Alcohol and Alcoholism Advance Access originally published online on December 18, 2006
Alcohol and Alcoholism 2007 42(2):92-102; doi:10.1093/alcalc/agl104
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RECOVERY OF HIPPOCAMPUS-RELATED FUNCTIONS IN CHRONIC ALCOHOLICS DURING MONITORED LONG-TERM ABSTINENCE
1 Division of Clinical Neuroscience, Max-Planck-Institute of Experimental Medicine Hermann-Rein-Str. 3, 37075 Göttingen, Germany
2 Department of Clinical Psychology and Psychotherapy, Georg-August-University Gosslerstr. 14, 37073 Göttingen, Germany
*Author to whom correspondence should be addressed at: Prof. Hannelore Ehrenreich, MD, DVM Division of Clinical Neuroscience, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075 Göttingen, Germany. Tel: +49 551 389 9628; Fax: +49 551 389 9670; E-mail: ehrenreich{at}em.mpg.de
Received 22 October 2006; first review notified 31 October 2006; accepted 2 November 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Aims: The hippocampus (HC) is characterized by high vulnerability to noxious influence, but also by a considerable regenerative potential. Although deficits in HC-related functions are among the most commonly reported cognitive sequelae in alcoholism, little and conflicting information is available concerning regeneration upon abstinence. The present study has been designed to evaluate (i) the frequency of measurable dysfunction in so called HC tests and (ii) its predictive value for risk to relapse in a cohort of 50 severely affected chronic alcoholic patients and (iii) to monitor recovery of HC-related functions upon strict abstention from alcohol. Methods: Patients underwent a 2-year neuropsychological follow-up including HC-associated tests (Verbal Learning Test, VLT; Nonverbal Learning Test, NVLT; ‘City Map Test’ of Learning and Memory Test, LGT-3), as well as tests of intelligence and attention in the framework of OLITA (Outpatient Long-Term Intensive Therapy for Alcoholics), a programme with careful abstinence monitoring. Results: At study entry, 30/50 (60%) alcoholics had HC dysfunction which tended to predict a lower long-term abstinence probability (P = 0.058). Of the subgroup that could be followed under conditions of strictly monitored alcohol abstinence (n = 32; age 44.7 ± 6.2 years; 23 men, 9 women), 53% (17/32) exhibited distinct HC dysfunction at inclusion which returned to normal after 2 years. Patients with initially normal HC function (9/32) and patients with additional brain damage of different aetiologies (6/32) failed to show improvement on HC-related tests. While the former displayed stably normal HC test performance, the latter remained on a performance level below normal. Conclusions: Demonstrating slow but remarkable regeneration of HC functions upon strict abstention from alcohol, our data strongly support abstinence-oriented long-term treatment of alcoholics. The absence of functional recovery in patients with additional causes of brain damage might be explained by the ‘dual hit’ exhausting the regenerative potential of the HC.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Chronic extensive alcohol consumption affects basically all organs, including most brain areas (Pfefferbaum et al., 1988
; Lishman, 1990; Kril et al., 1997; Heather and Stockwell, 2001). Among those, the hippocampus (HC) is characterized by a particular vulnerability to any noxious input ranging from hypoxia/ischaemia or toxic compounds to inflammatory or neurodegenerative processes (Meyer et al., 2001; Geddes et al., 2003). Alcohol consumption, be it sporadically or chronically, impairs HC function and morphology as documented in vitro and in/ex vivo (Ryabinin, 1998; White et al., 2000), using animal experiments (Bonthius et al., 2001), human post mortem brains (Harding et al., 1997), or human imaging studies (Sullivan et al., 1995, 1996; Agartz et al., 1999; Laakso et al., 2000). The ethanol-induced HC damage has been explained by different mechanisms, ranging from neuronal loss (Cadete-Leite et al., 1988; Bengochea and Gonzalo, 1990) to glial cell diminution (Korbo, 1999), dendritic alterations in HC cells (King et al., 1988; Durand et al., 1989), decrease in HC neurogenesis (Herrera et al., 2003), or attenuated long-term potentiation (Tremwel and Hunter, 1994). In rodent studies, ethanol-induced reduction in HC volume was reversible upon abstinence (White et al., 2000). In fact, the HC has a strong regenerative potential due to considerable neuroplasticity, involving adult neurogenesis (Shors et al., 2001; Eriksson, 2003), gliogenesis (Steiner et al., 2004), synaptogenesis (Marrone et al., 2004), synaptic and dendritic sprouting (Spigelman et al., 1998; Bear, 2003; Schmidt-Hieber et al., 2004).
