ethanol reduces rcfb activation of left dorsolateral prefrontal cortex during a verbal fluency task

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Brain and Language 77, 197–215 (2001) doi:10.1006/brln.2000.2434, available online at http://www.idealibrary.com on Ethanol Reduces rCFB Activation of Left Dorsolateral Prefrontal Cortex during a Verbal Fluency Task Peter E. Wendt Department of Psychology, University of Lund, Lund, Sweden and Jarl Risberg Department of Clinical Neuroscience, Section of Psychiatry, and Department of Psychology, University of Lund, Lund, Sweden Published online March 9, 2001 In a previous study in normal subjects (Wendt et al., 1994), using a reversing checkerboard as activation stimulus, we found that the coupling between local neuronal activity and regional cerebral blood flow was preserved following ethanol, and that a right-sided occipital activation response seen during sobriety became symmetrical during inebriation. In the present study we investigated if ethanol has a detrimental effect also on the activation of the left dorsolateral prefrontal cortex found in normals during verbal fluency. Measurements of regional cerebral blood flow in 20 healthy, young, male, right-handed volunteers during rest and verbal fluency were made during sobriety and inebriation (0.06% blood alcohol concentration) with a 1-week interval. We found a decrease in word production during inebriation. The normal activation within the frontotemporal part of the left dorsolateral prefrontal cortext was preserved during inebriation. The activation of this region seems thus to be robust to the effects of ethanol. During inebriation no activation response to the word fluency test was found in the anterior prefrontal part of the dorsolateral prefrontal cortex. This region is important for working, temporal, and short-term memory functions, processes that are affected by ethanol. Hemi- spheric functioning and specialization seem to be adversely affected by ethanol, regardless of which hemisphere is most involved while sober. 2001 Academic Press Key Words: regional cerebral blood flow; functional lateralization; ethanol; cortical asym- metry; verbal fluency; DLPFC. INTRODUCTION Several investigations of normal, healthy subjects have revealed that moderate eth- anol inebriation is followed by a global increase in cerebral blood flow (CBF) during rest (Mathew & Wilson, 1986; Newlin, Golden, Quaife, & Graber, 1982; Sano et al., 1993). Most likely this is caused by a global vasodilatatory effect of ethanol (Greenberg et al., 1993). Doses of 0.7 and 1.5 g alcohol/kg of body weight caused average increases of CBF by 12 and 16%, respectively (Sano et al., 1993). During normal conditions the regional cerebral blood flow (rCBF) is tightly coupled to the function and oxygen and glucose metabolism of the brain (Edvinsson, Mackenzie, & Address all correspondence and reprint requests to Jarl Risberg, University of Lund, Department of Psychology, P.O. Box 213, SE-221 00 Lund, Sweden. 197 0093-934X/01 $35.00 Copyright 2001 by Academic Press All rights of reproduction in any form reserved.

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Page 1: Ethanol Reduces rCFB Activation of Left Dorsolateral Prefrontal Cortex during a Verbal Fluency Task

Brain and Language 77, 197–215 (2001)doi:10.1006/brln.2000.2434, available online at http://www.idealibrary.com on

Ethanol Reduces rCFB Activation of LeftDorsolateral Prefrontal Cortex during

a Verbal Fluency Task

Peter E. Wendt

Department of Psychology, University of Lund, Lund, Sweden

and

Jarl Risberg

Department of Clinical Neuroscience, Section of Psychiatry, and Department of Psychology,University of Lund, Lund, Sweden

Published online March 9, 2001

In a previous study in normal subjects (Wendt et al., 1994), using a reversing checkerboardas activation stimulus, we found that the coupling between local neuronal activity and regionalcerebral blood flow was preserved following ethanol, and that a right-sided occipital activationresponse seen during sobriety became symmetrical during inebriation. In the present studywe investigated if ethanol has a detrimental effect also on the activation of the left dorsolateralprefrontal cortex found in normals during verbal fluency. Measurements of regional cerebralblood flow in 20 healthy, young, male, right-handed volunteers during rest and verbal fluencywere made during sobriety and inebriation (0.06% blood alcohol concentration) with a 1-weekinterval. We found a decrease in word production during inebriation. The normal activationwithin the frontotemporal part of the left dorsolateral prefrontal cortext was preserved duringinebriation. The activation of this region seems thus to be robust to the effects of ethanol.During inebriation no activation response to the word fluency test was found in the anteriorprefrontal part of the dorsolateral prefrontal cortex. This region is important for working,temporal, and short-term memory functions, processes that are affected by ethanol. Hemi-spheric functioning and specialization seem to be adversely affected by ethanol, regardlessof which hemisphere is most involved while sober. 2001 Academic Press

Key Words: regional cerebral blood flow; functional lateralization; ethanol; cortical asym-metry; verbal fluency; DLPFC.

INTRODUCTION

Several investigations of normal, healthy subjects have revealed that moderate eth-anol inebriation is followed by a global increase in cerebral blood flow (CBF) duringrest (Mathew & Wilson, 1986; Newlin, Golden, Quaife, & Graber, 1982; Sano etal., 1993). Most likely this is caused by a global vasodilatatory effect of ethanol(Greenberg et al., 1993). Doses of 0.7 and 1.5 g alcohol/kg of body weight causedaverage increases of CBF by 12 and 16%, respectively (Sano et al., 1993). Duringnormal conditions the regional cerebral blood flow (rCBF) is tightly coupled to thefunction and oxygen and glucose metabolism of the brain (Edvinsson, Mackenzie, &

Address all correspondence and reprint requests to Jarl Risberg, University of Lund, Department ofPsychology, P.O. Box 213, SE-221 00 Lund, Sweden.

