Latent deleterious effects of binge drinking over a short period of time revealed only by electrophysiological measures
=======================================================================================================================

* Pierre Maurage
* Mauro Pesenti
* Pierre Philippot
* Frédéric Joassin
* Salvatore Campanella

## Abstract

**Background:** Episodic excessive alcohol consumption (i.e., binge drinking) is now considered to be a major public health problem, but whereas short- and long-term harmful consequences of this behaviour are clearly established at medical, social and cognitive levels, the cerebral correlates of these impairments are still unknown. Our study explores the midterm cerebral effects of binge-drinking behaviours among young adults.

**Methods:** We selected 2 groups of first-year university students with no history of drinking habits, paired for psychological and behavioural measures on the basis of their expected alcohol consumption during the forthcoming academic year. The binge drinker group expected to have high personal alcohol consumption, whereas the control group expected low consumption. We used a test–retest paradigm within a 9-month period (session 1 in September 2005, session 2 in May 2006). At each testing session, we recorded auditory event-related potentials while the participants performed an emotional valence judgment task.

**Results:** There were no differences between the groups in behavioural or electrophysiological measures at baseline. After 9 months, the binge drinkers had significantly delayed latencies for all event-related potential components (P1, N2, P3b) of emotional auditory processing compared with the control group (*p* < 0.006), with no behavioural differences.

**Limitations:** As the present study explored the electrophysiological correlates of binge drinking with an emotional task only, the results will have to be extended to other cognitive processes using various experimental tasks.

**Conclusion:** We report the first direct evidence that short-term binge drinking can produce marked cerebral dysfunction undetectable by behavioural measures alone. The observed latency abnormalities, similar to those observed in long-term alcoholism, constitute an electrophysiological marker of slowed cerebral activity associated with binge drinking.

## Introduction

Adolescents and young adults are at high risk of initiating alcohol use, which can lead to the development of later alcohol use disorders1 and is considered to be a major public health problem.2 Epidemiological studies show that binge drinking, the repeated excessive consumption of alcohol over a short period of time, affects about 40% of 18- to 24-year-olds.3 Although a single massive intake of alcohol may have dramatic acute consequences (e.g., increased risk of motor vehicle collisions, alcoholic coma, uninhibited sexual or violent behaviour4,5), repeated alcohol intake over a long period leads to negative long-term medical (e.g., cardiovascular disorders, gastrointestinal diseases, malignant neoplasms4) and social (e.g., poor academic results, problems of social integration6) effects. The neurotoxicity induced by long-term chronic alcoholism is also well established.7 Animal studies show that the adolescent brain, still immature and in a critical period of remodelling and development, is particularly sensitive to alcohol.8 For instance, the hippocampus is more sensitive to the acute effects of ethanol and its neurotoxic effects during adolescence.9 In adults with alcohol addiction, alterations in brain metabolites are observed in the frontal, cerebellar and thalamic regions, consistent with regional axonal damage (as inferred from *N*-acetylaspartate concentrations) and with changes in glial and general cell membrane metabolism.10 Moreover, voxel-based morphometry of grey matter revealed a susbtantial decrease in density in the precentral gyrus, middle frontal gyrus, insular cortex, dorsal hippocampus, anterior thalamus and cerebellum; there was also reduced density of white matter in the periventricular area, pons and cerebellar pedunculi.11 These structural brain connectivity alterations have clear deleterious effects on cognition. Indeed, various cognitive abilities, such as the allocation of attentional resources,12–14 visuo-spatial processing, short-term memory storage abilities15 and executive functions16 have been reported to be altered by long-term chronic alcohol abuse.17

With ambiguous messages about some positive medicinal effects of moderate alcohol consumption (e.g., reduced risk of heart attack18,19 or cognitive decline20), the detrimental effects of short-term alcohol consumption are not clear-cut. Young drinkers are often confused about what constitutes “moderate consumption” and what damage they may actually be doing to their health in general and to their brains in particular, especially because metabolic alterations and behavioural deficits have so far only been described after several years of binge drinking.10,13,16 Although the consequences of alcohol intake among young adults have been widely explored in studies focusing on behavioural and electrophysiological impairments owing to a positive family history of alcoholism,21,22 acute alcohol consumption23,24 or heavy drinking,25,26 the chronic midterm cerebral consequences of excessive alcohol consumption have not yet been explored in a controlled test–retest paradigm.

