Reduced anterior prefrontal cortex activation in young binge drinkers during a visual working memory task

Pos p in ( inal d a pos - e ee ing) Else ie Edi o ial Sys em( m) o D ug and Alcohol Dependence Manusc ip D a Manusc ip Numbe : WB-09-0310R1 Ti le: REDUCED ANTERIOR PREFRONTAL CORTEX ACTIVATION IN YOUNG BINGE DRINKERS DURING A VISUAL WORKING MEMORY TASK A icle Type: Full Leng h Repo Keywo ds: ERPs, eLORETA, binge d inking, uni e si y s uden s, wo king memo y, p e on al co ex. Co esponding Au ho : M Albe o C ego, ph.D s uden Co esponding Au ho 's Ins i u ion: Uni e si y o San iago de Compos ela (Spain) Fi s Au ho : Albe o C ego, ph.D s uden O de o Au ho s: Albe o C ego, ph.D s uden ; Soco o Rod íguez-Holguín, Ph.D; Ma ía Pa ada, Ph.D s uden ; Naya a Mo a-Mi anda, Ph.D s uden ; Mon se a Co al, Ph.D; Fe nando Cada ei a, Ph.D Abs ac : Wo king memo y (WM) is a majo cogni i e unc ion ha is al e ed by ch onic alcohol consump ion. This impai men has been linked o al e a ions in he hippocampus and p e on al co ex (PFC). Animal and human s udies ha e shown ha he adolescen b ain is mo e sensi i e o he neu o oxic e ec s o alcohol han he adul b ain, pa icula ly hose s uc u es ha ma u e la e on in de elopmen , such as he hippocampus and p e on al b ain. The aim o he p esen s udy was o assess isual wo king memo y and i s neu al co ela es in young uni e si y s uden s who pa ake in in e mi en consump ion o la ge amoun s o alcohol (binge d inke s). A sample o 42 binge d inke s and 53 co esponding con ol subjec s pe o med an iden ical pai s con inuous pe o mance ask (IP-CPT) in a combined E en -Rela ed Po en ial (ERP) and exac Low- Resolu ion b ain Elec omagne ic Tomog aphy (eLORETA) s udy. The esul s e ealed ha , despi e adequa e pe o mance, binge d inke s showed a smalle la e posi i e componen (LPC) associa ed wi h hypoac i a ion o he igh an e io p e on al co ex (aPFC) o ma ching s imuli, in compa ison wi h con ol subjec s. These indings may e eal binge d inking- ela ed unc ional al e a ion in ecogni ion wo king memo y p ocesses and sugges ha impai ed p e on al co ex unc ion may occu a an ea ly age in binge d inke s. Pos p in ( inal d a pos - e ee ing) Role o Funding Sou ce This esea ch was suppo ed by Conselle ía de Inno ación e Indus ia o Xun a de Galicia, g an numbe PGIDIT05CSO21103PR and INCITE08PXIB211015PR, by Plan Nacional sob e D ogas(PND) o Minis e io de Salud y Consumo o Spain, g an numbe 2005/PN014, and by Minis e io de Ciencia e Inno ación o Spain, g an e . EDU2008-03400. The Conselle ía de Inno ación e Indus ia o Xun a de Galicia, PND o Minis e io de Salud y Consumo o Spain and Minis e io de Ciencia e Inno ación o Spain had no u he ole in s udy design; in he collec ion, analysis and in e p e a ion o da a; in he w i ing o he epo ; o in he decision o submi he pape o publica ion. Con ibu o s All au ho s con ibu ed o and ha e app o ed he inal manusc ip . Au ho s Mon se a Co al, Soco o Rod íguez-Holguín and Fe nando Cada ei a designed he s udy and w o e he p o ocol. Au ho Albe o C ego managed he li e a u e sea ches and summa ies o p e ious ela ed wo k. Au ho s Naya a Mo a, Ma ía Pa ada and Albe o C ego collec ed da a. Au ho Albe o C ego unde ook he s a is ical analysis, and w o e he i s d a o he manusc ip . Au ho s Soco o Rod íguez-Holguín and Fe nando Cada ei a e iewed he inal manusc ip . Con lic o In e es All o he au ho s decla e ha hey ha e no con lic s o in e es . Au ho Disclosu es Pos p in ( inal d a pos - e ee ing) 1 REDUCED ANTERIOR PREFRONTAL CORTEX ACTIVATION IN YOUNG BINGE DRINKERS DURING A VISUAL WORKING MEMORY TASK Albe o C ego, Soco o Rod iguez-Holguín , Ma ía Pa ada, Naya a Mo a, Mon se a Co al, and Fe nando Cada ei a. Depa men o Clinical Psychology and Psychobiology, Uni e si y o San iago de Compos ela, Galicia, Spain Reques s o ep in s should be add essed o Albe o C ego, Depa amen o de Psicoloxía Clínica e Psicobioloxía, Facul ade de Psicoloxía, Campus Uni e si a io Su , E-15705, San iago de Compos ela, Galicia, Spain. Tel: +34-981-563100 (ex . 