1970093-934X/01 $35.00

Copyright 2001 by Academic PressAll rights of reproduction in any form reserved.

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198 WENDT AND RISBERG

McCulloch, 1993; Raichle, Grubb, Gado, Eichling, and Ter-Pogossian, 1976). It has,however, been shown that after alcohol consumption the glucose metabolism de-creases, which indicates that an uncoupling between the global levels of cerebralblood flow and metabolism has taken place (Volkow et al., 1990). The possibility thatthe uncoupling only involves the global flow level and not the regional distribution offlows has gained support via a recent study from our laboratory (Wendt, Risberg,Stenberg, Rosen, & Ingvar, 1994). Normally, when activating the brain by sensorystimulation or by a mental task, the flow of the regions functionally involved willincrease (Risberg, 1986b; Risberg & Ingvar, 1973). We addressed the questionwhether on top of the ethanol-related global CBF increase sensory activation stillwould cause regionally increased flow (Wendt et al., 1994). Changes of rCBF duringvisual–spatial stimulation (a reversing checkerboard) were measured in normal sub-jects during sobriety and following ethanol ingestion. A bilateral activation of theoccipital cortex was expected in line with positron emission tomographic (PET) find-ings using the same stimulation procedure in normal (sober) subjects (Fox, Miezen,Allman, Van Essen, & Raichle, 1987; Fox & Raichle, 1985; Phelps et al., 1981). Wefound that the normal flow distribution at rest with its hyperfrontability (Ingvar, 1979;Prohovnik, Hakansson, & Risberg, 1980), was preserved during inebriation (Wendtet al., 1994), corroborating previous findings (Sano et al., 1993). Also, a bilateralactivation of the occipital cortex was seen during both sobriety and inebriation. Thefinding that visual stimulation increases occipital flow also during ethanol inebriationindicates a preserved coupling between local neuromal activity and rCBF (Wendt etal., 1994). This has been confirmed by a recent fMRI study (Hager et al., 1997),where an increase in signal intensity in response to the Wisconsin Card Sorting Testwas found in prefrontal areas following ethanol as well as during sobriety.

During sobriety, the checkerboard stimulation resulted in greater right occipital andright parietal activation responses, in line with previous findings of right hemispheresuperiority for visuo-spatial information processing (Deutsch, Bourbon, Papanico-laou, & Eisenberg, 1988; Furst, 1976; Gur & Reivich, 1980; Kolb & Whishaw, 1990;Risberg, Halsey, Wills, & Wilson, 1975; Springer & Deutsch, 1998; Wendt & Ris-berg, 1994). It is also in line with several studies of evoked potentials using reversingcheckerboard or sine-wave gratings, which have shown larger right- than left-hemi-sphere amplitudes (Cohn, Kircher, Emmerson, & Dustman, 1985; Mecacci, 1993;Rebai, Mecacci, Bagot, & Bonnet, 1989; Shagass, Amadeo, & Roemer, 1976;Spinelli & Mecacci, 1990). Larger amplitudes from the right than from the lefthemisphere are also normally found in potentials evoked from central areas by pho-tic stimulation, an asymmetry that decreased following ethanol (Lewis, Dustman, &Beck, 1970; Rhodes, Obitz, & Creel, 1975). Likewise, in our study (Wendt et al.,1994), the asymmetric activation in the sober state disappeared during inebriation,and was replaced by a symmetrical activation occipitally together with a reducedasymmetry in the parietal cortex. Two independent fMRI studies have corroboratedour finding of an ethanol-induced reduction of right-sided asymmetric rCBF activa-tion: in visual cortext by the use of photic stimulation (Levin et al., 1998), and inprefrontal areas during the Wisconsin Card Sorting Test (Hager et al., 1997).

Ethanol seems thus to change the brain’s response to visual stimulation. The moresymmetric activation response indicates a less differentiated cortical information pro-cessing. The inferiority of bilateral hemisphere involvement is suggested by severalstudies in normal, sober subjects. A positive correlation was found between scoreson a complex visual–spatial task (cube analysis) and right . left rCBF asymmetryin posterior association cortex (Wendt & Risberg, 1994). Similar findings concerningthe right hemisphere were reported by Gur and Reivich (1980) correlating rCBF with

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ETHANOL REDUCES rCBF OF LEFT DLPFC 199

Street test performance, and by Furst (1976) recording EEG during miscellaneousvisuo-spatial tasks.

However, an EEG study from our laboratory (Stenberg, Sano, Rosen, & Ingvar,1994) using a mental-arithmetic activation task which normally causes higher activa-tion in the left than in the right hemisphere, revealed a more symmetric pattern follow-ing ingestion of alcohol. The resting EEG was also changed in the direction of greaterlateral symmetry. Thus, mechanisms of hemispheric specialization seem to be ad-versely affected by alcohol, regardless of the hemisphere most engaged in the activa-tion task (Wendt et al., 1994). Therefore, we decided to further explore the effectsof ethanol on functions lateralized to the left hemisphere.

Verbal (or word) fluency (to say as many words as possible beginning with aspecified target letter) is a task that engages an intentional system for intrinsic wordgeneration (Friston, Frith, Liddler, and Frackowiak, 1993), with the subject re-sponding to a stimulus letter that is not repeated but must be kept active in the mind;that is, responses are minimally specified by external cues (Frith, Friston, Liddle, &Frackowiak, 1991). In normal, healthy subjects activation by the verbal fluency testresults in an asymmetric activation of the left dorsolateral prefrontal cortex (DLPFC),according to two-dimensional measurements of rCBF (Cantor-Graae, Warkentin,Franzen, & Risberg, 1993; Warkentin, Risberg, Nilsson, Karlson, & Graae, 1991),as well as several PET studies (Friston & Frackowiak, 1991; Friston, Frith, Liddle, &Frackowiak, 1991b; Frith et al. 1991).