Because binge drinking is characterized by repeated periods of alcohol intoxication and abstinence leading to multiple withdrawals that are particularly deleterious for brain function,27,28 we hypothesized that cognitive impairments due to short-term binge drinking remain latent and that these impairments could be revealed by appropriate measures. Therefore, we used event-related potentials (ERPs), which allow us to monitor the electrical activity of the brain with high temporal resolution and detect even minor neurocognitive restrictions that are undetectable at the behavioural level.29 On the basis of the self-expected alcohol consumption, we selected 2 groups of 18 participants (controls and binge drinkers) and used a test–retest paradigm with a 9-month period separating the 2 testing sessions, corresponding to the beginning and the end of the participants’ first academic year. We recorded ERPs while the participants performed an emotional valence judgment task on auditory stimuli expressing negative or positive emotions. This task has been shown to be highly impaired in chronic alcoholic individuals who have a reduced amplitude and a delayed latency for the P3b, a long-lasting positive component appearing at parietal sites between 300 and 800 ms after stimulus onset and indexing the decisional and executive processing,30 but also earlier components associated with perceptual processes (i.e., P1, N2 and P2 waves).31 We thus expected functional impairments in binge drinkers on the same ERP components as those affected in chronic alcoholic individuals.

## Methods

### Participants

We screened a total of 462 students beginning their first academic year in the Faculty of Psychology, Catholic University of Louvain, Belgium. The screening was anonymous and comprised 2 parts:

*   psychological measures evaluating anxiety (State-Trait Anxiety Inventory, A and B32), depression (Beck Depression Inventory33), interpersonal problems (quantity and quality of social interactions, integration in the family and relationship background34) and alexithymia;35 and

*   a 75-item questionnaire, adapted from a binge-drinking habits questionnaire,36 evaluating previous and future alcohol–drug consumption, family history of alcohol consumption, social integration and medical problems.

To be included in our study, the students had to meet the following selection criteria: no positive family history of alcohol dependence; very low past alcohol consumption (mean consumption during 6 months preceding the study 1.61, standard deviation [SD] 1.84 units per week, where a unit corresponds with 10 g of pure ethanol); total absence of past binge-drinking habits; total absence of past or current drug consumption (including tobacco and any medication); no major medical problems; no central nervous system disease (including epilepsy); no auditory impairment; no moderate or high depression–anxiety scores; and no history of psychiatric disorder. The final selection criterion was the expected alcohol consumption during the academic year. We individually paired each member of the binge drinker group with a control participant for age, sex, education and psychological measures (state and trait anxiety, depression, interpersonal problems and alexithymia). We evaluated alcohol consumption based on individual self-estimated reports. All participants abstained from alcohol for at least 3 days before each testing session.

We provided participants with full details regarding the aims of our study and the procedure before they gave their informed consent. The ethical committee of the Faculty of Psychology of the University of Louvain approved our study.

### Stimuli

We administered an auditory task based on emotional valence detection (negative or positive) at each testing session. The participants had to decide which emotion was evoked by the stimulus by pressing 1 of 2 buttons with their right forefinger. The stimuli were audio recordings selected from a standardized battery37 consisting of the enunciation of a semantically neutral word (“paper”) with 2 emotional prosodies (anger or happiness) and 4 voices (2 female, 2 male) for each prosody. We manually edited all recordings to equilibrate pitch and duration. We presented each auditory stimulus with an intensity of 70 dB.

### Experimental design and procedure

The first testing session took place in September 2005; the second testing session occurred at the end of the same academic year in May 2006. During the ERP recording session, the participants sat in a dark room on a chair with their heads restrained in a chin rest; the auditory stimuli were presented via binaural headphones. The study consisted of 8 blocks of 32 stimuli (16 for each emotion); the order of the blocks varied across participants. A trial consisted of the following series of events: stimulus presented for 700 ms, an 800-ms time period during which the answer could still be given, and an interstimulus interval of random duration between 0 and 500 msec. The total duration of a trial thus varied from 1500 to 2000 ms, and the participants had 1500 ms to answer. We recorded response latencies and accuracy. The instructions emphasized the need to respond as quickly as possible while keeping errors to a minimum.

### Recording ERPs

We obtained electroencephalograms (EEGs) using 32 electrodes mounted in an electrode Quick-Cap. Electrode positions included the standard 10–20 system locations and intermediate positions. Recordings were taken with a linked mastoid physical reference but rereferenced using a common average. We used battery-operated amplifiers (Advanced Neuro Technology) with a gain of 30 000 and a band-pass of 0.01–100 Hz to amplify the EEGs. The impedance of all electrodes was always kept below 5 kW. We manually eliminated trials contaminated by electrooculogram artifacts (mean of 11%) off-line. Epochs were created starting 200 ms before stimulus onset and lasting for 1500 ms. Data were filtered using a 30 Hz low-pass filter. To compute different averages of ERP target stimuli for each participant, we coded 2 parameters for each stimulus: the condition type (anger or happiness) and the response type (correct or incorrect).

