The contribution of executive functions deficits to impaired episodic memory in individuals with alcoholism

Psychiatry Research 198 (2012) 116–122

Contents lists available at SciVerse ScienceDirect

Psychiatry Research journal homepage: www.elsevier.com/locate/psychres

The contribution of executive functions deficits to impaired episodic memory in individuals with alcoholism Xavier Noël a,⁎, Martial Van der Linden b, Damien Brevers c, Salvatore Campanella a, Catherine Hanak d, Charles Kornreich d, Paul Verbanck d a Belgium Fund for Scientific Research (F.R.S.-FNRS), Psychological Medicine Laboratory, Université Libre de Bruxelles (U.L.B), Brugmann Campus, 4 place Van Gehuchten, 1020 Brussels, Belgium b Department of Cognitive Psychopathology, University of Geneva, Switzerland c Belgium Fund for Scientific Research (F.R.S.-FNRS), Psychological Medicine Laboratory, Université Libre de Bruxelles (U.L.B), Belgium d Brugmann Universitary Hospital, Department of Psychiatry, Université Libre de Bruxelles (U.L.B), Belgium

a r t i c l e

i n f o

Article history: Received 26 September 2010 Received in revised form 9 October 2011 Accepted 11 October 2011 Keywords: Alcoholism Executive functions Episodic memory Relapse prevention

a b s t r a c t Individuals with alcoholism commonly exhibit impaired performance on episodic memory tasks. However, the contribution of their impaired executive functioning to poor episodic memory remains to be clarified. Thirty-six recently detoxified and sober asymptomatic alcoholic men and 36 matched non-alcoholic participants were tested for processing speed, prepotent response inhibition, mental flexibility, coordination of dual-task and a verbal episodic memory task. Compared with non-alcoholic individuals, the alcoholic patients showed impaired executive functions combined with below normal performance on both free and delayed recall. In contrast, processing speed, cued recall and recognition were preserved. Regression analyses revealed that 47% of alcoholics' episodic memory's free recall performance was predicted by mental flexibility and that 49% of their delayed recall performance was predicted by mental flexibility, manipulation of dualtask and prepotent response inhibition. Regarding participants' executive predictors of episodic memory performance, the slopes of β coefficients were significantly different between the two groups, with alcoholics requiring more their executive system than non-alcoholics. Once detoxified, alcoholic patients showed episodic memory deficits mainly characterized by impaired effortful (executive) processes. Compared with controls, patients used effortful learning strategies, which are nonetheless less efficient. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Alcohol dependence, characterized by compulsive preoccupation with alcohol consumption despite the devastating consequences, which affects social and occupational functioning (e.g. in the area of employment, family, education and health) (American Psychiatric Association, 1994), is a widespread psychiatric disorder with a reported prevalence of approximately 8–10% in many Western countries (World Health Organization, 2004). In agreement with other addictive disorders, individuals with alcoholism are very vulnerable to relapse after cessation of drinking (Anton et al., 2006). Long-term abuse of alcohol, in association with nutritional deficits (thiamin deficiency), can lead to classical neurological illnesses, i.e. Wernicke-Korsakoff syndrome (for a review, see Kopelman, 1995). However, during the last three decades, evidence for brain abnormalities in ’non-Korsakoff’ chronic alcoholics has been presented which includes electrophysiological (for a review, see Campanella et al., 2009), morphological and functional metabolism (for

⁎ Corresponding author. Tel.: + 32 24772705. E-mail address: [email protected] (X. Noël). 0165-1781/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2011.10.007

a review, see Sullivan and Pfefferbaum, 2005) as well as a wide range of neuropsychological deficits (for a review, see Bates et al., 2002). Typical cognitive deficits which charaterise a state of alcohol dependence include impaired episodic memory (e.g., Glenn and Parsons, 1992; Schwartz et al., 2002; D'Argembeau et al., 2006; Pitel et al., 2007a) and executive functions (e.g., Joyce and Robbins, 1991; Tivis et al., 1995; Moselhy et al., 2001; Brokate et al., 2003) which are likely to be predominant. By definition, episodic memory (EM) refers to a neurocognitive system that enables conscious recollection of personal happenings and events from one's personal past as well as the mental projection of anticipated events into one's subjective future (Wheeler et al., 1997). Importantly, executive functioning is of the greatest importance in EM functioning (Shallice et al., 1994; Tulving et al., 1994; Fletcher et al., 1995; Davidson et al., 2006), in that it facilitates both encoding and retrieval in this memory system (Kapur et al., 1994), maintaining a fixed sequence, and integrating diverse types of information (factual, temporal, spatial) into a meaningful representation (Baddeley, 2000). In the broadest sense, executive function is an umbrella term for all processes recruited for managing and controlling cognition in situations where the routine selection of actions is unsatisfactory and is involved in the genesis of plans and willed actions (Norman and Shallice, 1986;