According to Benton (1968), deficits in verbal fluency performance have followedleft frontal lesions, a finding also reported by Zangvill (cited from Milner & Petrides,1984; Warkentin et al., 1991), as well as by Milner and Petrides (1984). Schizo-phrenic patients have shown both a failure to activate the left DLPFC during verbalfluency and a severe defect in performance on the test (Cantor-Graae, Warkentin,Franzen, Risberg, & Ingvar, 1991). Patients with Huntington’s disease, Parkinson’sdisease, and schizophrenia have shown a reduced performance on verbal fluency—a difficulty in intrinsic generation interpreted as an interruption of prefrontal modula-tion of retrieval processes (Hanes, Andrewes, & Pantelis, 1995). Patients with fronto-temporal dementia typically also show a poor performance on the verbal fluency test(Elfgren, Passant, & Risberg, 1993; Elfgren, Ryding, & Passant, 1996). Moreover,several studies indicate that the frontal cortical regions are especially vulnerable tothe detrimental influence of alcohol (Adams et al., 1995; Charness, 1993; Johnson-Greene et al., 1997; Jones & Parsons, 1971; Volkow et al., 1992), with correlationsbetween abnormalities on tests of executive functioning and decreased metabolicrates for glucose in the frontal lobes of severe chronic alcoholic subjects (Adams etal., 1995; Johnson-Greene et al., 1997).

Verbal fluency was thus considered to be a suitable task to investigate the possibleinfluence of ethanol on a left-sided asymmetric rCBF activation response. Investiga-tions of the relation between performance on the verbal fluency test and CBF orglucose metabolism parameters have not yielded any consistent results. Two studiesfound negative correlations between the glucose metabolism of frontal regions(among others) and verbal fluency performance (Duara, Chang, Barker, Yoshii, &Apicella, 1986; Parks et al., 1988), while two rCBF studies found no correlations atall (Cantor-Graae et al., 1993; Warkentin et al., 1991). The rCBF studies using PETdid not address this issue (Friston & Frackowia, 1991; Friston et al., 1991b; Frith etal., 1991). Still, the possible relations between test performance and CBF parametersare interesting to explore.

On the basis of previous findings, the following hypotheses were formulated: (1)Alcohol consumption will result in global increases of cortical blood flow during

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both rest and activation. (2) The rCBF of the left DLPFC will be activated by theverbal fluency test during sobriety. (3) Alcohol will cause a reduction of the asymmet-ric activation response found during sobriety. (4) Performance on the verbal fluencytask will be negatively affected by alcohol consumption.

METHODS

Subjects

Twenty healthy right-handed young male volunteers (university students) were paid for participatingafter giving their informed consent. Their mean age was 25.3 years (range 22–29 years). Health statuswas evaluated by a questionnaire, with the exclusion of subjects with psychiatric diseases, certain somaticdiseases, and CNS-related diseases. Substantial use or abuse of alcohol and drugs was also an exclusioncriterion. The subjects were not taking any medication and were abstaining from alcohol-containingbeverages for at least 3 days before the measurements. A high degree of right-handedness was ensuredby the Edinburgh Handedness Inventory (EHI: Oldfield, 1971), as modificated by Schalling (Levander &Schalling, 1988). Following Bryden’s suggestion, writing-hand preference was given double weight (Bry-den, 1982). Due to the reported relation between high anxiety proneness and asymmetries to the rightof rCBF (Hagstadius & Risberg, 1989) and cerebral metabolic rates (Reivich, Gur, & Alavi, 1983) innormals, the subjects were also tested with the Spielberger State-Trait Anxiety Inventory, from Y (STAI;Spielberger, 1983) translated to Swedish by Schalling (personal communication). The study was ap-proved by the ethical committee of the Medical Faculty of the Land University and the Radiation SafetyCommittee of the University Hospital of Lund.

Measurements. Measurement of rCBF was made by the 133Xe inhalation technique, using a high-resolution system (Cortexplorer 256 HR; Ceretronix, Inc., Randers, Denmark) with 254 stationary detec-tors (10 3 10-mm NaI(TT) crystals) mounted in a pneumatically controlled helmet type of holder. Thesystem adjusts for differences in head sizes and shapes, and the positioning of the head is standardizedin relation to bony landmarks (nasion and ear channels) by means of light crosses (Risberg, 1987). Thismakes it possible to reposition the subject accurately on different occasions. One minute of 133Xe inhala-tion (70–100 MBq/L) was followed by 10 min of normal air breathing according to the standard proce-dure (Obrist, Thompson, Wang, & Wilkinson, 1975). Either 30 s of background (first measurement) or5 min of remaining activity (repeated measurements within 1 h) was recorded before administration ofthe isotope (Risberg, 1980). The gray matter flow parameter ( f1; ml/100 g/min) was used because ofits high sensitivity to flow changes and acceptable stability and reliability when flow levels are withinthe normal range (Obrist & Wilkinson, 1985; Risberg, 1986a). Regional distribution values (percentageof total mean) were transformed into seven regions of interest (anterior prefrontal, frontotemporal, supe-rior frontal, posterior temporal, central, parietal, occipital) in each hemisphere according to a predefined,previously developed classification (Minthon et al., 1993; Sano et al., 1993; Wendt et al., 1994). Theextension of the dorsolateral prefrontal cortex—that is roughly Brodmann’s areas 9, 10, 44, 45, and 46(Kolb % Whishaw, 1990) also including Broca’s area and its homologue (Broadmann’s areas 44 and45; Demonet et al., 1992; Kahle, 1986)—is more than well covered by three regions in each hemisphere:the anterior prefrontal, the frontotemporal, and the superior frontal regions. These regions will thereforebe the regions of interest (ROI’s) of the present investigation.

