Reversibility of brain-stem evoked potential abnormalities in abstinent chronic alcoholics: one year follow-up

REVERSIBILITY OF BRAIN-STEM EVOKED POTENTIAL ABNORMALITIES IN ABSTINENT CHRONIC ALCOHOLICS: ONE YEAR FOLLOW-UP Au ho s: Fe nando Cada ei a, Ma ga i a Co ominas, Soco o Rod íguez Holguín, Miquel Sánchez-Tu e , Ca les G au This is he pee e iewed e sion o he ollowing a icle: Cada ei a, F., Co ominas, M., Rod íguez Holguín, S., Sánchez-Tu e , M., & G au, C. (1994). Re e sibili y o b ain- s em e oked po en ial abno mali ies in abs inen ch onic alcoholics: one yea ollow-up. Elec oencephalog aphy and clinical neu ophysiology, 90(6), 450–455. h ps://doi.o g/10.1016/0013-4694(94)90136-8 This a icle may be used o non-comme cial pu poses in acco dance wi h Else ie e ms and condi ions o use o sel -a chi ed e sions. 1 Re e sibili y o b ain-s em e oked po en ial abno mali ies in abs inen ch onic alcoholics: One yea ollow-up Fe nando Cada ei aa, Ma ga i a Co ominasb, Soco o Rod íguez Holguína, Miquel Sánchez-Tu e b, Ca les G aub a Depa amen o de Psicoloxía Clínica e Psicobioloxía, Uni e sidade de San iago de Compos ela, Campus Uni e si a io, 15706 San iago de Compos ela (Spain), and b Depa amen de Psiquia ía i Psicobiologia Clínica, Uni e si a de Ba celona, Ba celona ( Spain) (Accep ed o publica ion: 21 Janua y 1994) Abs ac B ain-s em audi o y e oked po en ials (BAEPs) we e s udied in 34 ch onic alcoholics who had been abs inen o 1 yea , and in age- and sex-ma ched con ol subjec s. The pa ien s we e examined 3 imes, a 1 mon h, 5 mon hs and 1 yea a e he s a o he abs inence ea men . A 1 mon h o abs inence he alcoholics showed di e ences wi h espec o con ols in he peak V la ency (P < 0.01), and in he III–V (p < 0.01) and I–V (p < 0.01) in e als. A e 1 yea o abs inence a signi ican imp o emen in he V (p < 0.01), III–V (p < 0.01) and I–V (p < 0.01) pa ame e s was eco ded. The mos no able de elopmen was in he 5–12 mon h pe iod, wi h sho ening i la ency (p < 0.01) and in he I–V in e al (p < 0.01); in he i s 5 mon hs he e was only sho ening in he III–V in e al (p < 0.01). This imp o emen was also indica ed by a dec ease in he numbe o pa ien s wi h BAEP pa ame e abno mali ies. The eco e y o he unc ions impai ed by ch onic alcohol consump ion a e 1 yea o abs inence was incomple e, al hough he endency was owa ds no maliza ion. Keywo ds Alcoholism; Re e sibili y; B ain-s em audi o y e oked po en ials Nume ous biomedical s udies ha e epo ed al e -a ions in he cen al ne ous sys em (CNS) s uc u es and unc ions in alcoholics (Po jesz and Beglei e 1979; Ron e al. 1982). Al hough long- e m s udies o o me ch onic alcoholics mus be in e p e ed wi h cau ion because o he ypically high a es o d op-ou om he sample (Mackenzie e al. 1978), he e a e cu en ly a numbe o s udies o he e olu ion o abno mali ies p oduced by ch onic consump ion o alcohol du ing con inued abs inence. These s udies ha e mainly used neu o- adiological echniques (Ca ien e al. 1978; Ca ien 1979) which o e s uc u al mac oscopic da a on he e olu ion o al e a ions in di e en a eas o he b ain (co ex, midb ain). The e olu ion o hese al e a ions du ing abs inence has also been s udied om he neu opsychological poin o iew. These echniques ha e shown a pa ial eco e y om he beha iou al pe spec i e (B and e al. 1983; Yohman e al. 1985; Goldman and Goldman 1988). None heless he e a e ew s udies which o e mo e speci ic da a conce ning he unc ional e olu ion o subsys ems in CNS o alcoholic pa ien s which ha e become a ec ed. B ain-s em audi o y e oked po en ials allow e alua ion o he unc ional in eg i y o he audi o y pa hway, om he audi o y ne e o he halamic nuclei Pos -p in ( inal d a pos - e e eeing) 2 (Hashimo o 1989). Thei eco ding