HC-related functions are intimately connected with learning and memory processes (Givens et al., 2000; Laroche et al., 2000; Riedel and Micheau, 2001; Duzel et al., 2003; Stark and Squire, 2003; Prickaerts et al., 2004), especially visuospatial memory (Epstein and Kanwisher, 1998) and visuospatial orientation (Iaria et al., 2003), crossmodal sensory integration (Laroche et al., 2000; Gottfried and Dolan, 2003), consolidation of information (Laroche et al., 2000), and attention (Wall and Messier, 2001). Previous neuropsychological investigations in alcoholism measured a wide range of different cognitive domains, but covered HC-related functions only partially. These studies revealed inconsistent patterns of impairment, ranging from general cognitive deficiency (Fein et al., 1990; Tivis et al., 1995; Sullivan et al., 2000b) to mild (Parsons, 1983), selective (Ratti et al., 1999; Noel et al., 2001), or even no cognitive deficits (Sullivan et al., 1995). Visuospatial learning and memory deficits, however, are among the most frequently and consistently found cognitive sequelae in chronic alcoholism, including rodent models (Bowden and McCarter, 1993; Beatty et al., 1996; Ryabinin, 1998; Matthews and Morrow, 2000; Weitemier and Ryabinin, 2003; Berry and Matthews, 2004).
Reports on cognitive recovery in alcoholism are diverse and conflicting, ranging from rapid, full, or partial recovery within several weeks (Kish et al., 1980; Leber et al., 1981; Mann et al., 1999; Tracy and Bates, 1999), several months (Drake et al., 1995) or several years (Fein et al., 1990; Reed et al., 1992; Sullivan et al., 2000a) to studies that yielded residual deficits or no cognitive improvement after a year or more of abstention from alcohol (Brandt et al., 1983; Yohman et al., 1985; Schandler et al., 1996). Most of these results were obtained either from cross-sectional studies, comparing different patient populations, or from short-term longitudinal observation. As an exception, Rourke and Grant (Rourke and Grant, 1999) demonstrated in a combined longitudinal and cross-sectional study design significant cognitive improvement, particularly of executive functions, in the same male alcoholics after 2 years of alcohol abstention. However, data concerning abstinence has solely been based on patients' self-reports and the majority of included patients failed to stay abstinent.
The aim of the present study was to prospectively evaluate in a cohort of severely affected chronic alcoholic subjects (i) the prevalence of HC dysfunction, (ii) the potential of HC recovery over 2 years of abstinence, and (iii) the impact of HC dysfunction on clinical outcome parameters. For the purpose of strict abstinence monitoring, the OLITA (Outpatient Long-term Intensive Therapy for Alcoholics) setting provided an ideal and unique opportunity of long-term follow-up of patients (Ehrenreich et al., 1997; Krampe et al., 2006a).
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PATIENTS AND METHODS |
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Subjects
The study protocol has been approved by the Committee for Medical Ethics of the Georg-August-University, Göttingen, Germany. Subjects participated after written informed consent.