Arterial PaCO2 was estimated from recordings of end-tidal CO2 concentrations (Omeda gas-analyzer).Mean PaCO2’s for each subject were entered into a 2 states (sober/inebriated) 3 2 tasks (rest/verbalfluency) repeated-measures ANOVA. In case of any significant difference in PaCO2 between measure-ments, all absolute flow values would be corrected to a level of 40 mm Hg using the standard procedure(Maximilian, Prohovnik, & Risberg, 1980). Heart rate and respirator rate were monitored during eachrCBF measurement (Omeda gas-analyzer). Systolic and diastolic blood pressures were measured aftereach measurement. Blood alcohol concentrations (BAC) were determined with a breath analyzer (LionLaboratories, UK).

Experimental design. On arrival in the laboratory all subjects were first tested with the breath ana-lyzer and found to be sober. Supine rCBF measurements during resting wakefulness (first measurement)and activation (second measurement) were made. During both measurements eyes were closed and cov-ered. Auditory stimulation was kept at a minimum (instrumental noise). Activation, starting 1 min before133Xe inhalation, consisted of FAS, a verbal fluency task (Benton, 1968; Benton & Hamsher, 1977)slightly modified to suit the rCBF measurement (Warkentin et al., 1991). The subjects were instructedto report as many words as possible beginning with a specified target letter (F, A, S. . . ). Letters werechanged every minute during the total measurement epoch. The subjects were also informed that allkinds of words in Swedish except proper nouns were accpetable, but that no word could be used more

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ETHANOL REDUCES rCBF OF LEFT DLPFC 201

than once. A microphone was attached to one side of the throat of the subject, and a stethoscope washeld to the other side of the throat, enabling us to make notes of the number of correct words and to recordthe answers for further analyzes. However, the starting moment of the test was not always immediatelyapprehended by the subjects—in some cases they asked some questions—which gave them shorter timethan 1 min for the first letter presented. Also, the test stopped when the measurement stopped, and thiswas often not exactly after 1 min of processing the last word presented. Because of this, the first andthe last letter were excluded, and the 10 letters between were used for calculation of the performancescore.

All subjects were measured during sobriety as well as inebriation, with at least a 1-week intervalbetween. The order of the sober and inebriation sessions was randomized to control for the effects ofhabituation following repeated rCBF measurements (Prohovnik et al., 1980; Risberg, Maximillian, &Prohovnik, 1977; Warach et al., 1987). Both sessions took place in the morning to avoid influence fromcircadian variations of rCBF (Prohovnik et al., 1980; Prohovnik & Risberg, 1979). The health question-naire and the EHI, and STAI forms were completed by the subject after the breath analyzer test at thefirst session.

An effort was made to control for factors that influence blood alcohol concentration (Kalant, 1971;Ritchie, 1965). The subjects avoided food and beverages for 9 h preceding the inebriation session. Onarrival in the laboratory they were given a standardized breakfast. After breakfast their weight wasmeasured, and they were served alcohol in doses of 1 g/kg of body weight, mixed with orange juice(75% of total volume). Vodka (40% alcohol) was chosen because of its purity compared with otheralcohol-containing beverages (Leake & Silverman, 1971). The first rCBF measurement started 15 minafter drinking was completed and the subjects had rinsed their mouths thoroughly with water. TotalBAC was calculated as the average of three breath analyzer recordings: before, between, and after rCBFmeasurements. To estimate the average BAC’s during the actual measurement epochs, resting BAC(average of before and between measurements) and verbal fluency BAC (average of between and aftermeasurements) were calculated.

Statistical analysis. Data were transformed into cortical color flow maps combined with a statisticalmapping system (t test, two-tailed), displaying only groups of detectors where the difference in distribu-tion values between measurements was significant at the p , .001 level (see Fig. 2 and 3). This procedurewas used only as an exploratory and illustrative tool, not as a basis for statistical inference. In a PETsimulation study (Bailey, Jones, Friston, Colebatch, & Frackowiak, 1991) investigating the statisticalparametric mapping system of Friston and co-workers (Friston, Frith, Liddle, & Frackowiak, 1991a),the p , .001 level (omnibus significance) protected securely against false positives. Their system removesglobal changes by an ANCOVA instead of via distribution values, but in an actual investigation the twoprocedures gave practically the same results (Marenco, Coppola, Daniel, Zigun, & Weinberger, 1993).

For statistical inferences a priori designed repeated-measures ANOVA’s were considered the mostappropriate (Pawlik, 1991). A 2 states (sober/inebriated) 3 2 tasks (rest/verbal fluency) 3 2 hemispheres(left/right) repeated-measures ANOVA was performed on hemispheric means of f1 (absolute values).For f1 distribution values in regions of a priori interest (anterior prefrontal, frontotemporal, and superiorfrontal regions), 2 tasks 3 2 hemispheres repeated-measures ANOVA’s were performed for the soberand the inebriate state, respectively. Differences in activation response (distribution value changes fromrest to verbal fluency) between the sober and the inebriated states were investigated with a 2 states 3 2hemispheres repeated-measures ANOVA for the anterior prefrontal, frontotemporal, and superior frontalregions, respectively.

Performance on the verbal fluency test (total number of correct words) during sobriety and inebriationwas compared by a repeated-measures ANOVA. Relations between verbal fluency performance (duringsobriety and inebriation) and the following CBF parameter were investigated by Pearson correlations,where the level of significance was set at p , .01 due to the large number of comparisons (Pelosi etal., 1992).

