CORRELATION BETWEEN INHIBITION, WORKING MEMORY AND DELIMITED FRONTAL AREA BLOOD FLOW MEASURED BY 99mTc-BICISATE SPECT IN ALCOHOL-DEPENDENT PATIENTS
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(2) COGNITION AND BLOOD FLOW IN ALCOHOLICS. control to action. The first, called ‘contention scheduling’, is involved in routine situations in which actions are triggered automatically. The second, called the ‘supervisory attentional system’ (SAS), is a separate mechanism at the highest level of control of action, coping with novelty. This mechanism is required in situations where the routine selection of actions is unsatisfactory, and is involved in the genesis of plans and willed actions. Additionally, the authors conceived SAS as carrying out a variety of processes (Shallice, 1984, 1994). It should be noted that an analogy has been established between the SAS and the central executive component of the working memory model proposed by Baddeley (1986). The working memory refers to a system involved in the short-term maintenance and manipulation of information necessary for the performance of complex tasks such as reading and calculating. Baddeley’s model includes two slave systems ensuring temporary maintenance of information, the phonological loop and the visuospatial sketchpad, and an attentional control system, the central executive whose function is similar to that of the SAS. According to Baddeley (1986), an important function of the central executive concerns the ability to perform two tasks simultaneously. Inhibition was evaluated by means of the Hayling test (Shallice and Burgess, 1996). In this task, the participant is asked to fill in gapped sentences in which the last word is missing. What this word should be is strongly cued by the rest of the sentence. Two sections are presented. In the initiation section of the test (section A), participants have to complete the sentence with the missing word. In the inhibition section (section B), the subject must produce a word that makes no sense to the sentence. Therefore, the participant has to inhibit the dominant (automatic) response before generating the new one. Our recent unpublished data indicated that, like frontalinjured patients (Shallice and Burgess, 1996), alcoholic patients made more errors and took more time to respond in section B than did controls, because they seemed incapable of suppressing the predominant response. Working memory was evaluated by means of the Alphaspan task (Belleville et al., 1998). This task enables us to explore capacities to manipulate or modify the format of the to-be-recalled material. In fact, it compares the immediate recall of words, either in serial order (involving only short-term storage of information), or in alphabetical order (involving the ability to coordinate the storage and manipulation of information). In this task, alcoholic patients showed a dissociation between a normal performance in the serial recall condition and a very important deficit in the alphabetical condition, suggesting a deficit in the ability to manipulate stored information. In a recent PET study conducted in normal subjects, Collette et al. (1999a) showed that inhibition processes, measured by means of the Hayling test (in the inhibition condition), were related to an increase of metabolism bilaterally in the middle and inferior frontal gyrus. In another study, Collette et al. (1999b) found that manipulation of information in the Alpha-span task (i.e. reorganizing in alphabetical order the word sequences which are temporarily stored), induced activation bilaterally in the middle frontal gyrus and in the left parietal area. As the regional cerebral blood flow (rCBF) and metabolic rate for glucose are commonly considered as associated with functional activity of the neural cells (Bentourkia et al., 2000),. 557. we aimed to explore, with a 99mTc-Bicisate brain SPECT procedure, the relationship between both the inhibition processes and the ability to coordinate storage processing, and the rCBF studied at rest in recently detoxified non-neurological alcoholic subjects. We selected regions of interest (ROIs) that are particularly activated in PET studies (Collette et al., 1999a,b) in normal subjects during the working memory (Alpha-span) and inhibition (Hayling) tasks. 99mTc-Bicisate was preferred to 99m Tc-HMPAO because of a better in vitro stability, a rapid clearance from extracerebral tissue (Leveille et al., 1989, 1992) and a better radiochemical purity (Leveille et al., 1992). SUBJECTS AND METHODS Subjects Patients. 