in alcoholic pa ien s consis en ly show al e a ions in sho - e m abs inen pa ien s (Beglei e e al. 1981; Chu e al. 1982; Chan e al. 1985; Chu 1985). Using his echnique in ou labo a o y we ca ied ou a 1 yea ollow-up s udy on he e e sibili y o abno mali ies caused by ch onic alcohol consump ion in pa ien s who had emained abs inen o a long ime. The s udy in ol ed examina ions 1 mon h, 5 mon hs and 12 mon hs a e s a ing he abs inence in a g oup o alcoholics wi hou se ious neu ological al e a ions, in o de o s udy he possibili y o sho - and long- e m e e sibili y. This kind o ollow-up s udy, as well as o e ing da a conce ning he e olu ion o he al e a ions obse ed in he ne ous sys ems o hese long- e m abs inen pa ien s, may p o ide in o ma ion abou he na u e o he unde lying pa hology. Ma e ial and me hods Thi y- ou ch onic alcoholics ini ially pa icipa ed in his s udy, all males, diagnosed and ea ed by he Alcoholic Uni o he Hospi al Clínic i P o incial (Ba celona). They all me he DSM-III c i e ia o alcoholism and we e aged be ween 23 and 56 yea s (mean 40.4 ± 8.9). All he subjec s had his o ies o alcoholism o 8 yea s o mo e. In he selec ion p ocess he ollowing pa ien s we e excluded: (1) hose wi h se ious psychia ic diso de s; (2) hose wi h ca dio ascula , hepa ic o espi a o y disease; (3) hose wi h neu ological diso de s; (4) hose wi h his o ies o head auma, coma o anoxia- ischaemia; (5) hose who we e aund o ul il DSM-III c i e ia o d ug abuse o he han alcoholism, excep smoking. All pa ien s unde wen an ini ial neu ophysiological examina ion be ween 25 and 45 days a e gi ing up d inking. The ea men p og amme un by he Alcoholism Uni includes adminis a ion o s anda d medica ion (calcium ca bomide, an alcohol-abuse de e en ), and clome hiazole (a low- oxici y seda i e) in he i s week o ea men . No pa ien had ecei ed medica ion in he p e ious 72 h. Abs inence was moni o ed by he Alcoholic Se ice eam; alcohol le els we e measu ed be o e each examina ion. Pa ien s who we e p esen a all he medica! es s and g oup he apy sessions, and whose alcohol le el esul s we e nega i e, we e included in he abs inen g oup. Twel e o he 34 subjec s in he ini ial g oup emained abs inen o he ull yea . The membe s o his subg oup we e aged be ween 23 and 55, wi h an a e age age o 41.00 ± 6.8. The emaining 22 subjec s we e exluded om he sample. No e ha mean BAEP pa ame e alues o he 1-yea -abs inen subg oup as de e mined in he i s examina ion we e no signi ican ly di e en om he co esponding mean alues de e mined a he same ime o he whole ini ial 34- subjec g oup. The con ol g oup we e 34 male subjec s ma ched subjec - o-subjec wi h he alcoholics by sex and age (mean 36.1 ± 8.3 yea s). They me he addi ional selec ion c i e ia o he pa ien g oup and we e abs inen s o spo adic d inke s (unde 20 g alcohol/ day). EP eco ding BAEP eco ding was pe o med using pu e in elec odes posi ioned in an elas ic cap (Elec ocap, lnc.). S imula ion and ampli ica ion, il e ing, a e aging and g aphical Pos -p in ( inal d a pos - e e eeing) 3 analysis o he signa) we e ca ied ou using a SICAN neu ophysiological eco ding appa a us. Con amina ed ials we e elimina ed om u he analysis by an au oma ic a i ac ejec ion. Impedance e-mained unde 5 kΩ a all imes du ing sessions. The EP signals we e ob ained simul aneously, ipsila e ally and con ala e ally, by using e e ence elec odes loca ed on bo h mas oids and an ac i e elec ode a he e ex. We epo only ipsila e al eco ds in his s udy. The g ound elec ode was placed on he o ehead. Po en ials we e e oked by monau al audi o y s imuli consis ing o clicks o al e na e pola i y wi h a du a ion o 100 µsec, an in ensi y o 110 dB SPL, and a s imula ion equency o 10 Hz. The EP signal was