Of a total of 67 patients consecutively admitted to the OLITA programme (Ehrenreich et al., 1997; Krampe et al., 2006a) between 04/2000 and 06/2002, 50 subjects were neuropsychologically tested at 2–3 weeks after inpatient detoxification and of those, 32 subjects completed the neuropsychological study protocol (for overview and details see Figure 1 and Table 1).
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This subgroup of 32 patients fulfilled DSM-IV criteria for alcohol dependence and was representative of the total OLITA sample of severely affected chronic alcoholics (Krampe et al., 2006a
) concerning sociodemographic or addiction-related data. Mean age at entry was 44.7 ± 6.2 years with a male/female ratio of 23:9. Patients had 9.5 ± 2.0 years of school education, 3.1 ± 2.1 years of higher education, and 12.6 ± 3.5 years of total education. Duration of alcohol dependence was 19.8 ± 6.5 years, with 6.0 ± 8.8 inpatient detoxifications and 1.0 ± 1.0 inpatient long-term therapies. They had consumed beer, wine, and spirits, amounting to an average of 410 ± 207 g of pure alcohol daily before entering the OLITA programme.
Patients had no history of previous or current drug abuse other than alcohol, nicotine, and caffeine. Patients joined the OLITA programme directly following an inpatient detoxification period of 2–3 weeks. Most subjects had typical sequelae of alcoholism during early abstinence, such as hepatomegaly/fatty liver, polyneuropathy, signs of autonomic dysregulation, and withdrawal-associated epileptic seizures. During their first week of inpatient detoxification, patients received clomethiazole, magnesium, potassium, and vitamin B1. At 2–3 weeks of abstinence, they were put on low-dose acetaldehyde dehydrogenase inhibitors (calcium carbimide or disulfiram) (Krampe et al., 2006a) for at least 13 months. Abstinence was strictly monitored by urine analysis at each therapeutic contact (i.e. daily for months 1–3, 3–4 times weekly for months 4–6, 2 times weekly for months 7–18, 1 time weekly for months 19–24), as well as regular blood and/or breath analyses up to the end of the programme at 2 years. For follow-up of abstinence after termination of treatment, regular weekly to quarterly urine and/or blood examinations were performed.
Psychiatric comorbidity of patients with neuropsychological follow-up is presented in Table 2. DSM-IV Axis I disorders at baseline and after 2 years (end of the treatment) were diagnosed with the MiniDIPS, a German adaptation of the Anxiety Disorders Interview Schedule (Barlow, 1988; DiNardo and Barlow, 1988; Margraf, 1994). DSM-IV Axis II disorders were diagnosed using the International Diagnostic Checklists for Personality Disorders (IDCL-P) (Bronisch and Mombour, 1998). Two prerequisites were required for personality disorder diagnosis: (i) the rater had to have observed a subject throughout a variety of situations over several months; (ii) diagnosis of personality disorder was made only for patients who had passed the third abstinent month to avoid misinterpretation of temporary withdrawal-related dysfunctions as symptoms of personality disorders [for details see (Wagner et al., 2004; Krampe et al., 2006b)].
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Neuropsychological assessment
All 50 subjects underwent a standardized test battery for intelligence, attention, learning, and memory 2–3 weeks after inpatient detoxification. Of those, 32 patients completed all 5 testing time-points of the study protocol.
Each of the selected tests is extensively validated and provides normative data for direct comparison of test performance with a normal population. Neuropsychological examinations were split into two sessions to be carried out within 1 week, each lasting for about 1 h. Four different randomized test orders were defined and distributed to patients at random, to avoid systematic effects of tiredness/exhaustion on the test results. Patients were first tested 2–3 weeks after inpatient detoxification (T1), and at 3 months (T2), 6 months (T3), 12 months (T4), and 24 months (T5) of abstinence.
Neuropsychological test battery
Intelligence
Intellectual capacity was assessed at T1 as an important control variable for group classification and interpretation of test results. Information, Similarities, Picture Completion, and Block Design subtests of the revised German version of WAIS-R [HAWIE-R; (Tewes, 1991)] were used to determine full scale, verbal, and performance intelligence quotient (IQ). An additional estimation of premorbid intelligence was carried out (Wilson et al., 1978).