13915; Fax: +34-981-528071; E-mail: [email p o ec ed] *Manusc ip _ e ised Pos p in ( inal d a pos - e ee ing) 2 Abs ac Wo king memo y (WM) is a majo cogni i e unc ion ha is al e ed by ch onic alcohol consump ion. This impai men has been linked o al e a ions in he hippocampus and p e on al co ex (PFC). Animal and human s udies ha e shown ha he adolescen b ain is mo e sensi i e o he neu o oxic e ec s o alcohol han he adul b ain, pa icula ly hose s uc u es ha ma u e la e on in de elopmen , such as he hippocampus and p e on al b ain. The aim o he p esen s udy was o assess isual wo king memo y and i s neu al co ela es in young uni e si y s uden s who pa ake in in e mi en consump ion o la ge amoun s o alcohol (binge d inke s). A sample o 42 binge d inke s and 53 co esponding con ol subjec s pe o med an iden ical pai s con inuous pe o mance ask (IP-CPT) in a combined E en -Rela ed Po en ial (ERP) and exac Low-Resolu ion b ain Elec omagne ic Tomog aphy (eLORETA) s udy. The esul s e ealed ha , despi e adequa e pe o mance, binge d inke s showed a smalle la e posi i e componen (LPC) associa ed wi h hypoac i a ion o he igh an e io p e on al co ex (aPFC) o ma ching s imuli, in compa ison wi h con ol subjec s. These indings may e eal binge d inking- ela ed unc ional al e a ion in ecogni ion wo king memo y p ocesses and sugges ha impai ed p e on al co ex unc ion may occu a an ea ly age in binge d inke s. Keywo ds: ERPs, eLORETA, binge d inking, uni e si y s uden s, wo king memo y, p e on al co ex. Pos p in ( inal d a pos - e ee ing) 3 1. In oduc ion Alcohol abuse is p obably he mos common ype o d ug abuse in Wes e n coun ies. The e ec s o alcohol on he cen al ne ous sys em (CNS) ha e been widely s udied in animals, and he neu ocogni i e, neu oana omical and neu o unc ional consequences o alcoholism in humans is well-known ( o a e iew see Osca -Be man and Ma inko ic, 2007). In ecen decades, he e has been inc easing conce n ega ding he neu ocogni i e e ec s o alcohol in adolescen s and young people because o he high p e alence o alcohol abuse among his popula ion. Epidemiological s udies ac oss he USA and UK indica e ha a ound 40% o uni e si y s uden s a e binge d inke s (Gill, 2002; Weschle e al., 2000, 2002). In a ecen s udy by ou esea ch g oup in Spain (Caamaño e al, 2008), 37% o i s -yea uni e si y s uden s (N= 2700) we e ound o consume la ge amoun s o alcohol (" isky consump ion”) and 12.2 % we e classi ied as binge d inke s. Binge d inking (BD) is cha ac e ized by he consump ion o la ge amoun s o alcohol in a sho ime, ollowed by a pe iod o abs inence, as opposed o egula d inking in which a pe son may consume simila amoun s o alcohol weekly bu wi hou he ex emes o alcohol in oxica ion, and is common among young people, especially uni e si y s uden s, and pa icula ly on Thu sdays and weekend days (Bee s e al., 2009). A s anda dized concep ual de ini ion o BD was p oposed by he US Na ional Ins i u e on Alcohol Abuse and Alcoholism (NIAAA, 2004): “a binge is a pa e n o d inking alcohol ha b ings blood alcohol concen a ion o 0.08 g am pe cen o abo e. Fo he ypical adul , his pa e n co esponds o consuming i e o mo e d inks ( ou o mo e o emales), in abou wo hou s”. This de ini ion o BD is simila o ha used in mos epidemiological s udies, howe e , i does no speci y he ime pe iod o numbe o Pos p in ( inal d a pos - e ee ing) 4 binge e en s ha would desc ibe a long- e m BD pa e n. The inclusion o a minimum c i e ion o equency o BD episodes is necessa y o de ine a BD pa e n ( o a e iew, see Cou ney and Polich, 2009). This empo al aspec o a BD pa e n has been a iably de ined, mainly as a leas once in he p e ious wo weeks (Kelle e al., 2007; P esley and Pimen el, 2006; Sy e e al., 1997; Wechsle e al., 1994, Weschle and Aus in, 1998; Wechsle e al., 2000; Whi e e al., 2006) o in he p e ious mon h (G i i hs e al., 2006; Jenninson, 2004; McNally and Pal ai, 2001; Xing e al., 2006). In he USA, one s anda d alcoholic d ink equals 14 g o alcohol. Howe e , in Eu ope (excep Po ugal and UK) and Aus alia, one s anda d alcoholic d ink equals abou 10 g o alcohol, which ob iously a ec s he de ini ion o BD. Thus, mos widely accep ed and used de ini ion o BD pa e n includes wo c i e ia o minimum consump ion: a quan i y/ equency c i e ion (consump ion o i e o mo e s anda d alcoholic d inks -six in Eu ope and Aus alia- on he same occasion one o mo e imes pe