### Statistical analysis

We considered only correct responses for the analysis of response latencies and ERPs. For each participant and each component of interest (P1, N2 and P3b), we obtained individual peak amplitudes and maximum peak latencies from several electrodes separately for the ERPs to each type of stimulus: Oz, O1, O2, T5 and T6 for the early primary perceptive processing of auditory information (P1);38 T5 and T6 for the specific perceptive processing of human voices (N2);39 Pz, P3 and P4 for the decisional processes associated with the closure of the cognitive activities (P3b).40 We tested these values using repeated-measures analysis of variance (ANOVA, Greenhouse–Geisser correction applied when appropriate) and paired sample *t* tests.

Finally, we performed complementary analyses in the binge-drinker group to test the following effects.

*   Potential sex effect: Whereas groups were perfectly matched for sex, excluding a general influence of sex on the observed group differences, sex could influence the drinking pattern and/or the intensity of the latency impairment. We thus formed 2 subgroups in the binge drinker group according to sex, and we performed independent sample *t* tests to assess the potential sex influence on the quantity of alcohol consumed at Session 2 and the latency delays (as reported in Table 1) observed among binge drinkers for P1, N2 and P3b at Session 2.

*   Potential acute binge-drinking effect: Although all participants abstained from alcohol for at least 3 days before each testing session, the results in the binge drinker group could have been influenced by the last alcohol consumption. In other words, performance could vary as a function of the number of days elapsed since the last alcohol consumption (mean 8.34, SD 2.78) or of the number of doses consumed during this last occasion (mean 10.7, SD 3.91). To test this potential influence, we performed Pearson correlations between these last alcohol consumption characteristics and every behavioural–electrophysiological result.

*   The hypothesis of a link between latency impairments observed among binge drinkers for successive ERP components (see “Difference” line in Table 1 for the mean and SD of the delays for P1, N2 and P3b): Indeed, earlier studies41 in alcoholism postulated a continuum between the deficits described for the ERP components associated with perceptual, attentional and decisional stages. The greater the latency delay for perceptual stages (P100), the greater the delay for subsequent attention and decisional stages. To test this, we performed Pearson correlations between the delays observed for the 3 ERP components (P1, N2 and P3b).

*   The influence of binge-drinking intensity on the latency impairment observed at Session 2 among binge drinkers: Although a general latency delay is observed in the binge-drinker group, it is not clear whether this deficit varies according to the amount of alcohol intake (i.e., whether this deficit is proportional to the intensity of binge drinking habits). To test this hypothesis, we performed Pearson correlations in the binge drinker group between the mean alcohol consumption at Session 2 (in doses per week) and the latency delay observed for P1, N2 and P3b (see Table 1 for the mean and SD of these delays).

View this table:
[Table 1](http://jpn.ca/content/34/2/111/T1)

Table 1 
Latencies and amplitudes of each electrophysiological component as a function of group and session

## Results

### Participants

Of the 462 students we screened, 50 met our inclusion criteria. Of these, 25 participants expected to have a personal alcohol consumption greater than 20 units per week and were assigned to the binge-drinker group; the other 25 expected to have an alcohol consumption less than 3 units per week and were assigned to the control group. Seven participants in the binge-drinking group did not complete the study: 2 abandoned their studies, 2 had an alcohol consumption less than 10 units per week, and 3 smoked tobacco or cannabis. We excluded the 7 paired controls from the study, which left 2 groups of 18 participants for inclusion in our analysis. The mean age of participants was 18.16 (SD 0.86) years, and there were 7 men and 11 women in each group.

### Alcohol consumption and psychological measures

The 2 groups did not differ in their alcohol consumption at the first session (*t*17 = 0.43, *p* = 0.67), but at the second session binge drinkers had a higher total alcohol consumption (*t*17 = 7.01, *p* < 0.001), number of alcohol consumption occasions per week (*t*17 = 9.62, *p* < 0.001) and number of drinks per occasion (*t*17 = 11.84, *p* < 0.001) than participants in the control group. There were no group differences in depression (*t*17 = 1.93, *p* = 0.07), trait (*t*17 = 0.92, *p* = 0.37) or state (*t*17 = 2.02, *p* = 0.06 ) anxiety, interpersonal problems (*t*17 = 1.31, *p* = 0.21) or alexithymia (*t*17 = 0.73, *p* = 0.47) at the second session, which suggests that the experimental results were not influenced by these psychological factors. These data are summarized in Table 2.