Attention
Global attentional functions were examined using the subtest Alertness of the TAP (‘Computer-assisted battery for attentional testing’); (Zimmermann and Fimm, 1995). This test measures reaction time to a visual stimulus (Greek cross) appearing on the monitor screen, that is (‘tonic alertness’) or is not preceded by a cue sound. Speed of information processing, quality of reactions (omissions), and ability to enhance the level of attention in expectation of a high-priority stimulus (‘phasic alertness’) were measured. Crossmodal integration; This subtest of the TAP detects simultaneous control of input from different sensory information channels. The test subject has to simultaneously pay attention to an acoustic (high or low pitch of 530 or 790 Hz, respectively) and a visual stimulus (up or down arrow) and is asked to press a button whenever high pitch and upward arrow, or low pitch and downward arrow coincide (critical stimulus). Speed of information processing and quality of reactions (omissions, errors) are determined. The tertiary region of the sensory cortex, the supramodal control (Mesulam, 1981, 2000), and the superior colliculi (Calvert et al., 2001; Frassinetti et al., 2002) are believed to be neural substrates of this crossmodal integrative function, as are the temporoparietal junction (Macaluso and Driver, 2001) and, to some degree, HC connectivities (Gottfried and Dolan, 2003), providing certain overlap to the HC tests.
HC-related functions (referred to as ‘HC tests’)
Classical HC learning and memory functions were assessed using the recognition tasks Verbal Learning Test [VLT; German version of the Recurring Words Test; (Sturm and Wilmes, 1999)] and the Nonverbal Learning Test [NVLT; adoption of the Kimura Recurring Figures Test; (Sturm and Wilmes, 1999)]. Explicit recognition memory, as measured with the VLT and NVLT, is closely related to HC function [e.g. (Kimura, 1963; Falk et al., 2002; Papanicolaou et al., 2002; Manns et al., 2003), in particular in visual modality (Hammond et al., 2004). The number of correct positive and false-positive responses is recorded, and false-positive responses are subtracted from right responses to correct for guessing. A standardized parallel version of the VLT allows controlling for recall bias. Orientation and visuospatial memory were tested using the ‘City Map Test’ of the LGT-3 [‘Learning and Memory Test’; (Bäumler, 1974)]. This test evaluates 2D recognition/recall of map-like spaces and areas, and requires learning and remembering visuospatial configuration. The role of the HC in managing ‘spatial cognitive maps’ is well documented (Aguirre et al., 1996; Maguire et al., 1998; Matthews and Morrow, 2000). Considered a human equivalent of Morris water maze (Morris, 1984), this kind of task is highly associated with HC function (Beatty et al., 1996, 1997; Spiers et al., 2001). Subjects have to learn a defined route in a virtual street map within 60 s. After an interim period of 15 min, subjects are asked to reproduce this route from memory into an identical map. Two standardized parallel versions were given to the test subjects in alternating sequence (ABABA for 5 testing time-points). The selected HC tests (VLT, NVLT, and City Map Test), turned out to be well intercorrelated (r = 0.613 to r = 0.238), whereas there was no intercorrelation with the Crossmodal Integration Test of the TAP (r = –0.024 to r = 0.018).