20 right-handed male patients were recruited for this study from the Alcohol Detoxification Program of the Brugmann hospital. They all underwent complete medical, neurological and psychiatric examinations at the time of the selection. They were interviewed with the Structured Clinical Interview for Diagnosis for DSM-IV (American Psychiatric Association, 1994). Patients with diagnosis other than alcohol dependence on Axis I of the DSM-IV were excluded. Other reasons for exclusion were clinical evidence of an organic syndrome after psychiatric and neurological evaluation, of a cognitive dysfunction as assessed by the Mini-Mental State Examination (Folstein et al., 1975), or of head injury resulting in loss of consciousness for more than 30 min which would have affected the central nervous system, or medication that could influence cognition, or a history of significant medical illness. All subjects reported consuming at least 560 g of alcohol weekly for 2 of the 3 years preceding entry into the study. To increase the reliability of anamnestic information, the patient and the family were both questioned. The detoxification regime consisted of B vitamins and digressive doses of sedative medication (diazepam). The daily diazepam dose administered during the withdrawal and initial doses were successively reduced to 5 mg/day during the next 10–15 days in all patients. At the time of neuropsychological and SPECT evaluation, no patient had been taking detoxification medication for at least 7 days. The Montgomery and Asberg (1979) depression rating scale (MADRS) and the State–Trait Anxiety Questionnaire (Spielberger, 1993) were used to evaluate respectively the severity of depression and anxiety. Demographic and clinical data are presented in Table 1. Controls (only for neuropsychological evaluation). The normal control group was composed of 20 volunteers, recruited by word of mouth. They were matched by sex, age, and education. All subjects provided written consent and were not paid for their participation. All controls were drug-free (self-report and urine drug screening), had no Axis I diagnoses, and, on the basis of history and physical examination, were judged to be medically healthy. They were also excluded if they indicated having had a history of excessive substance use (e.g. an average of three drinks minimum per day over the last year, or more than occasional use of other drugs). Controls were advised to avoid alcohol in the 24 h prior to testing and to avoid using other.
(3) 558. X. NOËL et al. Table 1. Demographic and clinical variables of alcoholic patients and controls. Parameter. Alcoholics. Controls. Age Education (total years) Duration of alcohol misuse (total years) Daily alcohol consumption (g ethanol/kg body weight) Number of prior detoxifications Number of abstinence days Initial diazepam dose administered MADRS scorea Anxiety Trait State. 45.5 ± 7.5 11.7 ± 3.3. 44.7 ± 6.9 12.4 ± 3.4. 14.4 ± 8.1 3.9 ± 1.9. — —. 2.2 ± 2.3 18.8 ± 2.8 44.6 ± 5.65 16.7 ± 11.2. — — — 6.45 ± 2.7. 49.7 ± 13.11 44.8 ± 18.8. 33.15 ± 7.44 31.45 ± 6.2. Data represent the means ± SD of 20 subjects per group. MADRS, Montgomery and Asberg depression rating scale.. a. substances, including narcotic pain medication for the 5 days prior to testing. All patients and volunteers underwent a breathalyser test upon arrival at the laboratory. Neuropsychological evaluation All alcoholic subjects and the 20 controls performed the Alpha-span task (Belleville et al., 1998) and the Hayling test (Shallice and Burgess, 1996). They were also given the Progressive Matrix (Raven, 1960) as an abstract reasoning task and the California Verbal Learning Test (CVLT; Delis et al., 1987, 1988) because they are commonly considered to assess abstract reasoning and episodic memory respectively. Alcoholic patients performed all tests between 1 and 2 h before the imagery procedure. The Alpha-span task (Belleville et al., 1998) investigates 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 given to assess the span level of each subject. After the span measurement, the subject 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. For example, if a subject performed a span size of five words, he was asked to recall groups of four words in serial and alphabetical order. In the direct condition, the subject performed an immediate serial recall of ten sequences of words. In the alphabetical condition, the subject was asked to recall ten sequences of words in their alphabetical order. The subject’s performance was assessed by comparing the performance in alphabetical recall with that of the serial recall. In addition, a score calculation 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. The Hayling test (Shallice and Burgess, 1996) assesses the capacity to suppress (inhibit) an habitual response and was initially divided in order to examine both initiation and. inhibition processes. The Hayling task consists of 30 sentences in which the final word is omitted, but has a particularly high probability of one specific response (e.g.: complete the sentence ‘We mailed the letter without a …’ The answer is: ‘stamp’). The task is composed of two sections (A and B), each containing 15 sentences. In section A (initiation), sentences are read aloud to subjects who have to complete the sentence with the missing word. In section B (response suppression), sentences are read aloud to subjects who, this time, have to complete the sentence not with the expected word but with a word unrelated to the sentence. As Shallice and Burgess (1996) mentioned, there is a very low correlation in the performances in the Hayling A and the Hayling B tests by patients with frontal lesions, suggesting that these two parts would involve specific cognitive functions. The above authors believe that Hayling A requires the operation only in the contention scheduling system, since one must merely allow the prepotent response to occur, whereas Hayling B, in order to get an inappropriate response, requires some