1. Absolute flow hemispheric means during verbal fluency.2. Distribution value levels in the three ROI’s during verbal fluency.3. Changes from rest to verbal fluency in the three ROI’s.4. Left- . right-sided asymmetries in the three ROI’s during verbal fluency.5. Left- minus right-sided changes from rest to verbal fluency in the three ROI’s.To control for the influence of anxiety, STAI scores were introduced as covariates of an ANCOVA

on the rCBF distribution values of the three regions of a priori interest, and on the absolute hemisphericmean values. The possible influence of state and trait anxiety on verbal fluency performance was investi-gated with Pearson correlations.

PaCO2, heart rate, respiratory rate, and systolic and diastolic blood pressure were analyzed withrepeated-measures ANOVA’s for differences between the four measurements. Resting BAC vs. BACduring verbal fluency were also analyzed with repeated-measures ANOVA’s.

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RESULTS

Blood Alcohol Concentrations and Physiological Parameters

Total average BAC was 0.059%, which is exactly the same as in our previousinvestigation (Wendt et al., 1994). However, the BAC during verbal fluency (0.062%)was slightly but significantly higher than the resting BAC (0.055%; F9.54; df 1, 19;p , .006). However, although the difference is statistically significant, we considerit too small to have any importance for the interpretation of the main findings.

As shown in Table 1, there were no significant differences in PaCO2 between thefour measurements and therefore no corrections of absolute flow values were made.For heart rate a main effect of states (F 10.42; df 1, 19; p , .0044) was found,revealing faster heart rates during inebriation regardless of task, in line with previousfindings (Sano et al., 1993; Wendt et al., 1994). We also found a main effect of tasks(F 28.41; df 1, 19; p , .0001) indicating faster heart rates during FAS (verbal fluency)regardless of state. Moreover, a states ∗ tasks interaction (F 12.81; df 1, 19; p ,.002) was found. After inspecting Table 1 we found the interaction to be due toethanol and task demands potentiating each other with the fastest heart rates whenverbal fluency were performed during inebriation. Alcohol consumption was not thecause of any other significant effects or interactions between the tabled variables.

For respiratory rate a main effect of tasks (F 7.4; df 1, 19; p , .014) was found,indicating a faster respiratory rate during verbal fluency activation in both the soberand the inebriated state. This is also in line with previous findings (Wendt et al.,1994), although the tasks in the two experiments are very different (looking passivelyat a reversing checkerboard vs. solving a test of a verbal ability with eyes closed).Possibly, directing attention to any kind of task might demand an increase in oxygenconsumption. Main effects of tasks were also found for both systolic (F 6.72; df 1,19; p , .018) and diastolic (F 12.76; df 1, 19; p , .002) blood pressure. The increasesin blood pressure were, however, small and hardly of any importance for the interpre-tation of the main results.

Handedness and Anxiety Proneness

The analysis of the degree of handedness gave the following laterality quotients(LQ; the scale goes from 1100 5 strong right-handedness, to 2100 5 strong left-handedness): Fifteen subjects had LQ 1 100; 1 subject had LQ 187.5; 3 subjectshad LQ 186.7; and the last subject had LQ 185.7. With the 10-item scale, right-handedness is considered when LQ’s range from 148 to 1100 (Oldfield, 1971).Thus, the subjects of the present study were all considered to be right-handed.

Test results from the STAI were compared to those of American college students

TABLE 1Acute Effects of Alcohol on Physiological Variables in 20 Subjects; Mean Values and

ANOVA Results

Sober Inebriated Main effect Interaction

Variable Rest FAS Rest FAS States Tasks States ∗ Tasks

PaCO2, mm Hg 37.8 37.8 38.2 38.4 ns ns nsHeart rate, beats/min 75.4 78.4 79.2 90.0 p , .0044 p , .0001 p , .002Respiratory rate, inspirations/min 10.8 12.5 10.8 13.1 ns p , .0136 nsSystolic blood pressure, mm Hg 127.3 131.3 131.8 135.0 ns p , .0179 nsDiastolic blood pressure, mm Hg 69.0 74.3 68.8 71.0 ns p , .002 ns

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ETHANOL REDUCES rCBF OF LEFT DLPFC 203

(most similar to our group among the available norm groups; Spielberger, 1983).Our group of subjects was lower in anxiety proneness than the average for this normgroup (average state anxiety 30.9, norm 36.5; average trait anxiety 32.1, norm 38.3).Thus, as in a previous investigation (Wendt & Risberg, 1994), high anxiety pronenesswas not a feature of the present group (subjects with high anxiety proneness are notlikely to volunteer for this kind of experiment). Neither state nor trait anxiety hadany significant impact on any of the tested variables.

Hemispheric Mean CBF

The ANOVA on hemispheric gray matter flow levels (ml/100 g/min) revealed amain effect of states (F 14.33; df 1, 19; p , .001). This was due to an average globalabsolute flow increase following ethanol—10% during rest and 13% during verbalfluency (Fig. 1). Further, a tasks ∗ hemispheres interaction (F 30.24; df 1, 19; p ,.0001) was found, revealing that the absolute flow increases from rest to verbal flu-ency were significantly larger in the left hemisphere (Fig. 1), during both sobriety(left 3.74 ml/100 g/min, right 2.30 ml/100 g/min) and inebriation (left 6.20 ml/100g/min, right 5.28 ml/100 g/min) averaged together. No other effects or interactionswere found.

Regional CBF Distribution Values

The cortical flow maps (Fig. 2 and 3) displayed the expected hyperfrontal distribu-tion during rest (Ingvar, 1979; Prohovnik et al., 1980) in both the sober and theinebriated state. Comparing verbal fluency activation with rest during sobriety (Fig.2) revealed the expected (Warkentin et al., 1991) increases in most of the left DLPFC.Activation during inebriation (Fig. 3) caused significant flow increases exclusivelyin the frontal lobe part of the left frontotemporal region—no increases were seen in

FIG. 1. Hemispheric CBF mean values of f1 (ml/100 g/min) for the 20 subjects during the rest andthe verbal fluency test (FAS) in the sober and the inebriated state. Repeated-measures ANOVA maineffects of states (p , .001) and a tasks ∗ hemispheres interaction (p , .0001) were found.