ampli ied 100,000 imes and il e ed wi h a bandpass o 200-3000 Hz (12 dB/ oc a e). Each po en ial was ob ained om he a e age o 2000 esponses o a 10 msec pe iod. P ocedu e To pe o m he neu ophysiological es s, subjec s we e sea ed in a com o able a mchai in a sound-p oo ed dimly li and elec ically p o ec ed oom. The hea ing o pa ien and con ol g oups was assessed audiologically wi h he same clicks as used o BAEPs. Subjec s whose audiological h eshold was abo e 40 dB SPL we e no accep ed o BAEP s udies. All eco ding sessions ook place be ween 11.30 and 14.30 h o a oid he possibili y o ci cadian a ia ions. The componen s s udied we e he la encies o peaks I, III and V, and he in e peak in e als I-III, III-V and I-V o bo h ea s. These pa ame e s we e iden i ied by he compu e p og am wi hou ega d o subjec diagnosis. S a is ical analysis S a is ical analyses we e pe o med using he SPSS so wa e package. Da a o BAEP pa ame e s unde wen 2-way ANOVA o each g oup (alcoholics and con ols) X ea (le o igh ) o e alua e he di e ences be ween he alcoholic and con ol g oups. BAEP pa ame e s we e una ec ed by ea ; consequen ly, in u he calcula ions an a e age alue was aken o bo h ea s o he subjec examined, in o de o simpli y he analysis and in e p e a ion o he esul s. Linea eg ession analysis was used o in es iga e he posible e ec s o (a) he 25-45 days o abs inence p eceding he i s examina ion, and (b) age, on BAEP pa ame e alues in he alcoholic g oup a i s examina ion and o e he e olu ion wi h sus ained abs inence. Nei he numbe o days o abs inence be o e he i s examina ion no age we e signi ican sou ces o a iance in BAEP pa ame e alues. Thus, hese ac o s did no a ec ou esul s. The in asubjec s udy o he BAEP pa ame e s o e he 3 examina ions was ca ied ou using epea ed measu es ANOVA. In all cases he Bon e oni-Holm p ocedu e was used o co ec he signi icance le el o he F alues. To s udy he e olu ion o he expe imen al g oup wi h espec o he con ol g oup du ing he i s yea o abs inence, a con idence in e al was es ablished a 97.5% o he alues o each o he BAEP pa ame e s o he con ol popula ion. The mean alue o he alcoholic g oup was la e compa ed in each o he 3 examina ions, wi h he con ol popula ion con idence in e al. Finally, we calcula ed he numbe o alcoholic pa ien s ha showed clinically abno mal eco ds. A BAEP eco d was conside ed o be abno mal i he alue o any o i s pa ame e s was 2.5 S.D. g ea e han he con ol g oup mean. Pos -p in ( inal d a pos - e e eeing) 4 Resul s E olu ion o BAEP pa ame e alues wi h abs inence A e 1 mon h o abs inence, he alcoholics showed la encies o peak V (p < 0.01) and in e peak in e als o III-V (p < 0.01) and I-V (p < 0.01) which we e signi ican ly longe han con ol g oup seo es. On s udying he e olu ion o each pa ame e in he subsequen examina ions using epea ed measu es ANOVA, we no ed a signi ican educ ion in he la ency o pa ame e s V (p < 0.01), III-V (p < 0.01) and I-V (p < 0.01) a e 12 mon hs o abs inence. The e olu ion was mos no able be ween 5 and 12 mon hs wi h sho ening o peak V la ency (p < 0.01) and he in e al I-V (p < 0.01), compa ed wi h he i s 5 mon hs, in which he e was only sho ening o he in e al III-V (p < 0.01) (see Table 1). Table I. F alues gi en by 1-way ANOVA o epea ed measu es o BAEPs o abs inen ch onic alcoholics. Resul s ob ained om he compa isons be ween 1 mon h and 5 mon hs, be ween 5 and 12 mon hs, and be ween 1 mon h and 12 mon hs o abs inence. G oup I III V I-III III-V I-V Alcoholics (1 m s. 5 m) F 0.92 0.47 3.55 0.03 12.18 3.26 p N.S. N.S. N.S. N.S. 0.00* N.S. Alcoholics (5 m s. 12 m) F 0.00 3.82 21.05 3.41 2.22 11.88 p N.S. N.S. 0.00 N.S. N.S. 0.01* Alcoholics (1 m s. 12 m) F 1.11 0.95 15.18 2.25 14.10 13.07 p N.S. N.S. 0.01* N.S. 