoel, 2006).

Ukuvuselelwa kwe-hypothetically, ngezikhathi ezithile eziphindaphindwayo zezindlela ze-mesolimbic DA 'kungashukumisa' uhlelo lokuvuza futhi kuholele ekukhuleni ekufuneni umvuzo (I-Robinson ne-Berridge, i-1993), okuthi, uma kuhlanganiswe nokulawulwa okungalungile kokulawulwa kwangaphambili kwe-cortex-Mediated inhibitory, kungahle kube nokuziphatha okuhlobene nokubonakala okushukunyiswa yi-DA. Ukukhishwa ngokweqile kwe-DA nokwenyusa kungadicilela phansi izitolo ze-DA kuholele ku-anhedonia nokudangala (U-Koob noLe Moal, i-1997). Ngempela, kubahlukumezi bezidakamizwa, ukuncipha komsebenzi wohlelo lwe-mesolimbic / mesocortical DA, njengoba kulinganiswa ukuqoshwa kwe-elekthronikhi kanye vivo i-microdialysis, iyaqina ngemuva kokukhula kokudla kwezidakamizwa. Lokhu kungadala isifiso (sokuphoqeleka) sokufuna imivuzo enamandla ukuze 'kugcwalise' ukuntula kwe-DA. Ukubonakaliswa kokuncipha kwe-striatal D2-like receptors kubasebenzisi be-cocaine abangapheli, nge-PET imaging (I-Volkow et al, 1999), iphakamisa ukujezelwa okuphansi kokuphendula kokuphakanyiswa okuphezulu kwe-postynaptic ye-DA, kuhambisana nomqondo oqondile wohlelo lwe-DA olungene ngemuva kokugqugquzelwa kaningi kokukhishwa kwe-DA. Ngakho-ke, okuqala njengokukhishwa kwe-DA okuholela ekwandeni komsebenzi we-ACC we-ventral kanye nokwenyuka kokufuna umvuzo (Ohlakaniphile, 2002) kungahle kuphele njengokushoshozela kokuya emazingeni akhuphukayo wokuvuselela umvuzo ukuze kubuyiselwe imiphumela yokushoda kwe-DA. Le drive ephoqelelayo ingavuselelwa ngokulawulwa kokungafaneleki kokwenza izinqumo kanye nokuthatha izinqumo, okuxhunyaniswe ne-orbitof Pambal, i-ventromedial prefrontal, ne-ACC (I-Adinoff, 2004). Kodwa-ke, ukuthi le hypothesis ihlobana kanjani nama-ICD athile kudinga ukuthi kwenziwe uphenyo ngqo.