temporary schema or novel strategy to come into operation, such as inhibition. If at any time during this stage of the test, subjects gave a sentence completion rather than an unrelated word, they were told that the word was incorrect, and the task instructions were then 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. The overall semantic relationship of each response to its stimulus sentence was also measured with a penalty scale: three penalty points were given if the word was a straightforward completion of the sentence (score 3), one point for a word semantically related to the sentence (score 1) in some way, and no points when the response fulfilled successfully the task requirements (score 0). Raven’s Progressive Matrix (Raven, 1960) is a multi-choice test of reasoning ability that is intended to make few demands on the subject’s verbal skills. Each of the 60 items, in this task, contains an incomplete figure. The subject’s task is to select the response that best completes the stimulus figure from the six to eight alternatives presented beneath. The CVLT (Delis et al., 1988) consists of five learning trials of a 16-word target list. The mean number of words correctly recalled on 1–5 trials was calculated. Brain SPECT procedure Cerebral imaging was done with 99mTc-Bicisate (Neurolite; Dupont Pharma) using a gamma camera (Sopha DSX rectangular) equipped with a high-resolution parallel collimator. The energy window was set to 140 KeV ± 10%. A syringe containing the 740 Mbq dose in a small volume (± 1 ml) was placed on the bed, and counted for 1 min just before injection to achieve the injected dose, and then under the patient’s head to measure the cranial attenuation. The bolus was injected via an antecubital vein catheter, and a 150 × 1 s dynamic acquisition was performed using 128 × 128 matrix size. After this equilibrium period, cerebral blood flow distribution was measured by SPECT: the camera performed a 64-step 360° rotation. Each projection (128 × 128 matrix) had a 15 s preset time. Reconstruction was performed by filtered back projection using a Hann filter (cut-off 1 Ny) without attenuation correction. Sagittal slices were rotated to horizontalize the y-axis (see Talairach and Tournoux, 1988) and summed by 3 to obtain six 14 mm slices centered on each stereotactic.
(4) COGNITION AND BLOOD FLOW IN ALCOHOLICS Table 2. Stereotactic ROI coordinates Parameter Alpha-span task Left inferior/superior parietal (BA 7) Right middle frontal gyrus (BA 10/46) Hayling test Left middle frontal gyrus (BA 10) Left inferior frontal gyrus (BA 47). x (mm). y (mm). z (mm). –28 38. –62 50. 44 12. –40 –46. 46 36. 2 –06. x, y, z (in mm) refer to coordinates in the Talairach space (Talairach and Tournaux, 1988) for regions of interest in the Alpha-span (Collette et al., 1999a) and Hayling task (Collette et al., 1999b).. coordinate (see Table 2). For dynamic processing, a cerebral region was drawn and a 150 × 1 s curve derived. After a short uptake period, a plateau was reached. The mean value between 60 and 90 s after the maximum was compared to the injected dose and corrected for cranial attenuation. For slice processing, all regions took the form of a cube: 3 × 3 pixels area and 3 pixels depth of slice. The size of one pixel is 4.6 mm; therefore, each side of the ROIs was ~14 mm. The ROIs were selected from data showing that the inhibition process of the Hayling test involves bilateral BA 10 and BA 47 (Collette et al., 1999a), and that the manipulation of information in working memory involves bilateral BA 10/46 and left BA 7 (Collette et al., 1999b; see Fig. 1). Since no relationship has been found between occipital lobe metabolism, inhibition and working. 559. memory (Collette et al., 1999a,b), bilateral CBF (mean CBF of left and right occipital ROIs) measured in BA 19 was our region of reference. SPECT imaging data were evaluated by semi-quantitative analysis and calculated as the ratio of mean cortical ROI activity to mean cerebellar activity. We chose cerebellar activity to normalize the data because it was reported that CBF did not change in alcoholics unless cerebral degeneration occurred (Gilman et al., 1990; Melgaard et al., 1990). Statistical analysis Pearson’s correlation coefficient was performed to investigate the relationship between neuropsychological performance and SPECT parameters. Differences of cognitive performance between groups were analysed using two-tailed Student’s t-test or analysis of variance (ANOVA) and post-hoc analyses (Newman–Keuls test) with an α level of 0.05. All analyses were performed using SPSS 8.0. (SPSS, Inc., Chicago, IL, USA). RESULTS Affective measures With the t-test, alcoholic subjects had higher scores of depression measured on the MADRS [t(1,38) = 3.98, P < 0.001] and anxiety measured on the Spielberger scales [Trait, t (1,38) = 4.91, P < 0.001; State, t(1,38) = 3.01, P < 0.01], in comparison with controls.. Fig. 1. SPECT ROIs according to Table 2. On the left side, sagittal view of the brain showing our localizations of regions of interest for both the Alpha-span and Hayling tests in a normal subject. On the right side, sagittal view of the brain showing activation in black for performance of Alpha-span and Hayling test (data from Collette et al., 1999a,b)..