0.00* 0.01* *p < 0.01 as co ec ed by he Bon e oni-Holm p ocedu e. Fo he s udy o he e olu ion o he esul s o he alcoholic g oup wi h espec o he con ol g oup, we calcula ed he in e al o con idence (97.5% o he con ol g oup alues) o each pa ame e in he con ol popula ion (I: 1.46-1.56; III: 3.535-3.785; V: 5.29-5.54; I-III: 2.00-2.30; III-V: 1.66-1.87; 1-V: 3.76-4.06). Bea ing in mind he mean alues o he alcoholic g oup shown in Table I, we see ha a 1 and 5 mon hs o abs inence he alcoholics showed alues which a e highe han he con ols and beyond he uppe limi s o he p e ious V, III-V and I-V in e als o con idence. A e 1 yea o abs inence, peak V la ency was g ea e han he uppe limi o he in e al, peak III-V was a he highes poin bu wi hin his limi , and I-V showed no mal alues (see Table II and Fig. 1). Indi idual impai men The calcula ion o he numbe o indi idual impai men s is shown in Table III; we see a p og essi e all o e he i s yea o abs inence in he numbe o pa ien s wi h abno mali ies in he pa ame e s V, III-V and I-V (in acco dance wi h he c i e ion conside ed). A e 1 mon h o abs inence, 5 pa ien s o he 12 ha ollowed he ea men o 1 yea showed impai men in a leas one BAEP pa ame e , 3 alcoholics showed abno mali ies a e 5 mon hs, and a e 1 yea only 2 pa ien s s ill had impai ed pa ame e s. Du ing he yea o abs inence he e was imp o emen in all he subjec s Pos -p in ( inal d a pos - e e eeing) 5 who p esen ed anomalies in BAEPs, bo h among pa ien s whose pa ame e s had become no mal and among hose whose pa ame e s we e s ill abno mal. Table II. Means (m) and s anda d de ia ions (S.D.) o BAEPs o abs inen ch onic alcoholics ob ained a e 1 mon h, a e 5 mon hs, and a e 1 yea o abs inence, and hei con ol be ween 1 mon h and 12 mon hs o abs inence. G oup I III V I-III III-V I-V Alcoholics (1 m) m 1.50 3.75 5.78 2.25 2.03 4.28* S.D. 0.08 0.15 0.20 0.16 0.20 0.22 Alcoholics (5 m) m 1.53 3.77 5.71* 2.24 1.94 4.18* S.D. 0.11 0.17 0.21 0.16 017 0.22 Alcoholics (12 m) m 1.53 3.71 5.59* 2.18 1.88 4.06 S.D. 0.11 0.14 0.21 0.18 0.20 0.21 Con ols m 1.51 3.66 5.42 2.15 1.76 3.91 S.D. 0.08 0.18 0.16 0.21 0.16 0.20 *Va iables exceeding he uppe limi o he con idence in e als. Fig. l. BAEPs o (i) a ypical alcoholic-g oup subjec (A) a he 3 examina ions (a e 1, 5 and 12 mon hs o abs inence) and (ii) he co esponding con ol subjec (C). No e he ini ially long peak V la ency and 1-V in e al in A, and he dec easing end o hese pa ame e s o e he s udy pe iod. Discussion E ec s o ch onic alcohol abuse Pos -p in ( inal d a pos - e e eeing) 6 As desc ibed in p e ious wo ks om ou and o he labo a o ies (Po jesz and Beglei e 1979; Cada ei a 1988; Cada ei a e al. 1991) he exis ence o neu ological abno mali ies in he b ain-s em o ch onic alcoholics a e 1 mon h is con i med: leng hening o he peak V la ency (p < 0.01) and he in e peak in e als III-V (p < 0.01) and I-V (p < 0.01). Table III. Numbe (N) o alcoholics wi h abno mal pa ame e s a e 1 mon h, 5 mon hs and 1 yea o abs inence ( alues 2.5 S.D. highe han con ol g oup mean). Pa ame e N (1 m) N (5 m) N (12 m) I 0 0 0 III 0 0 0 V 5 3 2 I-III 0 0 0 III-V 3 1 1 I-V 4 2 0 Abno m. in some pa ame e s 5 3 2 E olu ion wi h abs inence Du ing he 5 i s mon hs o abs inence he e was imp o emen in he alcoholic g oup and dec ease in he mean alues o he abno mal BAEP peaks, e en hough he dec ease was only signi ican in he III-V in e al (p < 0.01). F om he clinical poin o iew, we obse ed a all in he numbe o pa ien s wi h abno mal BAEPs. These esul s coincide pa ially wi h hose o Chan e al. (1985), who ound a signi ican sho ening o he I-III (p < 0.01)) and I-V (p < 0.01) in e als. The di e ences in e ms o impai men and e olu ion o he I-III in e al may be due o he cha ac e is