View this table:
[Table 2](http://jpn.ca/content/34/2/111/T2)

Table 2 
Group characteristics for binge drinkers and controls

### Behavioural results

A 2 × 2 ANOVA with session (first, second) as a within-subject factor and group (binge drinkers, controls) as a between-subject factor revealed a main effect of session, with longer latencies at the first session than the second (mean 789, SD 87.5 ms v. mean 765.4, SD 95.7 ms, respectively; *F*1,34 = 8.94, *p* = 0.005), but there was no main effect of group (*F*1,34 = 0.16, *p* = 0.68) and no interaction (*F*1,34 = 0.023, *p* = 0.88). There was no main effect or interaction for accuracy (session *F*1,34 = 0.56, *p* = 0.46; group *F*1,34 = 2.19, *p* = 0.15; interaction *F*1,34 = 0.17, *p* = 0.68).

### Electrophysiological results

For each electrophysiological component of interest (P1, N2 and P3b), we computed a 3-way repeated-measure ANOVA with session (first, second) and localization (Oz, O1, O2, T5 and T6 for P1; T5 and T6 for N2; Pz, P3 and P4 for the P3b) as within-subject factors and group (binge drinkers, controls) as a between-subject factor separately for latencies and amplitudes (Table 1). These results are illustrated in Figure 1. For latencies, there was no main effect of group (except on P1, but this effect was qualified by a group by session interaction) or session. We observed significant interactions between group and session for each electrophysiological component. The 2 groups did not differ at the first session, but at the second session binge drinkers had a significantly delayed latency for the ERP components functionally associated with the P1, N2 and P3b components. For the P1 component (*F*1,34 = 18.24, *p* < 0.001), the binge drinkers had longer P1 latencies than controls at session 2 (*t*17 = 4.11, *p* < 0.001) but not at session 1. For the N2 component (*F* 1,34 = 18.24, *p* < 0.001), the binge drinkers had longer N2 latencies than controls at session 2 (*t*17 = 2.96, *p* = 0.009) but not at session 1. For the P3b component (*F*1,34 = 8.65, *p* = 0.006), the binge drinkers had longer P3b latencies than controls at session 2 (*t*17 = 2.43, *p* = 0.023) but not at session 1. This was not modulated by the topography of the electrodes (all *p* > 0.3). Finally, there were no main effects or interactions for the amplitudes of the various components.

![Fig. 1](http://jpn.ca/https://www.jpn.ca/content/jpn/34/2/111/F1.medium.gif)

[Fig. 1](http://jpn.ca/content/34/2/111/F1)

Fig. 1 
Delayed latencies observed only at session 2 for binge drinkers on the P1 and N2 components, recorded at occipito-temporal sites (T5, T6), and the P3b component, recorded at parietal sites (Pz). These components overlapped at session 1. We observed the slowed cerebral processing for binge drinkers at session 2 at occipito-temporal and parietal sites.

### Complementary analyses

Our complementary analyses on the binge drinker group showed the following.

*   There was no sex influence on the quantity of alcohol consumed at session 2 (*t*16 = 1.31, *p* = 0.21) or on the latency delays at session 2 for P1 (*t*16 = 0.76, *p* = 0.46), N2 (*t*16 = 0.48, *p* = 0.63) and P3b (*t*16 = 1.19, *p* = 0.25). These results suggest that sex did not influence alcohol consumption pattern nor the intensity of the latency impairment among binge drinkers.

*   There was no significant correlation between last alcohol consumption characteristics and behavioural or electrophysiological results at session 1 or 2 (*p* > 0.05 for every correlation).

*   We observed significant positive correlations between the delays for the 3 ERP components (P1–N2 *r* = 0.537, *p* = 0.021; P1–P3b *r* = 0.731, *p* = 0.001; N2–P3b *r* = 0.622, *p* = 0.007). The more important the latency impairment at the perceptual level (P1), the more important it will be at subsequent levels (N2 and P3b), which confirms among binge drinkers the observation made in earlier studies among alcoholic patients.

*   We observed significant positive correlations between mean alcohol intake and each ERP component (P1 *r* = 0.531, *p* = 0.022; N2 *r* = 0.593, *p* = 0.009; P3b *r* = 0.619, *p* = 0.007), suggesting that the latency impairment is proportionate to the intensity of binge drinking habits.