X. Noël et al. / Psychiatry Research 198 (2012) 116–122

Miyake et al., 2000). As explained by Moscovitch and Winocur (1992), executive functions are involved in the conscious and strategic aspects of memory performance which may operate at both encoding and retrieval phases; this can be considered as “working-with-memory processes”, which improve memory functioning through the use of efficient strategies. Our hypothesis therefore relates to the fact that a decline in executive functioning, which is a hallmark of alcoholism, is involved in frequently reported impairments of episodic memory (EM). In individuals with alcoholism (and abstinent for a period ranging from several days (Pitel et al., 2007), to several months (Munro et al., 2000) and even years (Brandt et al., 1983)), EM disorders have been identified with the help of psychometric tasks such as the Wechsler Memory Scale (e.g., Glenn and Parsons, 1992; Fama et al., 2004), the learning of face-name associations (e.g., Beatty et al., 1995; Tivis and Parsons, 1995), lists of words (e.g., Brokate et al., 2003; Hildebrandt et al., 2004), and even addresses and stories (Fama et al., 2009). However, the underlying processes for this EM impairment and related brain structures remain unclear (see the critical view by Pitel et al., 2007a). Some findings suggest that effortful retrieval and encoding processes are impaired in chronic alcoholism (Weingartner et al., 1996; Schwartz et al., 2002; Pitel et al., 2007a; Chanraudet al., 2009). For example, memory tasks, which measure accuracy in judging the source of what is remembered and require reflective processes (i.e., self-monitoring performance and suppress cognitive responses), showed that a subsample of alcoholics made errors in acurately identifying the source of correctly remembered knowledge (Weingartner et al., 1996). Such findings suggest that cognitive processes underlying alcoholics' episodic memory disorders are worthy of further clarification. In addition to EM abnormalities in non-amnesic alcoholics who are recently detoxified, disturbances in the executive system are one of the most consistent and predominant impairments in sober alcoholics (e.g., Joyce and Robbins, 1991; Dao-Castellana et al., 1998; Noël et al., 2001b; Brokate et al., 2003; Oscar-Berman et al., 2004). Indeed, such patients are generally less efficient than comparison subjects controls in carrying out two tasks simultaneously; for example, to inhibit prepotent response, to detect rules, to shift between multiple sets of responses and to plan and to generate concepts. One interesting study showed that alcoholics had reduced mental flexibility, when assessed by verbal fluency tasks, which accounts for approximately 40% of diminished free recall performance (Pitel et al., 2007a). However, some issues remained to be addressed. Firstly, the impact of a general slowing down of processing speed which was not assessed in this study. Secondly, patients were tested only at the start of alcohol detoxification whereas the neuropsychological profile of alcoholic subjects receiving treatment evolves rapidly during the first 3 weeks (e.g., Carlen and Wilkinson, 1983; Bartsch et al., 2007). Thirdly, this study (Pitel et al., 2007a) did not include important aspects of executive functioning that may impact on effortful aspects of both encoding and retrieval of episodic memory. This includes suppression (inhibition) of pre-potent response or the capacity to realize two tasks simultaneously (Repovs and Baddeley, 2006; Clarys et al., 2009). Finally, in the present study, we tested inpatient alcoholic subjects who had been sober for 3 week on average and 1 week after stopping all detoxification medication. This period corresponds to the moment when patients are usually discharged from the alcohol detoxification program, which increases the clinical interest of this article. We hypothesized that poor mental flexibility, prepotent response inhibition and difficulty in the coordination of dual tasks would be responsible for poor verbal recollection in sober alcoholics’ episodic memory. 2. Method 2.1. Participants 2.1.1. Alcoholic patients Thirty-six male alcoholic patients were recruited for this study from the Alcohol Detoxification Program of the Brugmann Psychiatric hospital at Brussels. They all

117

received a complete medical, neurological, and psychiatric examination at the time of selection. Exclusion criteria were, a) other current DSM-IV (American Psychiatric Association, 1994) diagnoses for axis I than alcohol dependence, b) a history of significant medical illness, c) head injury which resulted in loss of consciousness for more than 30 min that would have affected the central nervous system, and d) prescribed medication that could influence cognition or overt cognitive dysfunction as assessed by the Mini-Mental State Examination (MMSE b 24, Folstein et al., 1975). To increase the reliability of anamnestic information, the patient and their family were interrogated separately. All alcohol abusers had consumed at least 560 g of alcohol (e.g., ±8 drinks per day) for at least 2 of the 3 years preceding entry into the study. The detoxification regime consisted of B-vitamins and various doses of sedative medication (Diazepam). After a complete description of the study to the subjects, written informed consent in accordance with the declaration of Helsinki was obtained. Current clinical status was rated on the self-administrated Montgomery and Åsberg depression rating scale (Montgomery and Asberg, 1979) and the Hamilton Anxiety Rating Scale (Hamilton, 1959). Clinical and demographic measures are presented in Table 1. 2.1.2. Healthy participants (CONT) The healthy individuals comprised 36 male volunteers, recruited by word of mouth. They were matched for gender, education and age. All the subjects provided written informed consent and were not paid for their participation. All included participants were drug-free (self-report and urine drug screening), had no Axis I diagnoses (American Psychiatric Association, 1994), and, on the basis of their history and physical examination, they were judged to be medically healthy. They were also excluded if there were histories of excessive substance use (e.g., an average of three drinks or more per day over the last year or more than occasional drug use). They were advised to avoid both alcohol and other substance abuse drugs in the 24 h prior to testing as well as narcotic pain medication for the 5 days prior to testing. All subjects underwent an alcohol breathalyzer test on arrival at the laboratory. 2.2. Cognitive evaluation 2.2.1. Processing speed In order to measure processing speed, the time to complete the part A of the Trail Making test, the color-naming and the reading parts of the Stroop test were considered. 2.2.1.1. Episodic memory. California Verbal Learning Test (CVLT; Delis, 1987; Delis et al., 1988; French adaptation, unpublished data). The CVLT consists of five learning trials of a 16-word target list comprising four words from four different semantic categories. The list is read aloud by the examiner at the rate of one word per second. After each trial, the examinee was instructed to freely recall as many words as possible, in any order. A similarly constructed interference list was then presented for one learning trial, followed by ‘short-term’ free and cued recall of the target list. After a 20-min interval filled with non-verbal tasks, ‘long-term’ free recall, cued recall, and recognition were assessed. The recognition condition used a yes/no paradigm, with 28 distractors mixed in with the 16 targets. The CVLT yields measures of recall, recognition, learning characteristics, and intrusion and perseveration errors. The recall and recognition measures used in this study were (i) free recall on the immediate (as well as the number of intrusions) and long-term conditions, (ii) total number errors (intrusions plus perseveration) and (iii) the number of correct hits on recognition (Table 2). 2.2.2. Working memory, coordination of storage and manipulation of information Alpha-span task (Belleville et al., 1998). This task investigated the ability to manipulate information stored in working memory by comparing the recall of information in serial order (implicating mainly a storage component) and in alphabetical order (implicating storage and manipulation of information). Firstly, a classical word-span task was administrated to assess the span level of each subject. After the span measurement, the subject

Table 1 Mean (SD) scores on demographic and clinical variables of alcoholics and healthy participants.

Age Years of heavy drinking Education (total years) TLIE (kg/kg)a Number of drinks per day Number of prior detoxification treatments Number of abstinence days MADRSb score Anxietyc

Alcoholics

Healthy participants

(n = 36)

(n = 36)

43.3 (11.1) 14.4 (12.0) 12.0 (2.9) 27.2 (5.2) 17.2 (9.3) 2.4 (1.8) 21.8 (0.3) 11.0(6.3) 12.3 (6.2)

40.9 (10.9) – 11.8 (3.6) 2.0 (0.7)*** 1.9 (1.1)*** 3.7 (1.5)*** 3.1 (1.9)***

Significant difference, * p b 0.05, **p b 0.01, ***p b 0.001.sa. a TLIE, total lifetime intake of ethanol. b MontgomeryÅsberg Depression Rating Scale. c Hamilton Anxiety Rating Scale.

118

X. Noël et al. / Psychiatry Research 198 (2012) 116–122

Table 2 Mean (SD) score on the California verbal learning test in alcoholic and healthy participants.