ics o hei pa ien s. Chan s udied pa ien s wi h We nicke-Ko sako synd ome who ecei ed i amin ea men and a sui able die du ing hei ime in hospi al. The di e ences in he componen s a ec ed and apid eco e y a e cha ac e is ic o his ype o pa ien . In acco dance wi h hese esul s, Po jesz and Beglei e , in hei e iew o 1985, e e ing o unpublished da a, epo ed an imp o emen in la encies and cen al ansmission ime in a g oup o hospi alized ch onic alcoholics a e 4 mon hs o abs inence, e en hough he e we e s ill di e ences wi h espec o he con ol g oup. A e 1 yea o abs inence ou esul s show signi ican sho ening in he V la ency (p < 0.01) and in he III-V (p < 0.01) and I-V (p < 0.01) in e peak in e als. We no e ha he eco e y a e is highe be ween 5 and 12 mon hs han in he i s pe iod. Howe e , eco e y is no comple e since he mean o he I-V in e al is abo e he uppe limi es ablished o he con ol g oup. These esul s co ela e wi h hose o he neu o adiological s udies. The CT scans show abno mali ies in he alcoholic g oup wi h e idence o en icula dila a ion and enla gemen o he co ical sulci. The mo phological abe a ions o alcoholics a e pa ially e e sible du ing he i s yea o abs inence (Ca len e al. 1978; Ca len 1979; Ron e al. 1982; Cala e al. 1983; Ca len e al. 1986) bu he eco e y is no comple e as compa ed wi h he p e alence o a ophy in he sample o he gene al popula ion. So ne au ho s (Lynch 1960; Muu onen e al. 1989) de ec anomalies in a eas o he mid-b ain in e alua ions 5 yea s a e cessa ion o d inking. Acco ding o hese s udies, he e a e abno mali ies ha pe sis a e long pe iods o abs inence. The p og essi e e olu ion o he alues o he pa ame e s, s udied in he sample o alcoholic pa ien s du ing he i s yea o abs inence, sugges s ha he e olu ion Pos -p in ( inal d a pos - e e eeing) 7 owa ds no mali y may ake place la e in hose pa ien s who ha e no shown a comple e eco e y du ing he i s yea . Howe e , a long- e m longi udinal ollow-up s udy would be necessa y o de e mine whe he his e olu iona y endency con inues, o whe he so ne anomalies a e pe manen . Po jesz and Beglei e (1985), again e e ing o unpublished da a, ound no abno mali ies in b ain-s em po en ials, in a sample o non-hospi alized alcoholic pa ien s who had emained abs inen o a pe iod o be ween 3 and 10 yea s; none heless, hese pa ien s had no been examined a he s a o abs inence, so we do no know whe he hey showed b ain-s em po en ial abno mali ies. In ou sample o alcoholic pa ien s he abno mali ies caused by he ch onic consump ion o alcohol e ol e a ou ably wi h con inued abs inence. None heless, he scale o his e olu ion is s ill o be de e mined, as is he ques ion o whe he he deg ee o unc ional imp o emen is independen o he se e i y o he ini ial impai men . Wi h ega d o he la e ques ion i would be impo an o de e mine whe he he e is a le el o impai men beyond which eco e y is impossible, o beyond which he e is some de e io a ion. This in o ma ion would be o g ea use in es ablishing a hypo hesis abou he pa hophysiological mechanisms o hese impai men s. The cha ac e is ic abno mali ies in he la e BAEP peaks o alcoholics ha e gene ally been in e p e ed as being due o a d op in he speed o signa! ansmission in he audi o y pa hway (speci ically he cen al and pos e io pon ine). This may be due o any o a ious ac o s including demyelina ion, p obably as a esul o elec oly ic dis u bances (Kleinschmid -DeMas e s and No enbe g 1981, 1982), changes in memb ane p ope ies, changes in g oss o ine neu onal s uc u e. The classic s udy o Víc o e al. (1959) showed ha , in alcoholic pa ien s, loss o neu ones occu s in he in e io oli es, he es ibula nuclei and o he b ain-s em nuclei. Mo e ecen ly, Chu (1985) epo ed ha in abs inen o me alcoholics