Group design
Alcoholic subjects were divided into three groups, based on their results in HC-related tests at baseline (T1): (i) patients without HC dysfunction on entry; (ii) patients with HC dysfunction on entry; (iii) patients with additional brain damage (Figure 1). The inclusion criterion termed as ‘HC dysfunction’ was fulfilled if a patients' performance was at least 1 SD below normal (T-value 
40; percentile 16) in at least two out of the three predefined HC tests applied (see above). None of the patients of groups 1 and 2 had any evidence (by history, physical examination, technical, or laboratory tests) of liver cirrhosis, splenomegaly, or pancreatic failure. Patients of group 3 had the following diagnoses consistent with an additional brain damage: previous stroke in the right middle cerebral artery territory (2 patients); aneurysm of the anterior cerebral artery/past subarachnoid haemorrhage (1 patient); liver cirrhosis/hepatic encephalopathy (3 patients); schizophrenia (2 patients); astrocytoma with subtotal unilateral hippocampectomy (1 patient). All of these brain syndromes could potentially show an independent influence on neuropsychological test performance, in addition to alcohol-related changes. Therefore, and also because of its heterogeneity and small number, this patient group is not included in all statistical analyses.
Imaging
For financial reasons, computed tomography (CT) or magnetic resonance imaging (MRI) of the brain have not been part of the follow-up study design. However, available routine imaging data of the patients obtained during inpatient detoxification before inclusion into the OLITA programme have been employed for analysis.
Statistical analyses
All numerical results are presented as mean ± SD. Analyses (dependent and independent t-tests, 
2-tests, correlations, univariate and repeated measures ANOVA and ANCOVA, Kaplan–Meier survival analysis, Cox regression analysis) were carried out using SAS 8.02 (SAS, 2001) and SPSS 11.5 (SPSS, 2003). Kaplan–Meier survival analyses were performed to investigate the time-to-event measure of days from first outpatient contact to relapse over a follow-up period of up to 4 years (Kleinbaum, 1996). Cox proportional hazard models were used to examine associations of time-invariant predictors (i.e. initial neuropsychological test performance expressed as sum score after z-transformation of HC test raw scores) with time to relapse. Cases are censored if they have not experienced an event (i.e. relapse) by the end of follow-up. Statistical significance was set at 0.05 for all analyses.
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RESULTS |
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Patient groups, cognitive performance and imaging on study entry
All patients tested at T1 (N = 50) were classified according to our group design. Whereas as many as 30 patients had HC dysfunction on entry, only 11 patients were without HC dysfunction, underlining that HC dysfunction is a frequent syndrome in chronic severe alcoholism (
2 = 8.805, df = 1, P = 0.03). Figure 2 demonstrates the different neuropsychological profile of these two patient groups on initial testing.
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Sociodemographic and alcohol-related data for all patients of the three groups who remained abstinent and could be followed over 2 years are presented in Table 1. Comparison between groups 1 and 2 revealed significant differences in education (school education: P = 0.029; total education: P = 0.029), duration of dependence (P = 0.03), number of inpatient detoxifications (P = 0.03), and amount of daily alcohol intake (P = 0.022), but no difference on measurements of intelligence (WAIS-R), estimated premorbid intelligence (Wilson et al., 1978
) and attention (Tables 3 and 4). Nevertheless, the different duration of education had to be interpreted as potential difference in intellectual capacity. Univariate ANCOVA (analysis of covariance) reassured that neuropsychological test performance at baseline, and therefore group classification, could neither be explained by intellectual capacity (covariate: intelligence – estimated full scale IQ) nor by alcohol-related variables (covariates: daily alcohol dose, duration of dependence, number of detoxifications). Only for initial performance on VLT, the IQ (F = 10.62, df = 1, P = 0.003) rather than group association (F = 2.71, df = 2, P = 0.085) predicted performance. Importantly, an unbalanced effect in the different groups of psychiatric comorbidity on neuropsychological test performance appears unlikely, since there was (i) a statistically equal distribution of anxiety, depression, other Axis I disorders as well as personality disorders at baseline and (ii) a comparable reduction of comorbid Axis I disorders from T1 to T5 (Table 2).