Mean learning in 1–5 trials free recall Errors (intrusions + perseverations), 1–5 trials Free recall after presentation of the interference list Cued recall Differed recall Differed cued recall Trials 5 – long-term recall Recognition

Alcoholics

Healhy participants

(n = 36)

(n = 36)

11.4 (2.5) 6.8 (2.5) 11.2 (4.5) 13.5 (2.4) 12.5 (3.8) 13.5 (2.8) 0.89 (0.3) 15.6 (1.1)

12.1 (1.0) * 3.8 (1.3)*** 13.5 (1.2)** 14.0 (1.0) 14.1 (0.9)* 14.8 (0.9)** 0.67 (0.2) 15.8 (0.4)

Significant difference, * p b 0.05, **p b 0.01.

was asked to repeat word sequences in two different conditions: direct recall and alphabetical recall. In both conditions, the number of words to be recalled corresponded to the subject's span minus one item. In the direct condition, the subject performed an immediate serial recall of 10 sequences of words. The subject was then asked to recall 10 sequences of words in alphabetical order. The subject's performance was assessed by comparing the performance on alphabetical recall to that of serial recall. Moreover, a manipulation score was also derived for each individual subject as follows: ((score in direct condition − score in alphabetical condition)/direct condition)⁎ 100. This represents the performance reduction experienced by each subject when performing the alphabetical recall relative to the direct recall. 2.2.3. Executive functions tasks 2.2.3.1. Response inhibition tasks. Hayling Inhibition task (Burgess and Shallice, 1996) and Stroop test (Stroop, 1935). The Hayling task assesses the capacity to suppress (inhibit) a habitual response and was initially divided into two sections to examine both initiation and inhibition processes. The Hayling task consists of sentences in which the final words are omitted, but there is a particularly high probability of one specific response. The task consisted of two sections (A and B), each containing 15 sentences. In section A (initiation), sentences were read aloud to the subject who had to complete the sentence with the missing word. In section B (response suppression), sentences were read aloud to the subject who then had to complete the sentence which did not contain the expected word but with a word unrelated to the sentence. If at any time during this stage of the test, the subject gave a sentence completion rather than an unrelated word, he or she were told that the word was too related to the sentence, and the task instructions were repeated. If a subject did not produce a word within 30 s, that trial was terminated and a response latency of 30 s was recorded. Different measures of response suppression abilities were used in the analysis. Firstly, there were responses that were sensible completions of the sentence, thus clearly violating the task instructions (3 penalty points). For example, in the sentence “The captain wanted to stay with the sinking….”, the response “boat” would yield a score of 3. Secondly, there are responses that are semantically connected to the sentence in some way (1 penalty point). Thirdly, there were those responses that were unrelated to the sentence, as required by the task instructions (0 penalty point). The Stroop task is composed of four different cards shown in a fixed sequence. The first task, named ‘reading condition’, is to read the color-words printed in black as quickly as possible. The second task, named ‘denomination condition’, consists of the color-naming of color patches. The third task, named ‘interference condition’ is the original interference paradigm: color-naming of color words printed in an incongruent color (e.g., ‘red’ printed in blue) while ignoring the word content. The dependent variables of this task were the interference index: time in seconds needed to read the third (interference) card minus the time needed to read the second card, divided by the sum of these two realization times.

The TMT requires the participant to join together with a penciled line; firstly the letters of the alphabet distributed randomly across a sheet of paper (Trail A) and, secondly, the letters of the alphabet and the numbers 1 to 20 alternately and in correct ascending order (Trail B). The measure calculated was the time need to complete the Trail A minus the time needed to complete Trail B. On the flexibility and creativity test, the subjects were instructed to consider some common objects. Each object had a common use, which the investigator stated. The subject's task was to orally generate less common uses for the object or its part. For example, a newspaper is commonly used for reading, but alternatively it can be used to start a fire, to wrap garbage, to swat flies, etc. The measure calculated in the present article was the total number of correct infrequent uses of three objects. 2.3. Procedure Neuropsychological examinations were performed on each patient and each control. Patients were evaluated after they had abstained from alcohol for a minimum period of 21 days, which was at least 1 week after a standard detoxification with diazepam and vitamin treatment. The examination took place in a quiet and dedicated area near the patient's hospital unit. Testing began only when subjects were completely willing to co-operate. All tests were administered over a 2-day period by clinical neuropsychologists specifically trained in, and familiar with, the tests used. 2.4. Data analysis Differences on demographic and clinical data between alcoholics and healthy controls were determined using t-tests. Cognitive performance univariate analysis of variance (ANOVA), repeated-measures ANOVAs, and post-hoc analyses (Bonferroni-corrected pairwise comparisons) with a level of 0.05 or less. In order to find out whether executive dysfunction could explain episodic memory impairments in alcoholism, we initially carried out correlational analyses between all episodic memory measures and executive scores in both alcoholic and control groups. Then, based on our hypotheses of a relationship between executive functioning and episodic memory, we carried out stepwise regression analyses in the alcoholic group with (i) measures of prepotent response inhibition (i.e., the penalty score of the Hayling task, the interference score and the number of inhibition errors made on the Stroop task), (ii) mental flexibility (i.e., the flexibility index and the number of flexibility errors made on the Stroop task, the number generated on the alternated verbal fluency task, the TMT score and the score of the fexibility and creativity test) and (iii) coordination of dual tasks (i.e., the manipulation score of the alphaspan task) as predictor and the mean number of words on free and on delayed recall as dependent measures. Finally, we compared the β coefficients of the two groups to estimate whether alcoholic patients invoked the same learning strategies as controls.

3. Results 3.1. Demographic and clinical data The groups were similar with respect to age and education, t(70) = 1.0, p = 0.32; t(70)= 0.19, p = 0.43, respectively. Alcoholics consumed a higher number of drinks per day and had a higher total lifetime intake of ethanol than controls, t(70) = 32.1, p b 0.001; t(70)= 32.46, p b 0.001, respectively. They were also more depressed, t(70) = 2.35, p b 0.001, and more anxious, t(70) = 8.32, p b 0.001. When we carried out analyses of covariance (ANCOVAs) with depression and anxiety scores as covariates, we found no effects of any of these variables when the alcoholic and control groups were compared. Subsequently all other analyses utilised ANOVAs. 3.2. Cognitive evaluation

2.2.3.2. Flexibility tasks. Flexibility condition of the Stroop task; Phonologic, semantic and alternated verbal fluency task (VF; Perret, 1974; Milner, 1968); Trail Making Test (TMT; Reitan, 1955); Flexibility and creativity test (Grattan and Eslinger, 1989; Eslinger and Grattan, 1993). On the ‘flexibility condition’ of the Stroop task, the subject was instructed to name the color of coloured-words printed in an incongruent color and to read the word content each time the word is underlined. The dependent variable of this task was the flexibility indices calculated as followed: time in seconds needed to read flexibility card minus the time needed to read the second card, divided by the sum of these two realization times. In the VF, participants were given 120 s to generate aloud a list of words beginning with a target letter (phonetic condition) but excluding proper names and variants of the same word. Then, we proceeded in the same way with a semantic category (e.g., ‘clothes name’; categorical condition) and with two categories alternatively (e.g., ‘clothes name’ and ‘animal name’; alternated condition). The number of words generated (without errors and repetitions) was recorded for each condition (phonologic, semantic and alternated). This task requires the ability to initiate and sustain word production while maintaining an organized retrieval strategy, as well as inhibitory and shifting attentional mechanisms.