IMINININGWANE EHLANGANISEKILEYO YOKUQHUTYELWA KOKUGQIBELA, IMIMISELO, NO-DA

Amamodeli wokucindezelwa nokuphoqelela afaka ibhalansi phakathi kwe-5-HT (2A, 2C) receptor umsebenzi kuzindawo ze-VMPFC / OFC ezilawula izici zokuvinjwa kokuphendula, nethoni ye-DA ku-loops ye-ventral exhumanisa i-ventral ACC ene-ventral striatum / nucleus isimilo. I-neurotransication ye-DA, ikakhulukazi ukukhishwa kwe-phasic, kuma-nucleus accumbens kuhlotshaniswe nokufuna umvuzo kanye nokuqiniswa (I-Schultz, i-2002). Kuhlongozwe isijeziso esingalindelekile (ukulahleka kwemali) ukuze kudaleke idipho emaphakathi ne-dopaminergic, ekufundeni emuva, nasekunciphiseni ukufuna imivuzo (Frank et al, 2007). Izidakamizwa ze-Pro-dopamanergic, kufaka phakathi i-levo-dopa ne-pramipexole (i-D2-efana ne-DA receptor agonist), ihlotshaniswe nokuguqula ukufunda okubuyela emuva ekujezisweni okungalindelekile nama-ICD ezigulini ezinesifo sikaParkinson (Ipholisa, i-2006; Ukuphola et al, 2006). I-Pramipexole ibuye ihlotshaniswe nokutholwa kokulimazeka kokuziphatha okuhlobene nomvuzo kubahlanganyeli abanempilo, kuhambisana nedatha ebonisa ukuthi ukusayina kwe-phasic ye-DA kubalulekile ekuqiniseni izenzo eziholela kumvuzo (I-Pizzagalli et al, 2008). Kodwa-ke, eminye imininingwane ikhombisa ukuthi i-pramipexole, uma ihanjiswa kubantu abadala abanempilo, ayiguquli ukuziphathisa okuphoqelela, ukuphoqelelwa, noma ukwakha okuhlobene kufaka phakathi ukwehlisa ukubambezeleka, ukuthatha ingozi, ukuvimbela impendulo, noma ukubambezela (Hamidovic et al, 2008). Ngaphezu kwalokho, i-olanzapine, isidakamizwa esinezakhi zomphikisi emndenini we-receptor we-D2, ayikhombisanga ukuphakama kwe-placebo kuzilingo ezimbili ezilawulwa ezibandakanya izifundo nokugembula kwe-pathological (Fong et al, 2008; UMcElroy et al, 2008), futhi esinye isiphikisi esifana ne-D2, haloperidol, sitholakale sandisa izisusa ezihlobene nokugembula nokuziphatha kubantu abanokugembula kwe-pathological (UZack noPoulos, 2007). Izifundo zeRadioligand zibalulekile ukucacisa imisebenzi engaba khona ye-D3 ne-D2 receptors ku-pathophysiology yokugembula kwe-pathological, futhi izifundo ezinjalo ziyinkimbinkimbi ngalezi zi-receptors zokwabelana nge-affinities kuma-radioligands akhona.

Ukunaka lokhu okutholakele, ucwaningo olwengeziwe luyadingeka ukuqonda kangcono ubudlelwano phakathi kokuphoqelelwa, ukuphoqelelwa, nomsebenzi we-DA njengoba zihlobene nokuphazamiseka kwengqondo okufana nokugembula kwe-pathological. Ukuphazamiseka okuphoqayo noma okuphoqayo kungahle kutholakale ekushoneni kwe-mesolimbic DA. Kodwa-ke, abaphikisi abanjenge-D2 babonise inzuzo yokwelapha kwezinye (i-OCD), kepha hhayi ezinye (izigembula zokugembula) eziphawulwa yizici zokuphoqelela kanye / noma zokuphoqelela. Ukufuna kokubili ukujikeleza kwe-ventral kanye ne-dorsal striatal circry kwizifundo zabantu abanezifo ezithile eziphoqayo neziphoqayo ngokusebenzisa ama-ligotor-syotonergic nama-dopaminergic ligands kungaba isinyathelo esilandelayo sokuqonda lezi zimo. Kungaba nentshisekelo ethile ukuhlola imiphumela yabaphikisi be-5-HT2A nabama-2C ekuhanjisweni kwe-DA kulo mjikelezo. Lokhu kuphenywa kunganikeza ukuqonda okwengeziwe ngezici ezifana nokuncipha kokusebenza kwe-ventral striatal kanye ne-VMPFC okubonwe kuzo zonke izifundo ezibandakanya ukuphazamiseka kubelana ngezici eziphoqayo neziphoqayo, njengokugembula kwe-pathological and SAs (Ukubuyela emuva et al, 2005; Potenza, 2007a).

Ukuchazwa kwethu kwangaphambilini kokuphoqelela (ukuthambekela kokwenza okuphindaphindwayo ngendlela ejwayelekile / eyisisekelo yokuzama ukuvikela imiphumela emibi) nencazelo yamanje (ukudonswa kwesimo esiphikisayo esinjengokuhoxisa) kuhlobene ngokuqondile. Isibonelo, ukuphendula ngokujwayelekile emikhondweni yezidakamizwa kungathathwa njengendlela yokucabanga ngokuzenzakalelayo yesifo sokuwaxekisa esingavimbela amandla futhi sikugweme ngaphambi kokuthi kwenzeke. Imininingwane ixhumanisa lezi zindlela zokufunda (noma zokuphoqelela) ezingxenyeni ze-dorsal striatum (i-caudate ngokwesibonelo), njengoba kubuyekeziwe ngaphambili. Ubufakazi obamuva kakhulu manje buhlobanisa i-dorsal striatum (ingxenye yayo engemuva) nokufunda okukuphakamisayo kokufunda (Seymour et al, 2007). Ngakho-ke, ngokombono we-neural, ubufakazi buxhasa ukuvumelana phakathi kwale mibono emibili yokuphoqelelwa.