## Discussion

Knowledge about the cerebral effects of repeated excessive consumption of alcohol over short periods of time in adolescents and young adults is tremendously lacking. Our study compared young adult binge drinkers with perfectly matched paired controls before they started their drinking habits. Whereas the 2 groups did not differ on any psychological, behavioural or electrophysiological measures at the first session, after only 9 months the binge drinkers had a significantly delayed latency in the electrophysiological components indexing perceptive as well as decisional processes. It is noteworthy that this electrophysiological deficit was observed in the absence of any psychological or behavioural differences. Indeed, the only significant behavioural effect was a main effect of session (namely shorter reaction times during session 2 as compared with session 1) owing to greater familiarity with stimuli in session 2, which led to the classic test–retest effect. These ERP impairments concerned the latency of ERP components functionally associated with the early primary perceptual processing of information (P1), the specific perceptual processing of human voices (N2) and the decisional process associated with the closure of cognitive activities before starting the motor response (P3b). The deficits started with the early perceptual processes and lasted until the later decisional processes (as shown in Fig. 1). Importantly, complementary analyses suggested that the extent of these latency delays is proportionate to the severity of binge drinking behaviours. These latency abnormalities constitute the electrophysiological marker of a dysfunctional and slowed cerebral activity during the cognitive processing of complex stimuli. Various degenerative cerebral diseases and brain damage are known to cause abnormalities restricted to the latencies of ERP components. For instance, brain infarction slightly delays the P3b latency, without affecting its amplitude or scalp distribution.42 Anatomically, this P3b latency variability is mainly related to white matter connectivity,43 also known to be altered by alcohol consumption.11 This fits perfectly with the fact that only the latencies were affected in our study.

Behavioural deficits have already been described in patients with alcohol abuse but only after several years of binge drinking. Our results show that cerebral dysfunctions appear early and, importantly, before any detectable behavioural impairments. The use of modern electrophysiological and neuro-imaging techniques, therefore, appears fundamental to correctly evaluate the actual level of impairment produced by alcohol consumption. The presence of an ERP latency abnormality, which reflects a neurophysiologically delayed transmission between neural sources, is necessarily linked to minor neurocognitive restrictions that may not affect psychometric measures. The cognitive effects of binge drinking, which had so far been evaluated only on the basis of behavioural measures, could thus have been largely underestimated.

Finally, our results show that the ERP delays observed in binge drinkers are similar, even if less marked, to the neurophysiological deficits observed in chronic alcoholic individuals (as illustrated in Fig. 2).44,45 This supports the idea that binge drinking and chronic alcoholism may represent 2 stages of the same phenomenon.46 There is indeed a clear parallelism between the observed deficits. First, the perceptual deficit (namely for the P1 and N2 components) is absent in several other psychiatric disorders, including depression, anxiety or antisocial personality disorders. Second, the deficits in the binge drinkers were observed in the same complex emotional valence judgment task as that impaired in chronic alcoholic individuals.47 Third, as shown in the complementary analyses, the correlations between the deficits observed in successive ERP components, which had been described in earlier studies among alcoholic individuals,41 are also shown here among binge drinkers, confirming the parallelism in the deficits presented by these 2 populations. Our results show that even a short period of binge drinking is sufficient to lead to abnormal delayed ERP latencies, possibly representing a first step before extending to ERP amplitude values, as in chronic alcoholism. Our observations raise again the major health issue as to whether binge drinking is or is not an open door to chronic alcoholism. At the very least, our results highlight the need to study the patterns and correlates of binge drinking trajectories from early adolescence into adulthood. More broadly, showing that frequent binge drinking (i.e., more than 10 doses at least 2 times a week) rapidly leads to cerebral dysfunctions should lead public health officials to tackle this problem, notably by developing information programs and brief motivational interventions among college student drinkers.48

![Fig. 2](http://jpn.ca/https://www.jpn.ca/content/jpn/34/2/111/F2.medium.gif)

[Fig. 2](http://jpn.ca/content/34/2/111/F2)

Fig. 2 
Delayed and reduced P3b component recorded at parietal site (Pz) in adult chronic alcohol users in an emotional auditory task (adapted from Maurage et al.44).