3.2.1. Processing speed The comparison between each group (alcoholic and control) on the times required to complete the TMT-part 1 and the color words written in black (sub-test of the Stroop test) showed no significant difference, F(1,70) = 3.2, p = 0.08; F(1,70) = 3.3, p = 0.08, respectively. When we carried out ANCOVAs using processing speed, there were no effects of any of these variables between the alcoholic and control groups; therefore ANOVAs were performed. 3.2.2. Episodic memory California Verbal Learning Test (see Table 3). A two way 2 (group) ⁎ 5 (list A learning trials) ANOVA on the number of correct words recalled, revealed a main effect of learning, F(4,280)= 244.9, p b 0.001, and of

X. Noël et al. / Psychiatry Research 198 (2012) 116–122 Table 3 Mean (SD) scores on executive tests for alcoholic and healthy participants.

Hayling test Section B time (s) minus Section A time (s) Penalty score Stroop test Interference index Flexibility index Number of errors Verbal fluency tasks Phonologic Semantic Alternated Trail-making test Time (part A–part B) Flexibility task Total score

Alcoholics

Healthy participants

(n = 36)

(n = 36)

67.5 (52.4)

33.8 (11.5)***

8.8 (3.6)

1.3 (0.9)***

0.23 (0.1) 0.34 (0.02) 6.9 (3.1)

0.30 (0.04)** 0.27 (0.02)*** 1.25 (2.2)***

28.1 (1.8) 22.5 (1.1) 16.8 (0.8)

27.7 (0.7) 24.4 (0.7) 23.1 (0.7)***

65.3 (68.6)

32.3 (8.9)**

16.3 (4.8)

18.8 (4.6)*

Significant difference, * p b 0.05, **p b 0.01, ***p b 0.001.

group, F(1,70) = 4.2, p = 0.04. The interaction between these two factors was not significant, F(4,280) = 1.20, p = 0.30. Alcoholics were less efficient in recalling words on both the short-term, F(1,70) =9.2, p =0.003, after presentation of the interference list, the long-delay recall, F(1,70) =6.0, p= 0.02, and on the long-delay cued recall, F(1,70) =7.1, p =0.009. However, the two groups performed similarly on the shortcued recall, F(1,70)= 1.5, p= 0.23, and on recognition, F(1,70) =1.4, p =0.25. Finally, alcoholics made more consistent errors in free recall, F(1,70) =23.0, p b 0.001. 3.2.3. Working memory On the Alpha-span task, the word spans in the alcoholics and the controls were similar (alcoholics: mean = 4.8, SD - 0.92; mean = 4.9, SD = 0.61), was similar, F(1,70) = 0.2, p = 0.64. The scores for serial and alphabetical recall (M = 5.3, SD = 2.1 for the ALC group; M = 8.9, SD = 1.5 for the control group) were then separately analyzed by a two-way 2 (group) ⁎ 2 (condition) ANOVA. The analysis showed a main effect of group, F(1,58) = 45.6, p b 0.001, and of condition, F(1,70) = 100.5, p b 0.001. A significant interaction between group and type of recall was also identified, F(1,70) = 61.6, p b 0.001, with the alcoholic patients showing a more significant decrease in performance from direct to alphabetical recall than controls, despite a similar performance in direct recall. In addition, the alcoholic patients (M = 44.2, SD= 24.4) had a higher manipulation score (i.e., the percentage of loss between serial and alphabetical recall) than controls (M = 5.2, SD= 1 .8), F(1,70) = 62.8, p b 0.001. 3.2.4. Executive functions (see Table 3) 3.2.4.1. Response inhibition tasks 3.2.4.1.1. Hayling task. The two-way 2 (group) ⁎ 2 (initiation, inhibition sections) ANOVA showed a significant group effect, F(1,70) = 12.62, p = 0.001, a main effect of condition, F(1,70) = 116.1, p b 0.001. In addition, the interaction between these two factors reached significance, F(1,70) = 14.2, p b 0.001, with alcoholics being slower only when expected words had to be suppressed. With respect to the number of response penalties, alcoholics gave more expected and related words on the inhibition part than controls, F(1,70) = 142, p b 0.001. 3.2.4.1.2. Stroop test. The interference index was calculated, as well as the sum of errors made by participants. Group comparisons revealed that alcoholics were not slower on inference condition, F(1,70) = 0.2, p = 0.67, but alcoholics made more errors than controls, F(1,70) = 73.1, p b 0.001.

119

3.2.4.2. Flexibility tasks 3.2.4.2.1. Stroop test. Group comparisons revealed that alcoholics were slower than controls, F(1,70) = 24.1, p b 0.001, and made more errors, F(1,70) = 73.1, p b 0.001. 3.2.4.2.2. Verbal fluency test. A two-way 2 (group) ⁎ 3 (phonologic, semantic and alternated conditions) ANOVA was computed. This analysis revealed a main effect of group, F(1,70) = 5.5, p = 0.02, and of condition, F(2,140) = 43.6, p b 0.001. The interaction between these two factors was significant, F(2,140) = 8.0, p = 0.001. Post-hoc comparisons revealed that alcoholics produced fewer words than controls only in the alternated fluency condition (p b 0.001). 3.2.4.2.3. Trail Making Test. A two-way 2 (group) ⁎ 2 (time part 1 and part 2) ANOVA showed a main effect of condition, F(1,70) = 65.2, p b 0.001, of group, F(1,70) = 10.2, p = 0.002, and a significant interaction between these two factors, F(1,58) = 8.2; p = 0.006, alcoholics being slower than controls only in trail B. 3.2.4.2.4. Flexibility test. Alcohlics generated fewer unusual utilizations of common objects than controls, F(1,70)=5.3, p=0.02.