mon h) and a speed o consump ion c i e ion ( i e o mo e s anda d alcoholic d inks in wo hou s, i.e., h ee o mo e pe hou ) (Minis e io de Sanidad y Consumo de España, 2008; NIAAA, 2004; Wo ld Heal h O ganiza ion, 2004). Animal s udies demons a e ha he in e mi en consump ion o high doses o alcohol causes majo al e a ions in he CNS (Hun , 1993; Jaa inen e al., 2003; Robe o e al., 2002; Tokunaga e al., 2006) and ha he adolescen b ain is mo e sensi i e o he neu o oxic e ec s o alcohol and BD han he adul b ain (C ews e al., 2000, 2006; Sil e s e al., 2003; Whi e e al., 2000). Alcohol pa icula ly a ec s hose s uc u es o he b ain ha ma u e la e on in de elopmen , such as he hippocampus and he p e on al co ex (PFC) (Mon i e al., 2005; Whi e and Swa zwelde , 2004). Human s udies ha e also e ealed he p esence o neu os uc u al and neu ocogni i e anomalies in adolescen s wi h alcohol use diso de s (AUDs). Acco ding Pos p in ( inal d a pos - e ee ing) 5 o he Diagnos ic and S a is ical Manual o Men al Diso de s, 4 h edi ion (DSM-IV: Ame ican Psychia ic Associa ion, 1994), AUDs include bo h alcohol abuse, which is cha ac e ized by a “maladap a i e pa e n o alcohol use mani es ed by ecu en and signi ican ad e se consequences ela ed o he epea ed use o alcohol”, and alcohol dependence, which is de ined as “a clus e o cogni i e, beha io al, and phsysiological symp oms (such as ole ance o alcohol and wi hd awal symp oms) indica ing ha he indi idual con inues o use alcohol despi e signi ican alcohol- ela ed p oblems”. These s udies ha e epo ed signi ican educ ions in he olume o hippocampus and PFC (De Bellis e al., 2000, 2005; Medina e al., 2008; Nagel e al., 2005), and a he neu ocogni i e le el, de ici s in unc ions ela ed o hese a eas, such as isospa ial a en ion, and pa icula ly wo king memo y (WM) (B own and Tape , 2004; Tape and B own, 1999; Tape e al, 2002), in adolescen s wi h AUD in compa ison wi h pai ed con ols. As ega ds BD, al hough ew s udies ha e in es iga ed he neu obiological and neu ocogni i e e ec s o his pa e n o alcohol consump ion in non-clinical samples o adolescen s and young people, i has been shown ha young people who indulge in BD expe ience di icul y in ca ying ou asks in ol ing p e on al co ex unc ions, such as WM, planning, a en ion and decision making (Ga cía-Mo eno e al., 2008; Goud iaan e al., 2007; Ha ley e al., 2004; Johnson e al., 2008; Townshend and Duka, 2005; Weissenbo n and Duka, 2003). Weissenbo n and Duka (2003) compa ed BD and non- BD s uden s and ound ha he pe o mance o he binge d inke s in a spa ial wo king memo y es was signi ican ly poo e han ha o he non-binge d inke s. Simila ly, Townshend and Duka (2005) ound ha emale binge d inke s pe o med wo se in a spa ial wo king memo y ask han non-binge d inke s. Wo king memo y is he e o e one o he cogni i e unc ions mos a ec ed by AUDs. Impai men o his cogni i e unc ion is p obably ela ed o he e ec s o Pos p in ( inal d a pos - e ee ing) 6 alcohol on b ain s uc u es such as he hippocampus and he PFC. S udies wi h young binge d inke s, al hough s ill sca ce, also indica e a possible de ici in his unc ion. The e o e, he aim o he p esen s udy was o explo e isual wo king memo y unc ion and i s neu al co ela es in young binge d inke s. One o he mos use ul asks in explo ing he neu al co ela es o WM is he con inuous pe o mance ask (CPT) (Baddeley, 2001; Bo ga o e al., 2003; Riccio e al., 2001). A ypical CPT equi es a en ion o a con inuous s eam o da a demons a ed by esponse o speci ic a ge s imuli. In his ask, subjec s a e ypically asked o moni o a long se ies o isually p esen ed digi s, le e s o o he cha ac e s appea ing a egula in e als, and o espond when hey obse e a p e-designa ed a ge (Ros old e al., 1956). A speci ic a ian o his ask, he iden ical-pai s con inuous pe o mance ask (IP-CPT) is a high p ocessing load e sion in which subjec s ha e o iden i y he consecu i e epe i ion o any i em in a sequence (Co nbla e al., 1988; Keilp e al., 1997). This ask has been used o assess psychia ic diseases, such as schizoph enia and a en ional-de ici hype ac i i y diso de , and has p o ed o be use ul in cha ac e izing neu al p ocesses associa ed wi h impai ed a en ion and WM in such