IMPUMELELO NOKULUTHA 'UKUZIPHATHA'

Ukugembula kwe-pathological kanye nama-SA abelana ngezici eziningi. Ukuphazamiseka kuvame ukuvela futhi kukhombisa ukufana maqondana namaphrofayili wophawu, umehluko wobulili, umlando wemvelo, kanye nokuqina komndeni (Isibonelelo kanye nePotenza, 2006). Ukugembula kwe-pathological ne-SA kukhombisa amazinga aphezulu okuxakwa emisebenzini ehlawula umvuzo, ehambelana nezinyathelo ezingezinhle zokusebenza (U-Bechara, i-2003) kanye nomphumela wokuphathwa kabi (I-Krishnan-Sarin et al, 2007) kubantu abane-SAs ngakho-ke bangaba nenani lokuqhubeka nokugembula okuvela emzimbeni kanye namanye ama-ICD. Imininingwane ye-Neurocognitive ne-fMRI iphakamisa ukugembula kwe-pathological futhi ama-SA abelana ngokufanayo kwe-neurocircuitry, okuthe, uma kuqhathaniswa nezifundo zokulawula, ukuncishiswa okuncishisiwe kwe-ventral striatum kanye ne-VMPFC kubonwe ekusebenzeni kwemivuzo kanye nezinye izinhlaka (amandla et al, I-2003a, I-2003b). Ukuqalwa okungejwayelekile kwe-fMRI ye-ventral striatum ngesikhathi sokulungiswa kwemivuzo sekutholakele emindenini yabantu abane-SA futhi kungahle kumelele ukhetho lokwenza umsebenzi wokugcina we-endophenotype wokuphazamiseka umlutha, yize lo mqondo udinga ukuhlolwa ngokuqondile ezihlotsheni ezingathinteki ze-pathological ukugembula kwe-phenands.

Ngokuhamba kwesikhathi, ukuphendula okwenzeka ngendlela engafanele ekugembeni kwe-pathological kanye ne-SA kungahle kuphendukele enkambisweni yokuziphatha okuphoqelela kakhudlwana, futhi kuye kwagcizelelwa ukuthi ukuqashwa okuqhubekayo kokuphazanyiswa komakhelwane okufana kanye nokwanda komoya, i-cortico-striatal loops kwenzeka ngendlela evulekile (I-Brewer nePotenza, 2008) ukukhumbuza ukujikeleza kokuqina kwe-striato-nigrostriatal kukhonjwe ku-primate (ILynd-Balta neHaber, 1994) ne-rodent (Belin et al, 2008) amamodeli wokuziphatha ashukunyiswayo enza amamephu wezinqubo zesikhashana kusuka ku-ventral kuya ku-drial striatum. Izifundo ezinokwenzeka, ezinde ngemuva kwalezi zinguquko ngaphakathi kwabantu ngokuhamba kwesikhathi kuzoba nokufundisa futhi kuhambelana nomtholampilo. Ukuthembisa ucwaningo kusuka ekwelapheni abantu ngokugembula kwe-pathological nabaphikisi be-opioid (I-Brewer et al, 2008) hhayi kuphela ukubandlulula ukugembula kwe-pathological kusuka ku-OCD, lapho abalingisi be-opioid abanjenge-naloxone bekhonjiswe khona ukwenza i-OCD ibe yimbi (I-Insel ne-Pickar, i-1983), kepha futhi sibonisa umsebenzi wokwelapha wabaphikisi be-opioid kwamanye ama-ICD ahlobene (Grant et al, 2007).