3.3. Relationships between episodic memory and executive functions After Bonferroni's correction, the only significant correlations between episodic memory measures and executive scores were identified in controls between mean 1–5 trials of free recall on the CVLT and the manipulation score of the alpha-span task r(36) = − 0.52, p = 0.001. In alcoholics, mean 1–5 trials of free recall on the CVLT correlated with (1) the flexibility score of the TMT (time part 1 minus time part 2), r(36) = −0.70, p b 0.001, (2) the inhibition score of the Hayling task, r(36) = − 0.45, p = 0.006. The 20-min delayed recall on the CVLT was correlated with the flexibility score of the TMT, r(36) = −0.58, p b 0.001, with the inhibition score of the Hayling task, r(36) = −0.45, p = 0.006 and with the manipulation score of the alpha-span task, r(36) = −0.59, p b 0.001. In the alcoholic group (see Table 4), the regression analysis showed that the flexibility score of the TMT (time part 1 minus time part 2) was predictive of mean 1–5 trials of free recall on the CVLT. This flexibility score together with the manipulation score of the alpha-span task and the inhibition score of the Hayling task were predictive of 20-min delayed recall on the CVLT. In the non-alcoholic group, the alpha-span task was predictive of mean 1–5 trials of free recall on the CVLT. The slopes (β coefficient) were significantly different between the two groups regarding participants’ executive predictors of episodic memory performance (see Table 5). Table 4 Stepwise regressions accounting for episodic memory impairments in alcoholic and control group assessed by the California Verbal Learning Test (CVLT).

Control group Dependent measure Free recall (mean 1–5 trials) 20-min delayed recall Alcoholic group Free recall (mean 1–5 trials) 20-min delayed recall a b c

Predictor

R2 change

β coefficient

First: Alpha-spana

0.26

− 0.52

0.001

First : Trial making testb

0.47

− 0.69

b0.001

First: Trail making testb Second: Alpha-spana Third: Hayling testc

0.28 0.12 0.09

− 0.53 − 0.35 − 0.34

0.001 0.01 0.02

p value

None

Percentage of performance loss between alphabetical and serial order. Time part A minus time part B. Total penalty score.

120

X. Noël et al. / Psychiatry Research 198 (2012) 116–122

Table 5 Best predictors of the verbal episodic memory (free recall 1–5 trials and 20-min delayed recall) in the alcoholic and control Groups. β coefficient

Independent variable Free recall 1–5 trials Alpha-span Trait-making testa Independent variable 20-min delayed Recall Trail-making testb

Healthy participants

Alcoholics

Group differences between β coefficients

− 0.52* − 0.17

− 0.41 − 0.69*

NS p b 0.01

− 0.39

− 0.53*

p b 0.05

*Significant best predictor of episodic memory measure (see independent variable) within the group. a Percentage of performance loss between alphabetical and serial order. b Time part A minus time part B.

4. Discussion The aim of this study was to test the hypothesis that poor mental flexibility, prepotent response inhibition and coordination of dual responses for poor verbal recollection in sober alcoholics’ verbal episodic memory (EM). The results indicated that alcoholic patients perform poorly on several EM and EF tasks, which cannot be fully explained by a general slowing down of processing speed. Effortful/executive encoding and retrieval are main components of episodic memory impairment in alcoholics, with response inhibition and coordination of dual-tasks accounting for a non-negligible portion of these episodic disorders. Our data are in agreement with the findings of the majority of previous studies, which showed impaired episodic memory (EM) in sober alcoholics (e.g., Joyce and Robbins, 1991; Knight and Longmore, 1994; Nixon et al., 1998; Goldstein et al., 2004; Pitel et al., 2007a). Interestingly, patients improved their performance in both cued recall and recognition testing conditions, which would indicate than alcoholics are less efficient in actively retrieving information that is stored in episodic memory (Weingartner et al., 1996). Indeed, cued recall and recognition performance are generally less dependent on strategic retrieval operations, (the memory cues being presented to the subject), and do have to be actively searched for. It should be noted that active retrieval processes have been considered as a function of the EF (Shallice et al., 1994; Tulving et al., 1994; Fletcher et al., 1995; Davidson et al., 2006), with the prefrontal cortex playing a key role (for a review, see Fletcher and Henson, 2001). It is likely that alcoholics, like frontal lobe patients (Mayes et al., 1997), make more intrusion and perseveration errors than controls, thereby suggesting a deficit in the inhibition of competitive memory traces (Shimamura, 1995). We attempted to ascertain whether alcoholics' EF performance could explain their poor EM performance. Firstly, EF deficits were detected among alcoholics. Our results confirm previous studies of alcoholics that showed the presence of deficits affecting reasoning (Zinn et al., 2004), prepotent response inhibition (i.e., Dao-Castellana et al., 1998; Noël et al., 2001a,b; Goldstein et al., 2004; Hildebrandt et al., 2004; Zinn et al., 2004; Pitel et al., 2007a), coordination of dual-tasks (Rapeli et al., 1997; Sullivan et al., 2000; Noël et al., 2001a,b) and mental flexibility (Noël et al., 2001b; Hildebrandt et al., 2004). Secondly, stepwise regression analyses carried out in the alcoholic group, showed that the Trail Making Test's score (assessing mental flexibility) was mainly predictive (around 50%) of free recall performance. This contribution remained elevated when participants had to recall the same words after a 20-min interval (28%). In addition and as hypothesized, we found that the capacity to realize two tasks simultaneously and to inhibit pre-potent response predicted 12 and 9% of additional variation. The results for the alcoholics abstinent for longer periods of time and with different levels of performance on episodic memory and executive