(5) 560. X. NOËL et al.. Neuropsychological performances Data from neuropsychological measures are presented in Table 3. With the t-test, alcoholic participants showed a poorer performance than controls on the Raven’s Progressive Matrix (PM38) [t(1,38) = –3.79, P = 0.001]. On the CVLT, the t-test revealed that patients recalled fewer correct words than controls [t(1,38) = 14.8, P < 0.001]. With regard to the Alpha-span test, the alcoholics’ and controls’ word span was 4.25 (SD = 0.64) and 4.5 (SD = 0.60), respectively. A t-test carried out on the span size showed that the performance of both groups did not differ significantly [t(1,38) = –1.53, P = 0.13]. The scores for serial and alphabetical recall were then analysed using a two-way 2 (group) × 2 (condition) ANOVA. The analysis revealed a main effect of group [F(1,38) = 13.1, P < 0.01] and of condition [F(1,38) = 74.7, P < 0.001]. A significant interaction between group and type of recall was also found [F(1,38) = 33.6, P < 0.001], with alcoholic patients showing a greater decrease of performance from direct to alphabetical recall than controls, despite a similar performance in direct recall (Newman–Keuls test). Finally, the calculated score showed a greater reduction of performance in patients (mean = 34.1, SD = 19) than controls (mean = 6.2, SD = 11.3) [t(1,38) = 5.6, P < 0.001]. In the Hayling test, latency time was examined using a 2 (group) × 2 (section) ANOVA. It revealed a main effect of group [F(1,38) = 9.2, P < 0.01] and of condition [F(1,38) = 106.1, P < 0.001]. A significant interaction. between these two factors was also found [F(1,38) = 8.93, P < 0.01]. Post-hoc comparisons revealed that alcoholics were slower in giving a response than controls only in the inhibition condition (P < 0.001). The errors were classified, by two raters blind to the purpose of the study, into one of the three following categories: responses which were actual completion-response received an error score of 3; responses that were semantically connected to the sentence in some way received an error score of 1, and responses unrelated to the sentence, as required by the task instructions, received an error score of 0. The 600 responses (40 subjects × 15 sentences) were classified by the two raters. They agreed on 79.5% of these responses. The results presented are the average of the two ratings. It is noteworthy that the same results were observed when each rating was analysed individually. Thus, the proportions of the different types of response were analysed. The analyses revealed that patients gave more score 1 responses [t (1,38) = –5.5, P < 0.001] and fewer score 0 responses [t(1,38) = –5.2, P < 0.001] than controls. Nevertheless, they did not give more expected words (error score 3) [t (1,38) = 1.05, P = 0.3]. The average overall penalty scores (sum of score 0, 1 and 3) were, respectively, 8.8 (SD = 4.05) and 4 (SD = 2.1) for alcoholics and controls. A t-test analysis revealed that alcoholics had a higher overall penalty score than controls [t(1,38) = 4.7, P < 0.001]. SPECT data The mean ± SEM brain uptake, strongly related to global CBF, was 7.65 ± 1.59%. Ratios of all ROIs (including region of reference) are presented in Table 4.. Table 3. Neuropsychological performances Parameter. Alcoholics. Controls. P. PM38 CVLT free recall Alpha-span Serial score Alphabetic score Hayling test Latency time(s) Section A Section B Penalty scores (section B) Score 3 Score 1 Score 0 Overall penalty score. 38.1 ± 7.9 9.7 ± 2.66. 45.6 ± 5.5 12.1 ± 0.85. n.s.a n.s.a. 9.25 ± 1.21 6.2 ± 2.14. 9.4 ± 0.6 8.8 ± 1.05. n.s. <0.01b. 11.4 ± 0.91 74.3 ± 40.57. 11.3 ± 0.49 45.95 ± 11.2. n.s. <0.001b. 0.35 ± 0.49 7.75 ± 3.2 6.9 ± 3.4 8.8 ± 4.05. 