he e is a co ela ion be ween he BAEP abno mali ies and he p esence o s uc u al b ain-s em damage (enla ged b ain cis e ns and a ophy o he b ain-s em); hese s uc u al abno mali ies appea o be mo e se e e in alcoholics wi h We nicke-Ko sako synd ome, in whom lesions, including demyelina ion and, less equen ly, neu one loss, a e cha ac e is ically obse ed in he g ey ma e o he diencephalon and in b ain-s em. Seconda y e ec s associa ed wi h anoxia-ischaemia o malnu i ion, and changes in neu o ansmi e me abolism mus also be conside ed in he o igin o BAEP abno mali ies. Changes in he BAEPs o alcoholics a e a pe iod o abs inence may be a ibu able o comple e o pa ial e e sal o one o mo e o he abo e ypes o e ec . Ou esul s indica e ha mos o he ele an BAEP pa ame e s e-a ain no mal alues wi hin 1 yea o abs inence, whils a ew o he ele an pa ame e s emain abno mal beyond his ime. One possible explana ion o his pa e n is ha he obse ed eco e y o e 1 yea o abs inence is due o egene a ion o neu onal ine s uc u e (damage o axonic e mina- ions, loss o dend i ic connec ions ... ), and hose pa ame e s which emain abno mal beyond his ime a e he esul o pe sis en damage o he CNS a he g oss s uc u al le el (wi h neu onal loss o pe sis en unc ional disablemen ). Thus, ou esul s p o ide suppo o he hypo hesis ha he no maliza ion o BAEPs a e a long pe iod o abs inence is due o s uc u al eco e y a he han o mo e immedia e biochemical changes ha occu in he i s pe iod o abs inence. Indi idual impai men Pos -p in ( inal d a pos - e e eeing) 8 The esul s o each pa ien indica e ha indi idual di e ences exis in e ms o he ime necessa y o he e-es ablishmen o unc ional no mali y. Fu he s udies wi h la ge samples enabling us o s udy he possible co ela ion be ween he deg ee o eco e y and o he ac o s, such as he age o he pa ien s, a e necessa y. Ou da a a e no only along he same lines as esul s ob ained using o he me hodologies bu suppo he ea lie a i ma ion ha he e a e g ea di e ences in e ms o indi idual suscep ibili y o alcohol (Cada ei a e al. 1992). In he same way, no all he pa ien s wi h b ain-s em abno mali ies show an equally a ou able e olu ion du ing long- e m abs inence. In sum, du ing he i s yea o con inued abs inence he e is a p og essi e e olu ion owa ds no mali y in he unc ional abno mali ies de ec ed in he b ain-s em o ch onic alcoholic pa ien s. This e olu ion is mo e ma ked be ween 5 and 12 mon hs, al hough a e 1 yea o abs inence he e a e s ill signi ican di e ences compa ed wi h he con ol g oup. Consequen ly, al hough abno mali ies in b ain-s em po en ials caused by ch onic alcohol consump ion a e only pa ially e-e sible du ing his i s yea , he endency is owa ds no maliza ion. Funding This wo k was pa ially suppo ed by G an PM91-0159-C02- 01/02 om he Spanish Di ección Gene al de In es igación Cien í ica y Técnica (Minis e io de Educación y Ciencia). Re e ences Beglei e , H., Po jesz, B. and Chou, C.L. Audi o y b ain-s em po en ials in ch onic alcoholics. Science, 1981, 211: 1064-1066. B and , J., Bu e s, N., Ryan, C. and Bayog, M.D. Cogni i e loss and eco e y in long- e m alcohol abuse s. A ch. Gen. Psychia ., 1983, 49: 435-442. Cada ei a, F. Po enciales E ocados en Alcohólicos C ónicos Abs inen es. Thesis Doc o al, Uni e si y o San iago, 1988. Cada ei a, F., G au, C., Roso, M. and Sánchez-Tu e , M. Mul imodali y explo a ion o e en - ela ed po en ials in ch onic alco-holics. Alcoholism: Clin. Exp. Res., 1991, 15: 607-611. Cada ei a, F., Roso, M., G au, C. and Sánchez-Tu e , M. E ec s o age on e en - ela ed po en ials in ch onic alcoholics: a mul i-modal s udy. Neu opsychobiology, 1992, 25: 166-171. Cala, LA., Janes, B. and Bu ns, P. 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