### Limitations

Although based on a sound test–retest paradigm with a high control of potential bias, our results need to be generalized and extended. First, we only used stimuli from 1 sensory modality, namely audition. Future studies should thus generalize these results to other modalities, particularly vision. Moreover, our task was based on emotional judgments only, therefore we cannot rule out the possibility that the observed deficit was specific to emotional processing. Complementary work is thus needed to confirm that these alterations will also be observed using nonemotional stimuli. Finally, if electrophysiological data recorded here gave very useful insight into the deficits described at a temporal level (namely, a delay in the ERP components), nothing is known about the cerebral areas responsible for the alterations observed. The localization of the brain structures affected by binge drinking is thus a major priority for future studies.

## Acknowledgements

P.M. is a Research Assistant, F.J. a senior Research Assistant, and M.P. and P.P. are Research Associates at the National Fund for Scientific Research, Belgium.

## Footnotes

*   **Competing interests:** None declared.

*   **Contributors:** Drs. Maurage and Campanella designed the study. Dr. Maurage acquired the data, which all authors analyzed. Drs. Maurage, Pesenti and Campanella wrote the article, which Dr. Philippot reviewed. All authors gave final approval for publication.

*   Received February 29, 2008.
*   Revision received August 5, 2008.
*   Accepted September 18, 2008.

## References

1.  Zeigler DW, Wang CC, Yoast RA, et al. The neurocognitive effects of alcohol on adolescents and college students. Prev Med 2005;40: 23–32.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.ypmed.2004.04.044&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15530577&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000225455400004&link_type=ISI) 

2.  O’Connor PG, Schottenfeld RS. Patients with alcohol problems. N Engl J Med 1998;338:592–602.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1056/NEJM199802263380907&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=9475768&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000072175700007&link_type=ISI) 

3.  Miller JW, Naimi TS, Brewer RD, et al. Binge drinking and associated health risk behaviors among high school students. Pediatrics 2007;119:76–85.
    
    [Abstract/FREE Full Text](http://jpn.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6InBlZGlhdHJpY3MiO3M6NToicmVzaWQiO3M6ODoiMTE5LzEvNzYiO3M6NDoiYXRvbSI7czoxODoiL2pwbi8zNC8yLzExMS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

4.  Room R, Babor T, Rehm J. Alcohol and public health. Lancet 2005; 365:519–30.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/S0140-6736(05)17870-2&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15705462&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000226812500030&link_type=ISI) 

5.  Wechsler H, Davenport A, Dowdall G, et al. Health and behavioral consequences of binge drinking in college. JAMA 1994;272:1672–7.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1001/jama.1994.03520210056032&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=7966895&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=A1994PU75900026&link_type=ISI) 

6.  Viner RM, Taylor B. Adult outcomes of binge drinking in adolescence: findings from a UK national birth cohort. J Epidemiol Community Health 2007;61:902–7.
    
    [Abstract/FREE Full Text](http://jpn.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiamVjaCI7czo1OiJyZXNpZCI7czo5OiI2MS8xMC85MDIiO3M6NDoiYXRvbSI7czoxODoiL2pwbi8zNC8yLzExMS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

7.  Chanraud S, Martelli C, Delain F, et al. Brain morphometry and cognitive performance in detoxified alcohol-dependents with preserved psychosocial functioning. Neuropsychopharmacology 2007;32: 429–38.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1038/sj.npp.1301219&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17047671&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000243640500018&link_type=ISI) 

8.  Barron S, White A, Swartzwelder HS, et al. Adolescent vulnerabilities to chronic alcohol or nicotine exposure: findings from rodent models. Alcohol Clin Exp Res 2005;29:1720–5.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1097/01.alc.0000179220.79356.e5&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=16205372&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 

9.  White AM, Swartzwelder HS. Hippocampal function during adolescence: a unique target of ethanol effects. Ann N Y Acad Sci 2004; 1021:206–20.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1196/annals.1308.026&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15251891&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000222980100023&link_type=ISI) 

10. Meyerhoff DJ, Blumenfeld R, Truran D, et al. Effects of heavy drinking, binge drinking and family history of alcoholism on regional brain metabolites. Alcohol Clin Exp Res 2004;28:650–61.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1097/01.ALC.0000121805.12350.CA&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15100618&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000221068300018&link_type=ISI) 

11. Mechtcheriakov S, Brenneis C, Egger K, et al. A widespread distinct pattern of cerebral atrophy in patients with alcohol addiction revealed by voxel-based morphometry. J Neurol Neurosurg Psychiatry 2007;78:610–4.
    