I-TARGETS ENTSHA ENTSHA

Ukuyiqonda ngokugcwele i-neurobiology yokungafisi nokuphoqeleka kanye namandla okuthuthukisa ukwelashwa okusha, kungadingeka ukuthi sihlolisise ngale kwamasekethe we-neural okuxoxwe ngawo kulesi sihloko ukufaka ezinye izakhiwo ze-neural, njenge-insula. Imininingwane iphakamisa ukuthi i-insula ibalulekile ekuxhumaniseni izifiso 'zokwazi'. Izilonda ze-insula, ngokwesibonelo ngemuva kokushaywa unhlangothi, zihlotshaniswa nokuyeka ukubhema ngokushesha (Naqvi et al, 2007). Ukuvezwa kokuboniswa emvelweni, noma kwizimo zasekhaya ezinjengokuhoxa, ingcindezi, noma ukukhathazeka, kungahle kuvuse izethulo 'ezingaphakathi' ku-insula ehumushela ekubeni 'ukunxenxa' okubonakalayo. I-insula ixhumeke ngokomzimba futhi isebenza kahle kumasistimu we-neural ashiwo ngenhla afakwa ekuxhashazweni, ekuphoqeleleni nasekulawuleni ukuvimbela. Ngokuqondakalayo, i-insula ihlangana nezinqubo zokuphoqeleka nokuphoqeleka ngokudlulisa amasiginali (kusuka emvelweni noma i-viscera) kuya ku-5-HT 2C vs Ama-5-HT 2A receptors ku-prefrontal cortex. Ngakho-ke, amasignali wokungenelela axhumene ne-insula, ngakolunye uhlangothi, angenza imizwelo ye-neural ishayele ukungabi namandla noma ukuphoqeleka. Ngakolunye uhlangothi, umsebenzi we-insula ungahle 'udune' izindlela zokulawula i-prefrontal cortex futhi uguqule ukunakwa, ukubonisana, ukuhlela kanye nezinqubo zokwenza izinqumo kude kusuka ekuboneni imiphumela emibi yesenzo esithile, futhi kuya Ukwakha amasu wokufuna futhi wokuthola okuvusa amadlingozi njengezidakamizwa (Naqvi et al, 2007).

ISIPHETHO

Ngakho-ke, ukubuyela embuzweni wethu oshukumisayo: (i) kungakanani ukucindezelwa kanye nokuphoqelelwa kufaka isandla kulokhu kuphazamiseka, (ii) ancike kangakanani ngezinga elithile kulokho okwabiwe noma okuhlukanisiwe kwe-neural circry, (iii) yiziphi izindlela zokulamula ezilinganayo. iv) ingabe izici zokuziphatha eziphoqayo noma eziphoqelelayo zinanoma iliphi inani le-progicic elihlobene nokwelashwa, futhi (v) sikhona yini isibonelo sobunye obufana nedatha? Ngokobufakazi obukhona, ukufakwa, nokuphoqelelwa, ngalinye libonakala lingamazwe amaningi futhi lifaka okungenani ezinye iziyaluyalu eziphoqayo neziphoqayo, noma ngabe ukuphazamiseka kubonisa okudlayo, kepha futhi namaphrofayili ahlukile. Ngakho-ke, ukwehluleka okumangazayo ngaphakathi kwe-cortico-striatal neurocircuitry yokulawula izici zokubamba inhibitory kuye kwabonwa ocwaningweni lokucabanga kanye nokucabanga kwakho konke ukuphazamiseka okubuye kubhekwe, kepha ngenxa yokuphazamiseka okuthile idatha ihlala ingaphelele. I-Trichotillomania ingahle ihlukane njengokuphazanyiswa kokulawulwa kokushayiswa kwezimoto kanye nokungasebenzi kahle ngaphakathi kwe-RIF cortex kanye nokuxhumeka kwayo kwe-cortico-subcortical, kanti ukugembula kwe-pathological kuhlobene nokuxoshwa okuhlobene nokwenza izinqumo ezingekho emthethweni kanye nokujikeleza okungajwayelekile kwe-cortico-striatal circry, kubandakanya i-VMPFC kanye ne-ventral striatum, okuyihlonza kakhulu nama-SA. Amazinga aphezulu wokuxhunyaniswa okuhlobene nomvuzo okuhlobene nomvuzo ngomphumela ongemuhle wokuphathwa kwama-SA futhi angaba nokubaluleka kokuqhubeka kokugembula kwe-pathological namanye ama-ICD. Ukuziphatha okuphoqayo okwenzeka nge-autism kuhlotshaniswa nokukhubazeka okufanayo kokujikeleza komvuzo we-ventral. Ngakolunye uhlangothi, i-OCD, ikhombisa ukungahambi kahle kwezimoto nokuphoqelela, kuqondwe phakathi kokuphazamiseka kokujikeleza kwe-OFC-caudate, kanye ne-VLPFC, i-RIF cortex, i-cingulate kanye nokuxhumeka kwe-parietal. Kulezi ziphazamiso, i-serotonin ehlobene ne-DA, kanye ne-Noradrenaline kungenzeka ukuthi ibe nemisebenzi ebalulekile yokuguqula, kanye nezinye izinhlelo njengamanje ezingafakwanga kahle. Ngokuhamba kwesikhathi, ukuphoqelelwa kungavela kube ukukhuthazeka futhi okuphambene nalokho.