functions measures, reinforced the idea that executive functioning deficits were involved in episodic memory disorders in these patient. This important contribution to executive functioning on episodic memory functioning could be an illustration of a more general phenomenon, with alcoholic patients generally invoking higher-level cognitive systems than controls for the same task (Pfefferbaum et al., 2001). For instance, despite equivalent reaction time and accuracy performance by controls and alcoholics on verbal working memory tasks, a previous study revealed greater activations in the alcoholics than controls in left prefrontal cortex and right superior cerebellum (Desmond et al., 2003). This finding suggests that more far-reaching brain areas within the frontocerebellar system are needed to perform tasks at normal levels, with the potential disadvantage of a reduction of reserves to perform other tasks simultaneously (on a more complex task, such as the alpha-span task, for which compensatory processes are not sufficient to perform normally). Interestingly, the comparison of β coefficients showed that the two groups had different learning strategies; alcoholics require their executive system more than non-alcoholics do. This finding reinforces the hypotheses that subjects with alcoholism made an attempt to compensate for impaired automatic processes by implementing higher-order cognitive processes (Fama et al., 2004; Pitel et al., 2007b). Another interesting result relates to the contribution of a ‘slowing down’ of the processing speed to EF and EM deficits. In agreement with other studies (Nixon and Bowlby, 1996; O'Mahony and Doherty, 1995; Stetter et al., 1995; Joyce and Robbins, 1991; Noël et al., 2001b), it appeared that alcoholics were not slower than controls on (a) colornaming and reading sections of the Stroop test, (b) on part A of the Trail-Making Test and (c) on the initiation section of the Hayling task. Overall, this absence of slowing down of various tasks suggests that processing speed does not constitute an important contributing factor to the executive and episodic memory deficits observed in alcoholics. However, between-group differences for speed processing just failed to reach the level of significance (p = 0.08); we controlled its possible impact on other cognitive performances and found no covariate effect. With respect to storage/consolidation components of EM, it was shown that the alcoholics did not lose more information than controls between free and delayed (20 minutes later) recall, thus suggesting spared storage capacities in patients (for a similar conclusion, see Pitel et al., 2007a). This finding that alcoholics have preserved storage capacities (Sherer et al., 1992) is in contradiction to a number of previous studies (e.g., Beatty et al., 1995; Munro et al., 2000), which identified their low performance on delayed recall tasks. However, in these studies, performances on delayed recall were not contrasted with those of immediate recall, thus preventing the possibility of reaching any robust conclusion regarding storage capacities in alcoholics. Overall, performance analysis based on the California Verbal Learning Test revealed normal storage in alcoholics, together with the presence of active retrieval disorders. There are four main limitations to the present study which should be further investigated. Firstly, we cannot ascertain whether these cognitive deficits in alcoholics recover over longer periods of abstinence. Secondly, it was not ascertained whether alcoholics’ executive and episodic memory dysfunction developed as a result of chronic alcohol use (a neurotoxic effect) or constituted a developmental predisposing factor to this misuse. Binge drinking models indicate alcohol damages corticolimbic brain regions (Crews et al., 2000) causing reversal learning deficits indicative of executive function loss (Obernier et al., 2002). Genetics and adolescent age are risk factors for alcoholism that coincide with sensitivity to alcohol induced neurotoxicity. Cortical degeneration from alcohol abuse may increase impulsivity which contributes to the development, persistence and severity of alcohol use disorders. Thirdly, our sample of alcoholics contained only male subjects, thus obviating the generalization of our findings to subjects with alcoholism. Fourthly, the inclusion of patients who were still receiving treatment after 3 weeks may constitute a selection bias, with the most cognitive impaired patients

X. Noël et al. / Psychiatry Research 198 (2012) 116–122

being unable to stay in treatment for such long periods. However, compatible results were found in alcoholic patients at alcohol treatment entry (Pitel et al., 2007a). The potential clinical implications could be important. EM is crucial to changes in alcohol-related behaviors (Blume et al., 2005). For this reason, enhancement of EM in these patients might be a useful way to prevent alcohol relapse. Other possibilities include a neurophysiological tool such as transcranial magnetic stimulation, which may be capable of hastening memory processes (Gagnon et al., 2011). Cognitive rehabilitation could also be used with alcoholic patients with verbal EM and EF impairments. Further studies should be conducted to investigate these various options. In conclusion, recently detoxified males with alcoholism exhibit verbal EM disorders that are characterized by impaired effortful encoding and retrieval processes. The patients rely more on their impaired executive system than non-alcoholics, which partially explains the alcoholic subjects’ episodic memory deficits.

References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental disorders, 4th Edition. APA, Washington, DC. Anton, R., O'Malley,, S., Ciraulo, D., Cisler, R., Couper, D., Donovan, D., Gastfriend, D.R., Hosking, J.D., Johnson, B.A., LoCastro, J.S., Longabaugh, R., Mason, B.J., Mattson, M.E., Miller, W.R., Pettinati, H.M., Randall, C.L., Swift, R., Weiss, R.D., Williams, L.D., Zweben, A., 2006. COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA : The Journal of the American Medical Association 295, 2003–2017. Baddeley, A., 2000. The episodic buffer: a new component of working memory? Trends in Cognitive Sciences 4, 417–423. Bartsch, A.J., Homola, G., Biller, A., Smith, S.M., Weijers, H.G., Wiesbeck, G.A., Jenkinson, M., De Stefano, N., Solymosi, L., Bendszus, M., 2007. Manifestations of early brain recovery associated with abstinence from alcoholism. Brain 130, 36–47. Bates, M.E., Bowden, S.C., Barry, D., 2002. Neurocognitive impairment associated with alcohol use disorders: implications for treatment. Experimental and Clinical Psychopharmacology 10, 193–212. Beatty, W.W., Katzung, V.M., Moreland, V.J., Nixon, S.J., 1995. Neuropsychological performance of recently abstinent alcoholics and cocaine abusers. Drug and Alcohol Dependence 37, 247–253. Belleville, S., Rouleau, N., Casa, N., 1998. Effect of normal aging on the manipulation of information in working memory. Memory & Cognition 26, 572–583. Blume, A.W., Schmaling, K.B., Marlatt, G.A., 2005. Memory, executive cognitive function, and readiness to change drinking behavior. Addictive Behaviours 30, 301–314. Brandt, J., Butters, N., Ryan, C., Bayog, R., 1983. Cognitive loss and recovery in long-term alcohol abusers. Archives of General Psychiatry 40, 435–442. Brokate, B., Hildebrandt, H., Eling, P., Fichtner, H., Runge, K., Timm, C., 2003. Frontal lobe dysfunctions in Korsakoff's syndrome and chronic alcoholism: continuity or discontinuity? Neuropsychology 17, 420–428. Burgess, P., Shallice, T., 1996. Response suppression, initiation and strategy use following frontal lobe lesions. Neuropsychologia 34, 263–273. Campanella, S., Petit, G., Maurage, P., Kornreich, C., Verbanck, P., Noël, X., 2009. Chronic alcoholism: insights from neurophysiology. Clinical Neurophysiology 39 (4–5), 191–207. Carlen, P.L., Wilkinson, D.A., 1983. Assessment of neurological dysfunction and recovery in alcoholics: CT scanning and other techniques. Substance and Alcohol Actions/Misuse 4, 191–197. Clarys, D., Bugaiska, A., Tapia, G., Baudouin, A., 2009. Ageing, remembering, and executive function. Memory 17, 158–168. Crews, F.T., Braun, C.J., Hoplight, B., Switzer, R.C., Knapp, D.J., 2000. Binge ethanol consumption causes differential brain damage in young adolescent rats compared with adult rats. Alcoholism, Clinical and Experimental Research 24, 1712–1723. Dao-Castellana, M.H., Samson, Y., Legault, F., Martinot, J.L., Aubin, H.J., Crouzel, C., Feldman, L., Barrucand, D., Rancurel, G., Féline, A., Syrota, A., 1998. Frontal dysfunction in neurologically normal chronic alcoholic subjects: metabolic and neuropsychological findings. Psychological Medicine 28, 1039–1048. D'Argembeau, A., Van Der Linden, M., Verbanck, P., Noël, X., 2006. Autobiographical memory in non-amnesic alcohol-dependent patients. Psychological Medicine 36, 1707–1715. Davidson, M.C., Amso, D.A., Loren, C., Diamond, A., 2006. Development of cognitive control and executive functions from 4 to 13 years: evidence from manipulations of memory, inhibition, and task switching. Neuropsychologia 44, 2037–2078. Delis, D.S., 1987. New developments in the evaluation of mind-brain relationships. PsycCRITIQUES 32, 508–511. Delis, D.C., Freeland, J., Kramer, J.H., Kaplan, E., 1988. Integrating clinical assessment with cognitive neuroscience: construct validation of the California Verbal Learning Test. Journal of Consulting and Clinical Psychology 56, 123–130. Desmond, J.E., Chen, S.H., DeRosa, E., Pryor, M.R., Pfefferbaum, A., Sullivan, E.V., 2003. Increased forntocerebellar activiation in alcoholics during verbal working memory: an fMRI study. NeuroImage 19, 1510–1520.