diseases (Pe ls ein e al., 2003; Salgado-Pineda e al., 2003, 2004). Al hough i is di icul o each gene al conclusions because o he a iabili y among s udies as ega ds he design o speci ic asks, he analy ical echniques and he ou comes measu ed, i can be concluded ha IP- CPT in ol es ac i a ion o on al, limbic, subco ical and pos e io b ain s uc u es esponsible o senso ial in eg a ion (Keilp e al., 1997). Adle e al (2001) used MRI o explo e ce eb al ac i i y in subjec s execu ing an IP-CPT wi h a andom s eam o ou - digi nume als, in which he subjec s had o espond by p essing a bu on when he same ou -digi nume al appea ed wice in succession du ing he sequence. The au ho s ound ha his ask was associa ed wi h signi ican ly la ge ac i a ion o p e on al Pos p in ( inal d a pos - e ee ing) 7 co ex, bila e al pos e io empo al co ex, bila e al pu amen and halamus han occu ed in a simple CPT. The au ho s a ibu ed his inc ease in ac i a ion o inc eased memo y p ocessing demands by he IP-CPT. In he p esen s udy we eco ded e en - ela ed po en ials (ERPs) in o de o explo e he neu al co ela es o isual WM du ing IP-CPT. The IP-CPT elici s an ERP componen , named he la e posi i e complex (LPC), which has been closely ela ed o WM p ocesses and PFC ac i a ion (Düzel e al., 2001; Schendan and Mahe , 2009) and consis s o a b oad posi i e wa e o m wi h cen o-pa ie al maximum ampli ude and peak la ency a abou 500-700 ms pos -s imulus. I is known ha ERP s udies enable in es iga ion o he elec ical b ain esponses associa ed wi h cogni i e p ocesses wi h high empo al esolu ion, and ERPs (especially he P3 amily componen s) ha e been widely used o assess he neu ocogni i e e ec s o alcohol in di e en popula ions (ch onic alcoholics, abs inen ch onic alcoholics, child en o alcoholics) (Cada ei a.e al., 1991; Cohen e al., 1997; C is ini e al., 2003; Kama ajan e al, 2005; Miyaza o and Ogu a, 1993; Rod íguez Holguín e al., 1999). Howe e , o ou knowledge only wo s udies ha e used ERPs o explo e BD in young people. Ehle s e al. (2007) used a acial emo ional exp ession ecogni ion ask and e alua ed ERPs in young adul s wi h a his o y o BD du ing adolescence. They epo ed ha young adul s pa icipa ing in BD du ing adolescence displayed a lowe ampli ude in a la e subcomponen o P3 (P450) han subjec s who did no pa ake in BD du ing adolescence. The au ho s sugges ed ha hese anomalies may be associa ed wi h a loss o delay in he de elopmen o inhibi o y b ain sys ems in binge d inke s. Recen ly, Mau age e al. (2009) used a es - e es pa adigm and epo ed ha sho - e m BD can p oduce ma ked ce eb al dys unc ion unde ec able by beha io al measu es alone. The esul s o he s udy e ealed ha , a e nine mon hs o BD, subjec s p esen ed signi ican ly delayed la encies o P1, N2 and P3 Pos p in ( inal d a pos - e ee ing) 14 co ec esponses, alse ala ms and omissions we e analyzed by ANOVA, wi h wo be ween-subjec s ac o s: G oup (BD and con ol) and Gende (male and emale). 2.4.2. ERP analysis. All EEG da a we e analyzed wi h B ain Vision Analyze so wa e (Ve sion 1.05). The EEG was co ec ed o ocula a i ac s by he p ocedu e de eloped by G a on e al. (1983). I was hen digi ally il e ed o -line wi h a 0.1-30 Hz bandpass il e and segmen ed in o epochs o 1000 ms om 100 ms p e-s imulus o 900 ms pos - s imulus. Baseline co ec ion was applied, epochs exceeding ± 80 µV a any scalp elec ode we e ejec ed ( his c i e ion esul ed in less han 4% o ejec ed epochs) and EEG epochs co esponding o inco ec esponses (omissions o alse ala ms) we e excluded. A e age ERPs ime-locked o ma ching and non-ma ching s imuli we e compu ed sepa a ely o each pa icipan . The ERP da a we e examined by empo al P incipal Componen s Analysis ( PCA) o ensu e co ec iden i ica ion o LPC. This analysis is ecommended o iden i ying and quan i ying ERP componen s independen ly o he in luences o adjacen o subjacen componen s (Chapman and McC a y, 1995; Dien, 1998). I also enables iden i ica ion o hidden ERP componen s and p e en s possible misin e p e a ions ha occu wi h adi ional isual inspec ion o g and a e ages. The PCA p o ides wo ma ices, one o ac o loadings and ano he o ac o sco es. The i s shows he load o each ac o o e ime, and he second p o