0.2 ± 0.41 3.5 ± 1.3 11.3 ± 1.5 4 ± 2.1. n.s.a 0.001a 0.001a 0.001a. Values are means ± SD of 20 subjects per group. a Two-tailed Student’s t-test; bpost-hoc comparisons (Newman–Keuls). PM38, Raven’s Progressive Matrix; CVLT, California Verbal Learning Test.. Neuropsychological test performance and relationship to rCBF Pearson correlation analyses were conducted in order to examine, in the alcoholic group, the relationship between rCBF and Hayling/Alpha-span task’s performance. With the Hayling test, we selected the overall penalty score and the latency time of section B minus section A (inhibition time). There exists a significantly negative correlation between the overall penalty score and the CBF measured in bilateral BA 47 (left, r = –0.59, P < 0.01; right, r = –0.40, P < 0.05) and in bilateral BA 10 (left, r = –0.55, P < 0.01; right, r = –0.59, P < 0.01) but not in BA 19 (r = –0.13, n.s.). A significantly negative correlation was also observed between the inhibition time and the CBF in BA 10 (left, r = –0.47, P < 0.05; right, r = –0.45, P < 0.05). We also observed a negative correlation between the calculated score of the Alpha-span task and the CBF measured in bilateral BA 10/46 (left, r = –0.50, P < 0.01; right, r = –0.45, P < 0.05) but not in bilateral BA 7 (left, r = –0.12, n.s.;. Table 4. Semi-quantitative measures of regions of interest (including the region of reference) Ratio left BA 47/cerebellum 0.77 ± 0.14 Ratio left BA 10/46/cerebellum 0.92 ± 0.11. Ratio right BA 47/cerebellum 0.79 ± 0.14. Ratio left BA 10/cerebellum 0.93 ± 0.11. Ratio right BA 10/cerebellum 0.98 ± 0.09. Ratio occipital/ cerebellum 0.96 ± 0.11. Ratio right BA 10/46/cerebellum 0.89 ± 0.13. Ratio left BA 7/cerebellum 0.75 ± 0.12. Ratio right BA 7/cerebellum 0.78 ± 0.14. Ratio occipital/ cerebellum 0.96 ± 0.11. Values are means ± SD for ratios..
(6) COGNITION AND BLOOD FLOW IN ALCOHOLICS. right, r = –0.18, n.s.), nor in BA 19 (r = –0.06, n.s.). To summarize, the higher the penalty score, and the longer the inhibition time on the Hayling test, the lower the CBF measured in bilateral BA 47 and BA 10 areas. In the Alphaspan test, the higher the difference between the serial and the alphabetic recall, the lower is the CBF measured in bilateral 10/46. Neither age, nor daily alcohol consumption (g ethanol/kg body weight), nor depression and anxiety scores were correlated to any of the neuropsychological tasks and ROIs. None of the correlation observed was superior to 0.22 (data not shown). DISCUSSION The aim of the present study was to examine, in recently detoxified non-neurological alcoholics, the relationship between both working memory and inhibition processes and the measured CBF in regions selected a priori on the basis of recent PET studies conducted in normal subjects (Collette et al., 1999a,b). Firstly, the results show that alcoholics present deficits in a working memory task (the Alpha-span Task; Belleville et al., 1998) involving the ability to coordinate storage and processing. These data confirm those of previous studies (Rapeli et al., 1997; X. Noël, unpublished data). In addition, a significant negative correlation between performance calculated score of the Alpha-span task and rCBF measured in bilateral middle frontal gyrus areas (BA 10/46) was observed. Correlation between this performance and rCBF in both parietal areas (BA 7) and in the occipital region (BA 19) was not significant. According to Collette et al. (1999a), the parietal area (BA 7), which has been found to be related to the calculation of information in the Alpha-span task (along with middle frontal gyrus, BA 10/46), might be involved in ‘automatic’ attentional processes (e.g. directed attention to the first letter of the words; Posner, 1994; Nobre et al., 1997; O’Leary et al., 1997; Corbetta, 1998). By contrast, frontal regions (BA 10/46) are postulated to be involved in controlled (voluntary) attentional processes (e.g. manipulation of information). Secondly, inhibition processes, as assessed by the Hayling test (Shallice and Burgess, 1996), revealed that alcoholic patients committed more errors and spent more time than controls before responding to the inhibition section (B), but not to the initiation section (A). This dissociation suggests that alcoholism is associated with deficits affecting control process (inhibition of a dominant non-relevant response), but not with the processes involved in the production of an automatic response. Moreover, we found a significant correlation between the overall penalty score in the Hayling test and both the bilaterally inferior and the middle frontal gyrus (BA 47, BA 10), but not with an occipital region (BA 19). We also found another significant correlation between the time to respond in section A minus section B and CBF measured in bilateral BA 10. Our results showing correlation between rCBF and neuropsychological test performances did not allow us to establish that our patients manifested a hypo-perfusion in medial and inferior frontal regions, because we could not compare our CBF measures with those of normal subjects. However, numerous. 