    [Abstract/FREE Full Text](http://jpn.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiam5ucCI7czo1OiJyZXNpZCI7czo4OiI3OC82LzYxMCI7czo0OiJhdG9tIjtzOjE4OiIvanBuLzM0LzIvMTExLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

12. Giancola PR. Alcohol-related aggression during the college years: theories, risk factors and policy implications. J Stud Alcohol Suppl 2002; (14):129–39.
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=12022718&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 

13. Townshend JM, Duka T. Binge drinking, cognitive performance and mood in a population of young social drinkers. Alcohol Clin Exp Res 2005;29:317–25.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1097/01.ALC.0000156453.05028.F5&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15770105&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000227889200004&link_type=ISI) 

14. Zeigler DW, Wang CC, Yoast RA, et al. The neurocognitive effects of alcohol on adolescents and college students. Prev Med 2005;40: 23–32.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.ypmed.2004.04.044&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15530577&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000225455400004&link_type=ISI) 

15. Blume AW, Marlatt GA, Schmaling KB. Executive cognitive function and heavy drinking behavior among college students. Psychol Addict Behav 2000;14:299–302.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1037/0893-164X.14.3.299&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=10998956&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000089212600009&link_type=ISI) 

16. Hartley DE, Elsabagh S, File SE. Binge drinking and sex: effects on mood and cognitive function in healthy young volunteers. Pharmacol Biochem Behav 2004;78:611–9.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.pbb.2004.04.027&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15251270&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000222929000024&link_type=ISI) 

17. Ehlers CL, Phillips E, Finnerman G, et al. P3 components and adolescent binge drinking in Southwest California Indians. Neurotoxicol Teratol 2007;29:153–63.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.ntt.2006.11.013&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17196788&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 

18. Dorn JM, Hovey K, Williams BA, et al. Alcohol drinking pattern and non-fatal myocardial infarction in women. Addiction 2007;102:730–9.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1111/j.1360-0443.2007.01765.x&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17506150&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000245811300011&link_type=ISI) 

19. Mukamal KJ, Conigrave KM, Mittleman MA, et al. Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men. N Engl J Med 2003;348:109–18.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1056/NEJMoa022095&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=12519921&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000180263900003&link_type=ISI) 

20. Stampfer MJ, Kang JH, Chen J, et al. Effects of moderate alcohol consumption on cognitive function in women. N Engl J Med 2005; 352:245–53.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1056/NEJMoa041152&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15659724&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000226370500005&link_type=ISI) 

21. Hill SY, Steinhauer S, Locke J. Event-related potentials in alcoholic men, their high-risk male relatives, and low-risk male controls. Alcohol Clin Exp Res 1995;19:567–76.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1111/j.1530-0277.1995.tb01550.x&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=7573776&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=A1995RE22800007&link_type=ISI) 

22. Hill SY, Yuan H, Locke J. Path analysis of P300 amplitude of individuals from families at high and low risk for developing alcoholism. Biol Psychiatry 1999;45:346–59.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/S0006-3223(97)00525-8&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=10023513&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000078518800017&link_type=ISI) 

23. Franken IH, Nijs IM, Muris P, et al. Alcohol selectively reduces brain activity during the affective processing of negative information. Alcohol Clin Exp Res 2007;31:919–27.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1111/j.1530-0277.2007.00424.x&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17433007&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 

24. Krull KR, Smith LT, Parsons OA. Simple reaction time event-related potentials: effects of alcohol and diazepam. Prog Neuropsychopharmacol Biol Psychiatry 1994;18:1247–60.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/0278-5846(94)90091-4&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=7863015&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 

25. Nichols JM, Martin F. The effect of heavy social drinking on recall and event-related potentials. J Stud Alcohol 1996;57:125–35.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.15288/jsa.1996.57.125&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=8683961&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 

26. Bijl S, de Bruin EA, Böcker KE, et al. Effects of chronic drinking on verb generation: An event related potential study. Hum Psychopharmacol 2007;22:157–66.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1002/hup.835&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17397096&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 

27. Obernier JA, White AM, Swartzwelder HS, et al. Cognitive deficits and CNS damage after a 4-day binge ethanol exposure in rats. Pharmacol Biochem Behav 2002;72:521–32.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/S0091-3057(02)00715-3&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=12175448&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000176454400004&link_type=ISI) 

28. Pascual M, Blanco AM, Cauli O, et al. Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur J Neurosci 2007;25:541–50.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1111/j.1460-9568.2006.05298.x&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17284196&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000244783000024&link_type=ISI) 

29. Rugg MD, Coles MGH. Electrophysiology of mind. Oxford: Oxford University Press; 1995.
    
    

30. Porjesz B, Begleiter H. Alcoholism and human electrophysiology. Alcohol Res Health 2003;27:153–60.
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15303626&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000223800500005&link_type=ISI) 

31. Maurage P, Philippot P, Verbanck P, et al. Is disturbed P300 in alcoholism an effect of early visual deficits (P100, N170)? An odd-ball paradigm. Clin Neurophysiol 2007;118:633–44.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.clinph.2006.11.007&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17208045&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000244772600015&link_type=ISI) 

32. Spielberger DC, Gorsuch RL, Lushene R, et al. Manual for the state-trait anxiety inventory. Palo Alto (CA): Consulting Psychology Press; 1983.
    