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FIG. 2. Color flow maps showing the rCBF patterns ( f1; ml/100 g/min; % of total mean) in all partsof the superficial cerebral cortex from the vertex view, by a projection of the spheric shape into a two-dimensional plane (right hemisphere 5 right half; frontal 5 up). In the upper two maps yellow colorindicates values close to the total mean, while red denotes higher and green lower values in % of mean.These upper maps illustrate f1 distribution for the resting and the verbal fluency measurements for the20 subjects during sobriety. The lower left map shows changes in distribution values (% of total mean;same color scale) from rest to verbal fluency. The lower right map represents a statistical mappingprocedure (t test, two-tailed) displaying only groups of detectors (labeled ‘‘Cluster’’) where the dif-ference in distribution values between tasks was significant at the p , .001 level (increases 5 orange;decreases 5 green). Note the significant increases in most of the left DLPFC (lower right and leftmap).

the left anterior prefrontal or left superior frontal regions. The small areas showingdecreases were of no interest in the present study and were not further analyzed.

The repeated-measures ANOVA on anterior prefrontal distribution values showed,during sobriety, a task ∗ hemispheres interaction (F 54.36; df 1, 19; p , .0001)revealing an increase from rest to verbal fluency exclusively in the left hemisphere(3.75 vs. 0.60% decrease on the right side). As seen in Fig. 4a, the left-sided increaseresulted in a shift from a right-sided asymmetry during rest to a left-sided asymmetryduring verbal fluency. There were no significant changes during inebriation. Figure4b shows that the distribution values were symmetrical during both rest and verbalfluency. Comparing the sober flow changes from rest to verbal fluency to the changesduring inebriation in this region gave a main effect of hemispheres (F 5.28; df 1, 19;p , .033) and a states ∗ hemispheres interaction (F 23.30; df 1, 19; p , .0001),indicating that the sober flow changes (Fig. 4a) were significantly different than theones during inebriation (Fig. 4b).

In the frontotemporal region, the repeated-measures ANOVA on distribution val-ues in the sober state gave a main effect of tasks (F 12.21; df 1, 19; p , .0024), anda tasks ∗ hemispheres interaction (F 17.80; df 1, 19; p , .0005), revealing the samepattern as in the anterior prefrontal region, namely that a left-hemisphere increase(3.40%) changed the right-sided asymmetry during rest into a left-sided asymmetryduring verbal fluency (Fig. 5a). However, during inebriation, the pattern of flowchanges (Fig. 5b) was practicaly the same as during sobriety (Fig. 5a) in the fronto-

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FIG. 3. Color flow maps illustrating the f1 distribution for the resting and the verbal fluency measure-ments for the 20 subjects during inebriation (for explanations see Fig. 2). Note the significant left DLPFCincrease only in a part of the frontotemporal region (lower right and left map).

temporal region. This is statistically verified by a main effect of tasks (F 6.01; df 1,19; p , .024), and a tasks ∗ hemispheres interaction (F 24.36; df 1, 19; p , .0001),although the left-sided increase was somewhat small following ethanol (2.67%), andby the sober–inebriation comparison which showed only a main effect of hemi-spheres (F 30.15; df 1, 19; p , .0001) because of the increase exclusively in the lefthemisphere during both sobriety and inebriation.

Finally, in the superior frontal region the flow pattern during sobriety (Fig. 6a)was the same as in the two aforementioned regions—a right-sided resting asymmetrybecame a left-sided asymmetry during verbal fluency, verified by a tasks ∗ hemi-spheres interaction (F 11.93; df 1, 19; p , .0027). During inebriation, the asymmetryduring verbal fluency was close to absent (Fig. 6b).

Performance on the Verbal Fluency Test

Alcohol consumption resulted in a significantly lower total production of correctwords (average 169 words), compared to the sober state (average 190 words; (F 9.01;df 1, 19; p , .007). However, we found no significant correlations between the scoresand any of the CBF parameters.

DISCUSSION

The normal rCBF distribution at rest, with its typical hyperfrontality (Ingvar, 1979;Prohovnik et al., 1980), was preserved following ethanol, in line with previous find-ings (Sano et al., 1993; Wendt et al., 1994). Also in line with previous findings,hemispheric means of CBF increased following ethanol during both rest (e.g., Sanoet al., 1993; Wendt et al., 1994) and activation (Wendt et al., 1994). The rest-to-verbal fluency increases were larger in the left hemisphere during both sobriety and

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FIG. 4. (a) Illustration of the difference in f1 distribution values (% of total mean) for the 20 subjectsbetween the rest and the verbal fluency (FAS) measurements during sobriety in the anterior prefrontalregions. Repeated-measures ANOVA tasks ∗ hemispheres interaction (p , .0001) was found. (b) Sameas (a) during inebriation in the anterior prefrontal regions. Repeated-measures ANOVA ns.

inebriation, in line with the importance of this hemisphere for verbal processing (In-gvar, 1983; Kolb & Whishaw, 1990; Risberg et al., 1975; Springer & Deutsch, 1998).

During sobriety, we found the expected left-sided activation of the anterior prefron-tal, frontotemporal, and superior frontal ROI’s in response to the verbal fluency task.The changes in the superior frontal region following ethanol were between the twoother ROI’s. Since we did not state any hypothesis about expected changes of thisregion, we will concentrate our discussion to the other two regions.