561. PET and SPECT studies have documented the presence of medial and inferior frontal hypo-metabolism and hypo-perfusion in recently detoxified uncomplicated alcoholics (Adams et al., 1993; Nicolas et al., 1993; Dao-Castellana et al., 1998). In addition, hypo-perfusion of inferior frontal regions was observed in alcoholics with less than 4 years of sobriety (Gansler et al., 2000). Moreover, Dao-Castellana et al. (1998) indicated that a medio-frontal hypo-metabolism is correlated with ‘frontal’ test deficits (a reduced performance in a verbal fluency task, and an increased time response in the interference condition of the Stroop test). Another limitation of our study is that we cannot determine whether the alcoholic patients manifest deficits affecting the total brain uptake or the distribution of the tracer. However, it should be noted that the total brain uptake of 99mTc-Bicisate in our sample is quite comparable to the mean brain uptake data for normal subjects reported by Dupont Pharma, the manufacturer, and other studies (Friberg, 1994; Pupi et al., 1994). Thus, differences between our sample of alcoholic participants and normal subjects appear to characterize rCBF distribution but not global brain perfusion. In addition, a previous PET study showed that recently detoxified alcoholics manifested regional distribution abnormalities, even after normalization for global metabolic differences (Volkow et al., 1994). Concerning predictors of neuropsychological performance, and contrary to previous studies, we failed to identify any relationship between regional CBF and both the amount of ethanol consumed in the month prior to admission (Nicolas et al., 1993), and the years of alcohol misuse (Nicolas et al., 1994; Volkow et al., 1994). However, assessing alcohol history variables is hampered by problems of retrospective recall accuracy in patients known to have cognitive impairments. The present results show that uncomplicated alcoholic subjects manifest executive function deficits near the end of a period of detoxification, which have important clinical implications, particularly concerning alcohol relapse. According to Tiffany (1990), drug-use behaviour in the addict represents activity which is largely dependent on automatic processes. Furthermore, non-automatic (controlled or executive) cognitive processes are needed to impede or block a drug-use action plan and consequently to maintain abstinence. In other words, the existence of executive function deficits in alcoholics, as evidenced in the present study, could affect the capacity to maintain abstinence. Further studies are needed to explore the relationship between executive functioning and alcohol relapse. In conclusion, the present study has shown that two executive functions, namely inhibition and the ability to coordinate storage and processing of information, were impaired in recently detoxified uncomplicated alcoholic subjects. Our data also indicate a relationship between CBF in frontal areas measured with 99mTc-Bicisate brain SPECT and deficits affecting these two executive functions. Further studies conducted with a larger sample size are needed to confirm these results and to explore the relationship between executive deficits and alcohol relapse. Acknowledgements — The authors wish to thank all the assistants in psychology and the nurses of Nuclear Medicine and Addiction departments for their assistance in this experiment and A. M. Maut for his meticulous help with our English. The study presented in this paper was made possible by grants from the ‘Fondation Brugmann’..
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