Ngakho-ke, isithombe sibonakala sikude ne-diathesis elula elula enokuxakaniseka nokuphoqeleka okuhlala ezigxotsheni eziphambene, futhi 'imodeli' mhlawumbe ifaka ukuxhumana okuxakile kwezinhlayiya eziningi ezihlobene, ezihlangene, ezichazwe ngokuhlukile kula masekethe nezifo. Ukuphazamiseka okungathathekiyo nokuphoqelela kuhluka ngokugqamile, kwabelana ngezici zokungacabangi nokuphoqeleka, futhi kube nzima kakhulu futhi kube nzima kakhulu ukuhlukanisa ngokuhamba kwesikhathi. Isibonelo, ekuphazamisekeni kokuxhamazela nokulutha, ukubekezelela umvuzo kungakhula futhi nokuziphatha kungaqhubeka njengendlela yokunciphisa ukungakhululeki (okusho ukuthi baba yimpoqo ngokwengeziwe). Ngokuphazamiseka okucindezelayo, kungenzeka ukuthi ukusebenza kokuziphatha okuphindaphindayo uqobo kuyaqina ngokuhamba kwesikhathi, yize kunemiphumela emibi yesikhathi eside (okusho ukuthi baqhutshwa ngokuxhamazela). Ukwenza imephu ngalezi zinkinga usebenzisa ibhethri okuvunyelwene ngalo labamakayo be-endophenotypic marker kungaqhubeka kucacise ubudlelwano babo, futhi amabhizinisi okucwaninga abambisene ngokuzayo kuzo zonke izikhungo ezinobuchwepheshe obufanele kufanele akhuthazwe. Izindlela zenoveli zingadingeka ukuphenya ngokwanele ngokusebenzisa izindlela 'zonxantathu' njengokuxhumana okuyinkimbinkimbi. Mayelana nalokhu, amasu wokuhlonza amasistimu asebenzayo ebuchosheni kudatha ye-neuroimaging, enjengenqubo yezikwele ezincane (okuvumela nokuhlolwa kokuhlukahluka kokuziphatha nokuzicabangela), ingaba namandla amakhulu njengezinqubo zesikhathi esizayo kulo mkhakha. Singaphinde senze inqubekelaphambili ekuhlukaniseni izindlela zokwamukela ezithintekayo ekulawuleni isimilo esiyimpoqo nesiphuthuma ngokusebenzisa amalungiselelo e-transgenic egundane emisebenzini efanayo eyenzelwe amagundane (isb. 5-CSRTT kanye nokuguqula ukufunda) nokuhlola uhla oluphelele lwe-5- Ama-receptors we-HT asebenzisa ama-ligand amasha emithi.

Ukuvuma

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