ides in o ma ion abou he ex en o which each ac o is p esen in he a e aged ERPs a each elec ode si e. The ac o sco es a e ans o med alues o he o iginal ol ages, which may be conside ed as “clean ampli udes” and hus can be used as a measu e o he ampli ude. A co a iance-ma ix-based PCA was applied o bo h condi ions (ma ching and non-ma ching s imuli). The decision ega ding selec ion o he numbe o componen s Pos p in ( inal d a pos - e ee ing) 15 (o ac o s) was based on he esul s o he sc ee es (Ca ell, 1966). The numbe o da a poin s ( ac o s) abo e he “b eak” in he sc ee es was es ed by unning mul iple ac o analyses and manually se ing he numbe o ac o s o be e ained. Nine ac o s, which accoun ed o 94.8% o he o al a iance, we e inally selec ed. Ex ac ed ac o s we e hen submi ed o P omax o a ion. P omax o a ion was used because i minimizes miscalcula ions due o, e.g., misalloca ion o a iance (Dien, 1988). The empo al and spa ial cha ac e is ics o he componen s indica ed ha ac o 1 (explained a iance: 59%; la ency: 625ms) co esponded o he LPC. The nine empo al ac o s ex ac ed a e shown in Fig. 3. Inse Figu e 3 abou he e The ac o sco es co esponding o LPC om bo h ma ching and non-ma ching s imuli we e o ganized in o h ee egions, each wi h six elec odes: on al (F3, Fz, F4, FC3, FCz, FC4), cen al (C3, Cz, C4, CP3, CPz, CP4) and pa ie al (P3, Pz, P4, PO3, POz, PO4). P elimina y s a is ical analyses we e pe o med wi h he Gende ac o included, and once i was e i ied ha he e we e no majo gende e ec s o in e ac ions, his ac o was no conside ed in he design. A mixed model ANOVA wi h ou ac o s was used o he s a is ical analysis, wi h one be ween-subjec s ac o and h ee wi hin-subjec ac o s. The be ween-subjec s ac o was G oup (BD and con ol) and he wi hin-subjec ac o s we e Ma ch Condi ion (ma ching and non-ma ching s imuli), Region ( on al, cen al and pa ie al) and Elec ode (six channels). An expe imen -wise alpha le el o 0.05 was used. Whene e app op ia e, deg ees o eedom we e co ec ed by he conse a i e G eenhouse-Geisse es ima e. Pos p in ( inal d a pos - e ee ing) 16 All pos -hoc pai compa isons we e pe o med wi h he Bon e oni adjus men o mul iple compa isons, also wi h an alpha le el o 0.05. 2.4.3. eLORETA analysis. On he basis o he scalp- eco ded elec ic po en ial dis ibu ion, he exac low esolu ion b ain elec omagne ic omog aphy (eLORETA) so wa e (publicly a ailable ee academic so wa e, a h p://www.uzh.ch/keyins /lo e a.h m) was used o compu e he co ical h ee- dimensional dis ibu ion o cu en densi y a LPC o ma ching ials in bo h g oups. The eLORETA me hod is a dis ibu ed, linea weigh ed minimum no m in e se solu ion. The weigh s endow he omog aphy wi h he p ope y o exac localiza ion o es poin sou ces, yielding images o cu en densi y wi h exac localiza ion, albei wi h low spa ial esolu ion (i.e. neighbo ing neu onal sou ces will be highly co ela ed). The me hod and he p oo o i s exac ze o-e o localiza ion p ope y a e desc ibed in Pascual-Ma qui, 2007 and 2009. I is also impo an o emphasize ha eLORETA has no localiza ion bias e en in he p esence o s uc u ed noise. In his sense, eLORETA is an imp o emen o e p e iously de eloped omog aphies (LORETA: Pascual-Ma qui e al., 1994), and o e he s anda dized e sion, sLORETA (G eenbla e al., 2005; Pascual-Ma qui, 2002; Sekiha a e al., 2005). The p e iously de eloped ela ed omog aphies LORETA and sLORETA (Pascual-Ma qui e al., 1994, 2002) ha e been alida ed in se e al s udies combining LORETA wi h o he mo e es ablished localiza ion me hods such as unc ional Magne ic Resonance Imaging ( MRI, Mule e al., 2004; Vi acco e al., 2002), s uc u al MRI (Wo ell e al., 2000), Posi on Emission Tomog aphy (PET, Die ks e al., 2000; Pizzagalli e al., 2004; Zums eg e al., 2005), and in asi e implan ed elec odes Pos p in ( inal d a pos - e ee ing) 17 eco dings (Zums eg e al., 2006). The esul s o hese s udies also alida e eLORETA, owing o i s imp o ed localiza ion p ope ies. I is wo h emphasizing ha deep s uc u es such as he an e io cingula e co ex (ACC, Pizzagalli e al., 2004) and mesial empo al lobes (Zums eg e al., 2006) can be co ec ly localized wi h his me hod. Compu a ions we e made in a ealis ic head model (Fuchs e al., 