121

Eslinger, P.J., Grattan, L.M., 1993. Frontal lobe and frontal-striatal substrates for different forms of human cognitive flexibility. Neuropsychologia 31, 17–28. Fama, R., Pfefferbaum, A., Sullivan, E.V., 2004. Perceptual learning in detoxified alcoholic men: contributions from explicit memory, executive function, and age. Alcoholism, Clinical and Experimental Research 28, 1657–1665. Fama, R., Rosenbloom, M.J., Nichols, B.N., Pfefferbaum, A., Sullivan, E.V., 2009. Working and episodic memory in HIV infection, alcoholism, and their comorbidity: baseline and 1-year follow-up examinations. Alcoholism, Clinical and Experimental Research 33, 1815–1824. Fletcher, C.R., Arthur, E.J., Skeate, R.C., 1995. Top-down effects in a bottom-up model of narrative comprehension and recall. In: Weaver, C.A., Mannes, S., Fletcher, C.R. (Eds.), Discourse Comprehension: Essays in Honor of Walter Kintsch. Lawrence Erlbaum Associates, Hillsdale, NJ, pp. 195–210. Fletcher, P.C., Henson, R.N., 2001. Frontal lobes and human memory: insights from functional neuroimaging. Brain 24, 849–881. Folstein, M.F., Folstein, S.E., McHugh, P.R., 1975. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189–198. Gagnon, G., Schneider, C., Grondin, S., Blanchet, S., 2011. Enhancement of episodic memory in young and healthy adults: a paired-pulse TMS study on encoding and retrieval performance. Neuroscience Letters 488, 138–142. Glenn, S.W., Parsons, O.A., 1992. Neuropsychological efficiency measures in male and female alcoholics. Journal of Studies on Alcohol 53, 546–552. Goldstein, R.Z., Leskovjan, A.C., Hoff, A.L., Hitzemann, R., Bashan, F., Khalsa, S.S., Wang, G.J., Fowler, J.S., Volkow, N.D., 2004. Severity of neuropsychological impairment in cocaine and alcohol addiction: association with metabolism in the prefrontal cortex. Neuropsychologia 42, 1447–1458. Grattan, L.M., Eslinger, P.J., 1989. Higher cognition and social behavior: changes in cognitive flexibility and empathy after cerebral lesions. Neuropsychology 3, 175–185. Hamilton, M., 1959. The assessment of anxiety states by rating. The British Journal of Medical Psychology 32, 50–55. Hildebrandt, H., Brokate, B., Eling, P., Lanz, M., 2004. Response shifting and inhibition, but not working memory, are impaired after long-term heavy alcohol consumption. Neuropsychology 18, 203–211. Joyce, E.M., Robbins, T.W., 1991. Frontal lobe function in Korsakoff and non-Korsakoff alcoholics: planning and spatial working memory. Neuropsychologia 29, 709–723. Kapur, N., Ellison, D., Parkin, A.J., Hunkin, N.M., Burrows, E., Sampson, S.A., Morrison, E.A., 1994. Bilateral temporal lobe pathology with sparing of medial temporal lobe structures: lesion profile and pattern of memory disorder. Neuropsychologia 32, 23–38. Knight, R.G., Longmore, B.E., 1994. Clinical Neuropsychology of Alcoholism. Lawrence Erlbaum Associates, Hillsdale, NJ. Kopelman, M.D., 1995. The Korsakoff syndrome. The British Journal of Psychiatry 166, 154–173. Mayes, A.R., Daum, I., Markowisch, H.J., Sauter, B., 1997. The relationship between retrograde and anterograde amnesia in patients with typical global amnesia. Cortex 33, 197–217. Milner, B., 1968. Disorders of memory after brain lesions in man: preface: material-specific and generalized memory loss. Neuropsychologia 6, 175–179. Miyake, A., Friedman, N.P., Emerson, M.J., Witzki, A.H., Howerter, A., Wager, T.D., 2000. The unity and iversity of executive functions and their contributions to complex “Frontal Lobe” tasks: a latent variable analysis. Cognitive Psychology 41, 49–100. Montgomery, S.A., Åsberg, M.A., 1979. A new depression scale designed to be sensitive to change. The British Journal of Psychiatry 134, 382–389. Moscovitch, M., Winocur, G., 1992. The neuropsychology of memory and aging. In: Craik, F.I.M., Salthouse, T.A. (Eds.), The handbook of aging and cognition. Lawrence Erlbaum Associates, Publishers, Hillsdale, New Jersey, pp. 315–372. Moselhy, H.F., Georgiou, G., Kahn, A., 2001. Frontal lobe changes in alcoholism: a review of the literature. Alcohol and Alcoholism 36, 357–368. Munro, C.A., Saxton, J., Butters, M.A., 2000. The neuropsychological consequences of abstinence among older alcoholics: a cross-sectional study. Alcoholism, Clinical and Experimental Research 24, 1510–1516. Nixon, S.J., Bowlby, D., 1996. Evidence of alcohol-related efficiency deficits in an episodic learning task. Alcoholism, Clinical and Experimental Research 20, 21–24. Nixon, S.J., Paul, R., Phillips, M., 1998. Cognitive efficiency in alcoholics and polysubstance abusers. Alcoholism, Clinical and Experimental Research 22, 1414–1420. Noël, X., Paternot, J., Van der Linden, M., Sferrazza, R., Verhas, M., Hanak, C., Kornreich, C., Martin, P., De Mol, J., Pelc, I., Verbanck, P., 2001a. Correlation between inhibition, working memory and delimited frontal area blood flow measured by – super(99m) – Tc-Bicisate Spect in alcohol-dependent patients. Alcohol and Alcoholism 36, 556–563. Noël, X., Van der Linden, M., Schmidt, N., Sferrazza, R., Hanak, C., Le Bon, O., De Mol, J., Kornreich, C., Pelc, I., Verbanck, P., 2001b. Supervisory attentional system in nonamnesic alcoholic men. Archives of General Psychiatry 58, 1152–1158. Norman, W., Shallice, T., 1986. Attention to action. In: Davidson, R.J., Schwartz, G.E., Shapiro, D. (Eds.), Consciousness and Self Regulation: Advances in Research and Theory, vol. 4. Plenum, New York, pp. 1–18. Obernier, J.A., White, A.M., Swartzwelder, H.S., Crews, F.T., 2002. Cognitive deficits and CNS damage after a 4-day binge ethanol exposure in rats. Pharmacology, Biochemistry, and Behavior 72, 521–532. O'Mahony, J.F., Doherty, B., 1995. Comparability of correlates of original and revised Wechsler Adult Intelligence scales in an alcohol-abusing population. Journal of Clinical Psychology 51, 123–128. Oscar-Berman, M., Kirkley, S.M., Gansler, D.A., Couture, A., 2004. Comparisons of Korsakoff and non-Korsakoff alcoholics on neuropsychological tests of prefrontal brain functioning. Alcoholism, Clinical and Experimental Research 28, 667–675. Perret, E., 1974. The left frontal lobe of man and the suppression of habitual responses in verbal categorical behaviour. Neuropsychologia 12, 323–330.