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Of groups 1 and 2, routine imaging data were available for 17 patients (5/9 patients of group 1, 12/17 patients of group 2). Diagnostic findings were rated in a blinded fashion as ‘no cortical abnormality’, or ‘slight to moderate cortical abnormality’. Four out of 5 scans in group 1, and 5 out of 12 scans in group 2 were rated to have no cortical abnormality. Whereas performance in HC-related tests at baseline provided our group classification, cortical abnormality per se could not explain initial results of HC-related tests nor predict recovery (
2-tests, t-tests). As expected, all 6 patients with additional brain damage (group 3) were found to have ‘severely abnormal CT/MRI scans’.
Neuropsychological follow-up (time and time x group effects)
Complete neuropsychological data of groups 1 and 2 are summarized in Tables 3 and 4. Abnormal scores, i.e. 
1 SD below the test-provided normative data, are highlighted (grey shaded fields). Group 1 started out with normal baseline values (T1), and did not display significant alterations over time up to T5. Group 2 exhibited distinct but circumscribed deficits upon study entry in all of the 3 HC tests. Significant improvement to values within the normal range at 2 years of abstinence was noticed comparing data of T1 and T5 on VLT (P = 0.039), NVLT (P = 0.002), and City Map Test (P = 0.001). There was also a significant reduction of omission errors on TAP subtest Crossmodal Integration (P = 0.05) which partly reflects HC functions. Attention test performance had remained essentially unaffected by chronic alcohol use in both groups and hence did not show signs of recovery.
The small group 3 (n = 6) expectedly proved heterogeneous during neuropsychological follow-up with highly varying test results in the different cognitive domains. Nevertheless, a comparison of performance between all three groups over time on the City Map Test yielded significant results when repeated measures ANCOVA adjusted by WAIS-R estimated full scale IQ was applied (F = 5.405, df = 2, P = 0.01). Figure 3 illustrates the different recovery of the three patient groups in the City Map Test.
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Impact of HC dysfunction on clinical outcome
A question of high practical relevance was whether the absence or presence of HC damage and/or recovery had any effect on clinical outcome data. The impact of initial HC dysfunction on long-term abstinence probability is presented as Kaplan–Meier survival curves in Figure 4. Of all patients included (= baseline testing performed in N = 50), group 2 (with HC dysfunction; n = 30) has the tendency of a higher risk to relapse as compared to groups 1 and 3 (n = 11 and n = 9, respectively) (log rank = 3.54, df = 2, P = 0.17). This tendency is further supported by Cox regression analysis estimating the predictive value of initial HC performance on time to relapse (B = –0.524, SE = 0.276, Wald = 3.603, df = 1, P = 0.058). In fact, the higher the degree of recovery (delta T5–T1 of the 3 HC tests) over 2 years of strict abstinence (which in turn depends on the degree of initial damage), the higher the cumulative probability of relapse during the 4-year follow-up period (B = 1.472, SE = 0.7, Wald = 4.422, df = 1, P = 0.035).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The present investigation demonstrates that more than two thirds of a representative population of severely affected chronic alcoholics display prominent HC dysfunction after 2–3 weeks of monitored alcohol abstinence. Most importantly, we demonstrate that, in the absence of additional brain damage, there is a slow but considerable recovery of HC performance in alcoholic patients who remain strictly alcohol abstinent. Patients with normal HC performance after detoxification as well as patients with additional brain damage do not show any improvement in performance over an observation period of 2 years of monitored abstention from alcohol.