The frontotemporal region had a preserved activation response following ethanol(Fig. 3). The figure also shows that it was the frontal part of this region, most probablycomprising Broca’s area, that was activated. This indicates that the component ofthe active network that produces motor programs for speech is more robust to thedetrimental effect of ethanol inebriation than other parts of it. Further, the rCBFactivation response corroborates the preserved coupling between regional neuronalactivity and rCBF during ethanol inebriation previously found (Wendt et al., 1994).

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FIG. 5. (a) Illustration of the difference in f1 distribution values (% of total mean) for the 20 subjectsbetween the rest and the verbal fluency (FAS) measurements during sobriety in the frontotemporal re-gions. Repeated-measures ANOVA main effect of tasks (p , .0024) and a tasks ∗ hemispheres interac-tion (p , .0005) were found. (b) Same as (a) during inebriation in the frontotemporal regions. Repeated-measures ANOVA main effect of tasks (p , .024) and a tasks ∗ hemispheres interaction (p , .0001)were found.

In the rest of the left DLPFC, especially in the anterior prefrontal region, the activa-tion response was absent following ethanol. Warkentin and colleagues (1991) outlinefour functions related to the verbal fluency task, besides the one necessary for motoricoutput of vocalization. According to them, verbal fluency:

1. involves an active, self-generated, and continuous search of the internal vocabu-lary for new words, which indicates a retrieval of information;

2. necessitates response inhibition of external and internal interferences that maydisrupt the formation and execution of the verbal responses;

3. requires the realization of various executive steering functions;4. ‘‘. . . (demands) an ongoing level of performance, as prompted by the frequency

of letter shift, as well as the voluntary aspects of whatever particular strategy thesubject uses to perform this task. It can thus be inferred that an essential component

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FIG. 6. (a) Illustration of the difference in f1 distribution values (% of total mean) for the 20 subjectsbetween the rest and the verbal fluency (FAS) measurements during sobriety in the superior frontalregions. Repeated-measures ANOVA tasks ∗ hemispheres interaction (p , .0027) was found. (b) Sameas (a) during inebriation in the superior frontal regions. Repeated-measures ANOVA ns.

of this test is willed intention, or making plans for the structuring of behavior’’ (War-kentin et al., 1991, page 314).

Warkentin and colleagues (1991) suggest, referring to Goldberg and Bilder, thatit is primarily the fourth aspect of frontal lobe funtioning which causes the verbalfluency induced activation of the left DLPFC.

However, this is not the only plausible interpretation. Verbal fluency is conceivedof as being a task engaging an intentional system for intrinsic word generation (Fris-ton et al., 1993), where responses are minimally specified by external cues (Frith etal., 1991). Yet, an ‘‘intentional system for intrinsic word generation’’ ought to engagemany different kinds of functions. Analyzing functional connectivity, Friston, Frith,and collaborators (1993) identified several cortical regions (among them the leftDLPFC) involved in verbal fluency processing, but which of the functions that theleft DLPFC is especially important for, they leave without debate. The same group(Frith et al., 1991) found a distributed brain system of activated and inhibited regions

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during verbal fluency, but proposed that the left DLPFC is involved in intrinsic gener-ation, especially in modulating the functioning of the system and in strategic inhibi-tion processes. They also found the responsivity in a network—a distributed wordstore—containing the superior temporal gyrus to be modulated during verbal fluencyby the left DLPFC (Friston et al., 1991b). Furthermore, a reduced performance onthe verbal fluency test has also been found in patients with Huntington’s disease,Parkinson’s disease, and schizophrenia consistent with a difficulty in intrinsic genera-tion, which the authors interpreted as an interruption of prefrontal modulation ofretrieval processes (Hanes et al. 1995).

Interference inhibition (or control) is by some investigators underlined as a fre-quent contributor to the symptoms of the DLPFC-lesioned patient (Fuster, 1985;Milner & Petrides, 1984). Fuster states that: ‘‘. . . failure is not only evident in thedifficulty which the frontal patient has in forming and executing plans of action ingeneral, but in the special difficulty he has in the construction of highly integratedand complex patterns of behavior. Nowhere is that more evident than in a form ofbehavior which is unique of man: language’’ (Fuster, 1985, page 175). Thus, interfer-ence inhibition is also a candidate for the mechanism disturbed by ethanol duringverbal fluency.

Moreover, since the verbal fluency test obviously is within the verbal realm, it isthe left DLPFC which is activated to carry out the necessary functions. At least someof the above-mentioned functions could be included in the working memory system(e.g., interference inhibition might be a function used within the working memorysystem, without being confined to this system). Lesions to the prefrontal region ofmonkeys produce a deficit that is specific for working memory, which in turn isspecific to certain types of tasks (Kupfermann, 1991). Patients with unilateral corticallesions were tested by Petrides and Milner on two verbal and two nonverbal workingmemory tasks (subject-ordered pointing tasks). While patients with right frontal lobeexcisions showed deficits only on the two nonverbal tasks, patients with left frontallobe excisions were impaired on all four tasks. The deficits can be attributed to eitherpoor organization strategies or poor monitoring of responses, or both. The authorsspeculate that the left frontal cortex might be more important to an active workingmemory, because verbal mediation may be necessary in the programming of re-sponses (Petrides & Milner, 1982). According to Posner and Raichle (1994) a regionof great importance for the working memory for words lies within the left DLPFC.Although they describe it as situated in the lateral frontal lobe, their illustration de-picts it more precisely as situated anterior to Broca’s area. The part of the left DLPFCthat we found to lose its activation response following ethanol was also anterior toBroca’s area (Figs. 2 and 3), and at least a fair part of Posner and Raichle’s area forworking memory for words lies within our anterior prefrontal region. Therefore, yetanother plausible explanation for our findings is that ethanol causes a disturbance inworking memory, in the form of a loss of activation in the left DLPFC anterior toBroca’s area during verbal fluency and a diminished word production.