2002), wi h he MNI152 empla e (Mazzio a e al., 2001), and wi h he h ee-dimensional solu ion space es ic ed o co ical g ay ma e . The in ace eb al olume is pa i ioned in 6239 oxels a 5 mm spa ial esolu ion. Thus, eLORETA images ep esen he elec ic ac i i y a each oxel in neu oana omic Mon eal Neu ological Ins i u e (MNI) space as he exac magni ude o he es ima ed cu en densi y. Ana omical labels such as B odmann a eas a e also epo ed using MNI space. The g and mean LPC eLORETA images we e compu ed by i s calcula ing he eLORETA solu ion o each subjec in he ma ching condi ion, and hen a e aging he cu en densi y alues ac oss all subjec s o each g oup (BD and con ol). The eLORETA so wa e was hen used o pe o m oxel-by- oxel be ween- g oup compa isons o he LPC cu en densi y dis ibu ion. Speci ically, in o de o iden i y possible di e ences in he b ain elec ical ac i i y in ma ching ials be ween g oups (BD and con ol), nonpa ame ic s a is ical analyses o unc ional eLORETA images (S a is ical non-Pa ame ic Mapping; SnPM) we e pe o med wi h a log-F- a io s a is ic o independen g oups. The esul s co espond o maps o log-F- a io s a is ics o each oxel, o co ec ed P<0.05. As explained in he e iew by Nichols and Holmes (2002), he SnPM me hodology co ec s o all mul iple compa isons, and a he same ime does no equi e any assump ion o Gaussiani y. 3. Resul s Pos p in ( inal d a pos - e ee ing) 18 3.1. Beha io al esul s The beha io al da a o each g oup a e summa ized in Table 2. No signi ican di e ences be ween he con ol and BD g oups we e obse ed o RTs, pe cen age o co ec esponses, alse ala ms o omissions. Inse Table 2 abou he e 3.2. Elec ophysiological esul s The g and a e ages o he ERPs eco ded in he con ol and BD g oups a e shown in Figs. 4 and 5 espec i ely. The LPC was iden i ied by PCA, o bo h ma ching and non- ma ching condi ions. The la ency was app oxima ely 625 ms, and maximum ac o sco es we e ob ained a cen al and pa ie al loca ions. Inse Figu es 4 and 5 abou he e Analysis o he LPC e ealed ha Ma ch Condi ion (ma ching o non-ma ching s imuli) had a signi ican e ec [F(1,91) = 4.02, P<0.05]. The LPC ac o sco es we e signi ican ly la ge in he ma ching han in he non-ma ching condi ion. The analysis also e ealed ha Region had a signi ican e ec [F(2,182) = 116.19, P<0.001], wi h highe ac o sco es in pos e io han an e io egions: Pa ie al>F on al (P<0.001) and Cen al>F on al (P<0.001). The Ma ch Condi ion x G oup in e ac ion showed signi ican e ec s [F(1,91) = 4.85, P<0.05] wi h la ge LPC ac o sco es in he Con ol Pos p in ( inal d a pos - e ee ing) 19 han in he BD g oup in ma ching condi ion (see Fig. 6). Al hough he e we e no signi ican in e ac ions in ol ing Region, sepa a e analyses we e pe o med o each egion, and showed ha he di e ence be ween he wo g oups was only signi ican a he F on al [F(1,91) = 5.48, P>0.05] and Cen al [F(1,91) = 4.57, P>0.05] egions. Inse Figu e 6 abou he e 3.3. eLORETA esul s The eLORETA b ain maps ep esen ing co ical egions whe e BD and con ol subjec s showed maximal ac i a ion a LPC o he ma ching condi ion a e shown in Fig. 7. Inse Figu e 7 abou he e In he compa isons be ween he wo g oups, signi ican di e ences we e ound in ma ching ials. Signi ican ly less ac i a ion was obse ed in he BD g oup han in he con ol g oup o ma ching s imuli in he igh an e io p e on al co ex (aPFC) (B odmann a ea 10) (Log-F- a io = -2.85, co ec ed P<0.05). The eLORETA s a is ical nonpa ame ic maps compa ing elec ical neu onal ac i i y o BD and con ol subjec s o ma ching s imuli a LPC a e shown in Fig.8. Those b ain egions whe e he SnPM Log-F- a io s a is ic o independen g oups was s a is ically signi ican a e lis ed, along wi h he MNI coo dina es, in Table 3. Inse Figu e 8 and Table 3 abou he e Pos p in ( inal d a pos - e ee ing) 20 4. Discussion Li le is known abou he neu ocogni i e e ec s o epea ed and in e mi en excessi e consump ion o alcohol o e sho pe iods o ime (BD) in human adolescen s and young adul s. In he p esen s udy, ERPs we e eco ded in a g oup o young BD and con ol uni e si y s uden s du ing he execu ion o a isual wo king memo y ask, and he LPC was analyzed. The co ical sou ces o he LPC we e modeled and analyzed by eLORETA so wa e. The