122

X. Noël et al. / Psychiatry Research 198 (2012) 116–122

Pfefferbaum, A., Desmond, J.E., Galloway, C., Menon, V., Glover, G.H., Sullivan, E.V., 2001. Reorganization of frontal systems used by alcoholics for spatial working memory: an fMRI study. NeuroImage 14, 7–20. Pitel, A.L., Beaunieux, H., Witkowski, T., Vabret, F., Guillery-Girard, B., Quinette, P., Desgranges, B., Eustache, F., 2007a. Genuine episodic memory deficits and executive dysfunctions in alcoholic subjects early in abstinence. Alcoholism, Clinical and Experimental Research 31, 1169–1178. Pitel, A.L., Witkowski, T., Vabret, F., Guillery-Girard, B., Gesgranges, B., Eurstache, F., Beaunieux, H., 2007b. Effect of episodic and working memory impairements non semantic and cognitive procedural learning at alcohol treatment entry. Alcoholism, Clinical and Experimental Research 31, 238–248. Rapeli, P., Service E., Salin, P., Holopainen, A., 1997. A dissociation between simple and complex span impairment in alcoholics. Memory 5, 741–762. Reitan, R.M., 1955. The relation of the trail making test to organic brain damage. Journal of Consulting Psychology 19, 393–394. Repovs, G., Baddeley, A., 2006. The multi-component model of working memory: explorations in experimental cognitive psychology. Neuroscience 139 (1), 5–21. Schwartz, B.L., Parker, E.S., Deutsch, S.I., Rosse, R.B., Kaushik, M.A., 2002. Source monitoring in alcoholism. Journal of Clinical and Experimental Neuropsychology 24, 806–817. Shallice, T., Fletcher, P., Frith, C.D., Grasby, P., 1994. Brain regions associated with acquisition and retrieval of verbal episodic memory. Nature 368, 633–635. Sherer, M., Nixon, S.J., Parsons, O.A., Adams, R.L., 1992. Performance of alcoholic and brain-damaged subjects on the Luria Memory Words Test. Archives of Clinical Neuropsychology 7, 499–504. Shimamura, A.P., 1995. Memory and the prefrontal cortex. In: Rafman, J., Holyoak, K.J., Boller, F. (Eds.), Structure and Functions of the Human Prefrontal Cortex. Academy of Sciences, New York, pp. 151–159 (New York).

Stetter, F., Ackermann, K., Bizer, A., Straube, E.R., Mann, K., 1995. Effects of diseaserelated cues in alcoholic inpatients: results of a controlled ‘Alcohol Stroop’ study. Alcoholism, Clinical and Experimental Research 19, 593–599. Stroop, J.R., 1935. Studies of interference in serial verbal reactions. Journal of Experimental Psychology 18, 643–662. Sullivan, E.V., Pfefferbaum, A., 2005. Neurocircuitry in alcoholism: a substrate of disruption and repair. Psychopharmacology 180, 583–594. Sullivan, E.V., Rosenbloom, M.J., Pfefferbaum, A., 2000. Pattern of motor and cognitive deficits in detoxified alcoholic men. Alcoholism, Clinical and Experimental Research 24, 611–621. Tivis, L.J., Parsons, O.A., 1995. An investigation of verbal spatial functioning in chronic alcoholics. Assessment 2, 285–292. Tivis, R., Beatty, W.W., Nixon, S.J., Parsons, O., 1995. A Patterns of cognitive impairment among alcoholics: are there subtypes? Alcoholism, Clinical and Experimental Research 19, 496–500. Tulving, E., Markowitsch, H.J., Kapur, S., Habib, R., Houle, S., 1994. Novelty encoding networks in the human brain: positron emission tomography data. Neuroreport 5, 2525–2528. Weingartner, H.J., Andreason, P.J., Hommer, D.W., Sirocco, K.Y., Rio, D.E., Ruttimann, U.E., Rawlings, R.R., Eckardt, M.J., 1996. Monitoring the source of memory in detoxified alcoholics. Biological Psychiatry 40, 43–53. Wheeler, M.A., Stuss, D.T., Tulving, E., 1997. Toward a theory of episodic memory: the frontal lobes and autonoetic consciousness. Psychological Bulletin 121, 331–354. World Health Organization, 2004. Global Status Report on Alcohol. Department of Mental Health and Subtance Abuse, Geneva. Zinn, S., Stein, R., Swartzwelder, H., 2004. Executive functioning early in abstinence from alcohol. Alcoholism, Clinical and Experimental Research 28, 1338–1346.