However, some other memory aspects are also inherent in the verbal fluency task.One is keeping the target letter in the mind while searching a semantic memory forwords beginning with this letter. This could be conceived of as a short-term memoryoperation, and a short-term memory task has been found to activate the anterior fron-tal region of the ‘‘dominant’’ hemisphere in an rCBF study (Risberg & Ingvar, 1973).Moreover, frontal lobe patients (e.g., with basal forebrain strokes; chronic alcoholics)normally have short-term memory difficulties (Kolb & Whishaw, 1990). Monkeyswith lesions to the prefrontal region do poorly also on short-term memory tasks(Kupfermann, 1991).

Another memory aspect is keeping track of all the words already mentioned during

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the target letter, so not to say any word twice. The DLPFC is considered to be impor-tant for the temporal organization of memory. In both monkeys and humans, lesionswithin the DLPFC can lead to poor temporal memory (e.g., recency memory, delayedresponse, delayed alternation, delayed comparison, frequency of occurrence)—andwith verbal temporal memory tasks deficits are typically associated with left DLPFClesions—according to several investigations (Fuster, 1985; Ingvar, 1985; Kolb &Whishaw, 1990; Kupfermann, 1991; Milner & Petrides, 1984; Milner, Petrides, &Smith, 1985; Verin et al., 1993). In normal subjects a greater pattern of activationin the left DLPFC during delayed matching has been found with PET (Frackowiak,Friston, Frith, Dolan, & Mazziotta, 1997).

Therefore, it is possible that the lack of activation response in the more anteriorpart of the left DLPFC and the decreased word production represent a disturbance inone or some working memory, and/or temporal memory, and/or short-term memoryfunctions. More research is needed in the future to elucidate this question.

As stated in the Introduction, some investigations demonstrate that, due to a posi-tive relation between performance on the visuo-spatial task used and right minus leftasymmetric activation (Furst, 1976; Gur & Reivich, 1980; Wendt & Risberg, 1994),bilateral activation is not an advantage, at least not in tasks usually referred to asconvergent type (Guilford, 1967). The inferiority of processing information by bilat-eral activation was further suggested in the present study by the decrease in the num-ber of words produced during inebriation, compared with the sober state. The bilateralactivation of the anterior prefrontal region followed ethanol consisted of a loss ofasymmetry during both rest (right-sided) and verbal fluency (left-sided), with no in-creases in either hemisphere. This indicates a less differentiated processing of infor-mation in this region, with the loss of asymmetry eventually caused by diminishedinhibition (cf. Wendt et al. 1994). Thus, confirming our notion, hemispheric special-ization seems to be adversely affected by alcohol, regardless of which hemisphereis the one most involved while sober.

As in other rCBF studies, we found no correlation between verbal fluency perfor-mance and different CBF parameters. Warkentin and colleagues found that the sub-jects who did not activate the left DLPFC during verbal fluency had much higherdistribution values during rest than those with a left-sided activation, indicating aconcealment of the activation response in some subjects (Warkentin et al., 1991).This is further stressed by a study correlating frontal relative glucose metabolic rateswith verbal fluency performance, where it was found that high performers had a lowerresting metabolism than low performers (Boivin et al., 1992). We suggest yet anotherplausible explanation, based on our observation that some (possibly the verballyskilled) subjects had a tendency to report longer, more complex words, while others(possibly less skilled) reported shorter and simpler words. So, the rather simple factthat longer words take longer time to vocalize, and that you can produce more wordsin a minute if all are short, might conceal true skills when it is defined as numberof words produced. This issue could be addressed in future studies if one uses avariant of verbal fluency controlling for word length—e.g., to say as many four-letterwords as possible beginning with a specified letter in 1 min.

The present study, as well as the previous one (Wendt et al., 1994), has shownthat ethanol can be used as a means to experimentally induce transient changes inthe functional systems of the brain, and that changes in brain functions can be studiedby rCBF techniques also during ethanol inebriation. Two fMRI studies have revealedsimilar results (Hager et al., 1997; Levin et al., 1998).

Thus, our four main hypotheses were confirmed, while, as expected, we found norelation between verbal fluency performance and CBF parameters.

In conclusion, we found, in line with other investigations, that ethanol increases

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rCBF during both rest (e.g., Sano et al., 1993; Wendt et al., 1994) and cortical activa-tion (Wendt et al., 1994). We also found an activation of the left dorsolateral prefron-tal cortex during verbal fluency in the sober state, corroborating other studies (e.g.,Cantor-Graae et al., 1993; Warkentin et al., 1991). Moreover, we found that, at leastin parts of left DLPFC, an activation was found also during inebriation, like in theprevious study (Wendt et al., 1994). Finally, we propose that the activation to verbalfluency of the frontotemporal region within the left DLPFC during both sobrietyand inebriation, which seems to be more robust to the effects of ethanol/alcoholconsumption, represents Broca’s area that is part of a large-scale neurocognitive net-work subserving vocal speech production. Moreover, the part of the left DLPFC thatis detrimentally affected by ethanol, in that it is only activated by the verbal fluencytest in the sober state, and in a diminished word production compared to sobriety,represents a part of a large-scale neurocogitive network subserving working memory,or temporal memory, or short-term memory functions, or any combination betweenthese.

ACKNOWLEDGMENTS

This study was supported by grants from the Swedish Medical Research Council(Projects 4969 and 084), the Bank of Sweden Tercentenary Foundation (89/43), theSwedish Council for Research in the Humanities and Social Sciences, and theCrafoord Foundation, Lund.

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