Previous work on recovery of cognitive function in alcoholics yielded diverse and conflicting results. In contrast to our findings, several studies report on rapid improvement of functions (Kish et al., 1980; Leber et al., 1981; Drake et al., 1995; Mann et al., 1999; Tracy and Bates, 1999; Munro et al., 2000; Wegner et al., 2001) or do not find any signs of recovery but, instead, remarkable residual deficits (Brandt et al., 1983; Yohman et al., 1985; Parsons et al., 1990; Schandler et al., 1996). A recent study with long-term follow-up of female patients also reported slow recovery over as long as 4 years (Rosenbloom et al., 2004). Explanations of all these obvious discrepancies may be found in (i) a lack of objective abstinence control, (ii) a comparison of predominantly cross-sectionally analysed patient populations, resulting in restricted intra-individual follow-up data, (iii) the inconsistent exclusion of alcoholic patients with comorbid disorders/risk factors, (iv) the use of test batteries that do not allow to sensitively assess HC function, or (v) the time point of testing (e.g. during extended withdrawal). In fact, for investigating improvement of cognitive performance in alcoholics during periods of monitored alcohol abstinence, at least two different ‘phases of recovery’ have to be considered: A first phase that may be predominantly due to resolution of withdrawal symptoms together with recovery from acute intoxication, and a much more prolonged second phase of functional/morphological regeneration in which non-reported relapses may well interrupt cognitive recovery.
Importantly, patients with initial HC dysfunction in the absence of additional brain damage did not simply show global cognitive impairment. In most of these patients, there was a predominant HC impairment, whereas intellectual abilities and basal parameters of attention remained within the normal range. Also, preliminary analysis of a comprehensive set of executive function data did not reveal a simple association with HC performance (data not shown). The City Map Test proved to be the most sensitive test for evaluation of HC function in abstinent alcoholics and its recovery over time. It is a free recall test with purely visuospatial material, measuring orientation, processing of visuospatial information, learning, and memory. The fact that the group of patients without HC deficits upon entry showed a higher level of education and a lower amount of daily alcohol intake, raised the question of whether these two variables might explain the differences in HC function found between the two groups. Analysis of covariance, however, integrating these variables as covariates did not reveal an impact of intellectual abilities or alcohol dose on neuropsychological test results that would have changed the overall picture. Furthermore, a systematic effect of psychiatric comorbidity on HC test performance seems unlikely, with both groups showing a similar distribution and remission of comorbid psychiatric disorders. The same holds true for a potential influence of long-term deterrent medication on cognition. Groups did not differ with respect to dose and duration of intake of either disulfiram or calcium carbimide (data not shown). A major impact of practice through repeated testings can be excluded since neither the group without initial deficits in HC performance nor the group with additional brain damage showed any evidence of a ‘learning-curve’.
An interesting topic of the present investigation as well as of previous work of other authors (Franceschi et al., 1984; Fein et al., 1990) is the question of why approximately one-third of severely affected chronic alcoholics do not display any measurable deficits in HC performance. The most attractive interpretation of this result is the presence of predisposing versus protective factors in the nervous system of these individuals which might be either of genetic or/and of environmental nature. Investigations to come should include genetic evaluation of various neuroprotective systems, e.g. of antioxidative pathways, of calcium binding proteins, or of components of the erythropoietin system (Neiman, 1998; Dirnagl et al., 2003; Juul et al., 2004). Furthermore, future studies should try to make use of recent developments in imaging technology for follow-up of morphological recovery. Of note is the fact that in the present study, evaluation of routine brain imaging results was neither helpful in predicting HC test performance nor estimating potential of recovery. This finding is in agreement with previous literature (Pfefferbaum et al., 1988; Sullivan et al., 1995; Ratti et al., 1999), and questions the importance of routine imaging technology for neuropsychological follow-up studies.
Perhaps the most important take-home message of the present study is the finding, during strictly monitored long-term abstinence, of a slow but remarkable recovery process, which may well continue over more than the 2 years follow-up reported here (Rosenbloom et al., 2004) (Reed et al., 1992). Assuming that the degree of cognitive impairment acts as a predictor of probability to relapse (based on a clear tendency seen in our patient population), a strictly abstinence-oriented comprehensive long-term therapy programme will, by increasing the probability of cognitive recovery, improve global therapy outcome.
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ACKNOWLEDGEMENTS |
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This study was funded partly by the Max-Planck-Society and partly by a grant from the Ministry of Labor and Social Services, Lower Saxony, Germany.
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