speci ic aims we e o es ablish whe he he LPC di e s be ween binge d inke s and con ol uni e si y s uden s and o examine possible BD- ela ed di e ences in LPC neu al ac i a ion du ing p ocessing in a isual wo king memo y ask. The esul s e ealed a educ ion in he LPC and hypoac i a ion o he aPFC in he BD g oup in ma ching ials du ing he execu ion o he wo king memo y ask, al hough no beha io al di e ences be ween BD and con ol g oups we e obse ed. Ve y ew ERPs s udies ha e been ca ied ou in ela ion o BD. Ehle s e al. (2007) assessed ERPs du ing he execu ion o a acial emo ional exp ession disc imina ion ask in h ee g oups o Sou hwes Cali o nia Indians: Adul s wi h no egula BD du ing adolescence (mean in ake pe occasion be o e 18 was < i e d inks - o 14 g o alcohol- pe occasion) and no diagnosed d ug dependence; adul s wi h his o y o BD du ing adolescence (mean in ake pe occasion be o e 18 was > i e d inks pe occasion) wi h no diagnosed li e- ime d ug dependence, and adul s wi h his o y o BD du ing adolescence and diagnosed d ug dependence como bidi y. The esul s e ealed ha adul s wi h his o y o BD adolescence wi h no diagnosed li e- ime d ug dependence showed a lowe ampli ude o a la e subcomponen o P3 (P450) han adul s wi h no Pos p in ( inal d a pos - e ee ing) 21 egula BD du ing adolescence and no d ug dependence. Howe e , he dec ease in he ampli ude canno be a ibu ed exclusi ely o BD du ing adolescence, because amily his o y o alcohol and conduc diso de o an isocial pe sonali y diso de we e no excluded and we e signi ican co a ia es in he analysis. Recen ly, Mau age e al. (2009) compa ed young adul binge d inke s (mo e han 10 d inks o 10 g o alcohol a leas 2 imes a week) wi h ma ched pai ed con ols (bo h we e i s -yea uni e si y s uden ), in a es - e es pa adigm o e a nine mon h pe iod. In his s udy, he po en ially biasing a iables we e con olled and he subjec s included in he s udy had o mee s ic selec ion c i e ia: no posi i e his o y o alcoholism, o al absence o pas o cu en d ug consump ion (including obacco and medica ion), no his o y o psychia ic diso de and no mode a e o high dep ession-anxie y sco es. The esul s e ealed ha al hough he wo g oups did no di e in any psychological, beha io al o elec ophysiological measu es in he i s session (be o e he subjec s s a ed binge d inking habi s), nine mon hs la e , he binge d inke s displayed signi ican ly delayed la ency in he P1, N2 and P3 componen s elici ed by emo ional audi o y s imuli in a disc imina ion ask, ela i e o con ols, s ill wi h no beha io al di e ences be ween he wo g oups. These s udies ha e e ealed ha young binge d inke s show elec ophysiological anomalies in he p ocessing o emo ional s imuli, and he esul s o he p esen s udy sugges ha elec ophysiological anomalies also occu du ing WM p ocesses. In ac , anomalous elec ophysiological pa e ns associa ed wi h binge d inking du ing he execu ion o his WM ask do no only a ec LPC. In a p e ious epo by ou esea ch g oup (C ego e al., 2009) wi h he same subjec s and ask as in he p esen s udy, binge d inke s showed anomalies in he N2 and P3 componen s. The N2 componen elici ed by ma ching s imuli in cen al and pa ie al egions was signi ican ly la ge in he BD Pos p in ( inal d a pos - e ee ing) 22 han in he con ol g oup; he P3 componen , which was la ge in he ma ching han in he non-ma ching condi ion in he on al, cen al and pa ie al egions in he con ol g oup, did no di e signi ican ly be ween condi ions in he BD g oup. Thus, al hough ERPs s udies on BD a e s ill sca ce, and despi e he di e en na u e o he asks used, he esul s o he s udy by Mau age e al. (2009), ou p e ious s udy (C ego e al., 2009) and he p esen s udy appea o con i m ha heal hy binge d inke s (wi h no psychopa hological como bidi ies, AUDs, abuse o dependence on o he illegal d ug, o amily his o y o alcoholism) may display anomalies in he elec ophysiological esponses when p ocessing in o ma ion, e en in he absence o beha io al impai men . Al hough i is no en i ely clea which cogni i e p ocesses a e associa ed wi h he LPC, his componen is mainly ela ed o he ca ego ical esponse, possibly associa ed wi h execu i e unc ions in he p e on al co ex (Ki ino e al., 2000). In ac , o e oke LPC, i appea s necessa y o use high load p ocessing asks in which he subjec s ha e o do mo e han de ec a gi en s imulus and, o example, mus use WM o ca y ou a ask wi h a sub-goal ask. This componen appea s o be pa icula ly closely ela ed o WM and any synch onized ope a ion immedia ely ollowing a ge o ma ch de ec ion (Ga cía-La ea and Cézanne-Be , 1998), such as selec ion o a esponse ca ego y and e alua ion o he success o a ca ego y- ela ed decision o memo y ma ch (Schendan and Mahe , 2009). The esul s o he p esen s udy e ealed ha he LPC was la ge in ma ching han in non-ma ching ials, sugges ing ha , in his ask, he LPC may indica e WM ecogni ion and he de ec ion o memo y ma ch. The e o e, he signi ican educ ion in he ac o sco es o he LPC in ma ching ials ound in he BD g oup in compa ison wi h he con ol g oup may e eal anomalies in he elec ophysiological p ocessing Pos p in ( inal d a pos - e ee ing) 23 unde lying wo king memo y and memo y ma ch p ocesses in young binge d inking uni e si y s uden s. Neu opsychological s udies ha e e ealed ha adolescen s and young people wi h AUD pe o m wo se in wo king memo y asks (B own e al., 2000; Tape e al., 2002; B own and Tape , 2004). Howe e , s udies wi h heal hy you hs and adolescen s wi h a BD pa e n a e sca ce and he beha io al e ec s in wo king memo y asks a e no clea . Weissenbo n and Duka (2003) compa ed BD and non-BD s uden s and ound ha he pe o mance o he binge d inke s in a spa ial wo king memo y es was signi ican ly poo e han ha o he non-binge d inke s. Simila ly, Townshend and Duka (2005) also ound ha emale binge d inke s pe o med wo se in a spa ial wo king memo y ask han he co esponding con ol subjec s. In con as , Ha ley e al. (2004) did no ind any beha io al di e ences be ween binge and non-binge d inke s wi h he same spa ial wo king memo y ask. I is impo an o no e ha he subjec s in he i s wo s udies we e be ween 18 and 30 yea s old and he binge d inke s consumed la ge quan i y quan i ies o alcohol e e y week, whe eas subjec s in he la e s udy we e younge s uden s (aged 18-23 yea s) who consumed smalle amoun s o alcohol pe week, and pe haps hei d inking may no ha e eached he h eshold o du a ion needed o show beha io al impai men s. As ega ds he neu oana omical basis o he elec ophysiological dys unc ion ound in he p esen s udy, be ween-g oup compa isons o eLORETA da a e ealed BD- ela ed hypoac i a ion o he igh aPFC in he ma ching ials. Al hough alcoholism- ela ed co ical changes ha e been documen ed h oughou he b ain, mos s udies ha e consis en ly ound he on al lobes, especially PFC, o be mo e ulne able o alcohol- ela ed b ain damage han o he ce eb al egions (Chen e al., 2007; Demi e al., 2002; Gansle e al., 2000; P e e baum e al., 2001; Volkow e al, 1992, 1994). 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Am J Psychia y. 151, 178-183. Pos p in ( inal d a pos - e ee ing) Table 3. B ain a eas wi h signi ican ly lowe ac i a ion associa ed o LPC in he binge d inking han in he con ol g oup o ma ching s imuli. Ana omical egion (BA) MNI coo dina es Log-F- a io An e io P e on al Co ex (aPFC) Supe io F on al Gy us (10) (20, 65, 10) -2.88* Medial F on al Gy us (10) (15, 65, 15) -2.86* (10, 65, 15) -2.85* * co ec ed P<0.05; BA: B odmann a ea; MNI: Mon eal Neu ological Ins i u e. Table 3_ e ised Pos p in ( inal d a pos - e ee ing) Figu e 1_ e ised Click he e o download high esolu ion image Pos p in ( inal d a pos - e ee ing) Figu e 2_ e ised Click he e o download high esolu ion image Pos p in ( inal d a pos - e ee ing) Figu e 3_ e ised Click he e o download high esolu ion image Pos p in ( inal d a pos - e ee ing) Figu e 4_ e ised Click he e o download high esolu ion image Pos p in ( inal d a pos - e ee ing) Figu e 5_ e ised Click he e o download high esolu ion image Pos p in ( inal d a pos - e ee ing) Figu e 6_ e ised Click he e o download high esolu ion image Pos p in ( inal d a pos - e ee ing) Figu e 7_ e ised Click he e o download high esolu ion image Pos p in ( inal d a pos - e ee ing) Figu e 8_ e ised Click he e o download high esolu ion image Pos p in ( inal d a pos - e ee ing) Figu e 7 in black and whi e o p in e sion_ e ised Click he e o download high esolu ion image