    

33. Beck AT, Steer RA. Beck depression inventory manual. San Antonio (TX): Psychological Corporation; 1987.
    
    

34. Horowitz LM, Rosenberg SE, Baer BA, et al. Inventory of interpersonal problems: psychometric properties and clinical applications. J Consult Clin Psychol 1988;56:885–92.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1037/0022-006X.56.6.885&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=3204198&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=A1988R143600016&link_type=ISI) 

35. Bagby RM, Taylor GJ, Parker JD. The Twenty-item Toronto Alexithymia Scale–II. Convergent discriminant and concurrent validity. J Psychosom Res 1994;38:33–40.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/0022-3999(94)90006-X&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=8126688&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=A1994MQ14200004&link_type=ISI) 

36. Townshend JM, Duka T. Patterns of alcohol drinking in a population of young social drinkers: a comparison of questionnaire and diary measures. Alcohol Alcohol 2002;37:187–92.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1093/alcalc/37.2.187&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=11912076&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000174918300012&link_type=ISI) 

37. Maurage P, Joassin F, Philippot P, et al. A validated battery of vocal emotional expressions. Neuropsychological Trends 2007;2:63–74.
    
    

38. Bentin S, Allison T, Puce A, et al. Electrophysiological studies of face perception in humans. J Cogn Neurosci 1996;8:551–65.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1162/jocn.1996.8.6.551&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=20740065&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=A1996WF04200007&link_type=ISI) 

39. Joassin F, Maurage P, Bruyer R, et al. When audition alters vision: an event-related potential study of the cross-modal interactions between faces and voices. Neurosci Lett 2004;369:132–7.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.neulet.2004.07.067&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15450682&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000224438100009&link_type=ISI) 

40. Polich J. Clinical application of the P300 event-related brain potential. Phys Med Rehabil Clin N Am 2004;15:133–61.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/S1047-9651(03)00109-8&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15029903&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 

41. Maurage P, Campanella S, Philippot P, et al. Electrophysiological correlates of the disrupted processing of anger in alcoholism. Int J Psychophysiol. 2008;70:50–62.
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=18577404&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 

42. Korpelainen JT, Kauhanen ML, Tolonen U, et al. Auditory P300 event related potential in minor ischemic stroke. Acta Neurol Scand 2000;101:202–8.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1034/j.1600-0404.2000.101003202.x&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=10705944&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000085336300010&link_type=ISI) 

43. Cardenas VA, Chao LL, Blumenfeld R, et al. Using automated morphometry to detect associations between ERP latency and structural brain MRI in normal adults. Hum Brain Mapp 2005; 25:317–27.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1002/hbm.20103&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15834860&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000230016800004&link_type=ISI) 

44. Maurage P, Philippot P, Joassin F, et al. The auditory-visual integration of anger stimuli is impaired in alcoholism: an ERP study. J Psychiatry Neurosci 2008;33:111–22.
    
    

45. Kathmann N, Soyka M, Bickel R, et al. ERP changes in alcoholics with and without alcohol psychosis. Biol Psychiatry 1996;39:873–81.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/0006-3223(95)00289-8&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=9172708&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=A1996UJ09700007&link_type=ISI) 

46. Enoch MA. Genetic and environmental influences on the development of alcoholism: resilience vs. risk. Ann N Y Acad Sci 2006; 1094:193–201.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1196/annals.1376.019&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17347351&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000245807000015&link_type=ISI) 

47. Uekermann J, Daum I, Schlebusch P, et al. Processing of affective stimuli in alcoholism. Cortex 2005;41:189–94.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/S0010-9452(08)70893-1&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15714901&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000226935100011&link_type=ISI) 

48. Pearson H. The demon drink. Nature 2004;428:598–600.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1038/428598a&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15071571&link_type=MED&atom=%2Fjpn%2F34%2F2%2F111.atom)