Department of Psychiatry, Friedrich Alexander University of ErlangenNuremberg, Germany,
1 Anton Proksch Institute Vienna, Austria and
2 Department of Medical Informatics, Biometry and Epidemiology, University of NurembergErlangen, Germany
Received 14 January 2000; in revised form 23 March 2000; accepted 29 March 2000
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ABSTRACT |
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INTRODUCTION |
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Handedness continues to be the leading peripheral parameter for the determination of cerebral hemispheric dominance. In conjunction with the marked preponderance of right-handedness (RH) vis-à-vis non-right-handedness (NRH) among the general population (ratio 8:2), the results of a wide range of investigations, in particular those involving the high-risk group of schizophrenic psychoses, point to a deviation from normal distributions towards an increase in NRH (ratio 8:3) (Flor Henry, 1979; Geschwind and Behand, 1984
; Mednick and Machon, 1988
; McNamara et al., 1994
). The hypothetical question is, therefore, is there any relationship between mental deviations from the norm on the one hand, and peripheral laterality deviations as an indicator of deviant cerebral hemispheric organization on the other?
To date, this hypothesis has been applied mainly in the area of basic research into schizophrenic and affective psychoses, but also in addiction (Luchins and Weinberger, 1982; Lesch et al., 1988
; Lesch, 1990; Olsen, 1995
; Lesch and Walter, 1996
). LH in alcoholism might also be related to high-risk drinking associated with a high relapse rate and learning disorders (Lesch and Walter, 1996
). In addiction, in particular alcoholism, a subtle prenatal toxic effect of alcohol on the developing brain manifesting as a disturbed hemispheric organization has been discussed (London and Glick, 1988
).
A correlation between pre-, peri- and postnatal developmental risk factors and NRH as a possible marker of disturbed cerebral organization has not been shown for alcoholics. The present study evaluates the relationship between evidence of NRH and the risk for alcohol dependence, as well as psychiatric manifestations associated with heavy drinking, with special attention given to a subtype-oriented classification that differentiates between various aetiological factors in biological, psychological and social areas. The classification of Cloninger et al. (1988) distinguishes between two subtypes, depending mainly on age of onset, whereas that of Lesch et al. (1988) envisages four subtypes of alcoholism (see Table 1), which are briefly described as follows.
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Type II alcoholics make use of alcohol as a strategy for coping with conflicts. The anxiety-ameliorating effect of alcohol improves the communication skills of these alcohol-dependent patients. Without alcohol, they are over-conformers. An abstinence syndrome or sequelae of alcohol abuse are rare and not severe.
Type III alcoholics use alcohol for self-medication. In these patients, there is a family history of changes in mood and drive, as well as in well-being, and failure to maintain sleep is a frequent disorder. However, drinking aggravates the patient's situation. Aetiologically, alcohol itself can produce psychopathological disturbances.
In Type IV patients, certain disturbances are already clear before they embark on a career of drinking. In comparison with patients of Types I, II and III, these patients have more often evidence of prenatal cerebral damage (e.g. prenatal ischaemic brain damage, damage to cerebral white matter, ischaemic cerebral lesions, pre-eclampsia, intrauterine growth retardation, chronic intrauterine hypoxia) resulting in behavioural problems in childhood, for example, persistent stuttering, nail biting, nocturnal enuresis after the age of 3 years. Aetiological aspects under discussion are inadequate impulse control and a lack of critical faculty. At the centre of biological research are dopaminergic and serotonergic mechanisms. The suspicion of increased vulnerability in addiction, and in particular alcohol dependence, is prompted by the disturbances seen at various levels (genetic, biological, social, psycho-social).
Within the vulnerability model, and against the background of the resulting differentiation of subtypes, we may postulate an increased detection of meaningful trait markers in the most strongly pre-burdened Lesch Type IV subgroups and in the Type II group in Cloninger's classification. In a joint project undertaken by the University of Erlangen and the Anton Proksch Institut in Vienna involving a total of 250 alcohol-dependent patients, the question of laterality has been investigated with consideration being given to developmental risk factors.
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SUBJECTS AND METHODS |
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In accordance with the hypothesis noted in the Introduction, the parameters handedness and developmental risk history in subtype groups of alcohol-dependent patients were investigated. The members of the control group were recruited from volunteers of an athletics club (n = 122), a group of students (n = 84), and non-medical hospital staff (male and female nurses) (n = 44). Their ages ranged from 21.8 to 67.3 years. Alcoholism or other addictions in this group were excluded on the basis DSM-III-R criteria (American Psychiatric Association, 1987). In the initially non-differentiated overall group of alcoholics, at least seven DSM-III-R criteria for alcohol dependence were met by all the patients in the study. Patients were examined on average 28.3 days ± 2.4 days after admission.
Abstinence was ensured by regularly carrying out (unannounced) tests for blood alcohol (and the serum and blood enzyme and other studies including the parameters aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, mean corpuscular volume, carbohydrate- deficient transferrin). Subtyping of the alcohol-dependent patients was effected in accordance with the Cloninger classification and the Lesch typology (see Table 1). Both classification systems permit a subtype-specific categorization also on the basis of the criteria of developmental vulnerability.
Experimental design
Determination of handedness was carried out using the Shimizu design (Shimizu and Endo, 1985) involving 13 scores (see Table 2
). The individually determined results were then used to establish a summed score that made possible a definitive assignment of each patient to RH, LH and ambidexterity, which were included in the group of NRH. To clarify adequately the question of genetic influence on handedness (family handedness), the handedness of the immediately preceding and immediately following generations was determined using the same design (Shimizu questionnaire).
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Pregnancy. Questioning proceeded from the general (do you remember anything special about the pregnancy?) to the particular (did you have any infections?) and specific questions. If the mothers could not recall any difficulties, they were asked about specific prenatal, perinatal and obstetric complications using the maternal infectious disease and obstetric complications questionnaire developed by Stöber et al. (1997). The following complications were listed:
Prepartum. History of spontaneous abortion or perinatal death, trauma, obesity, diabetes mellitus, pre-eclampsia, eclampsia, blood group incompatibility, signs of imminent abortion, premature rupture of membranes, placental infarction, hydramnion, oligohydramnion, vaccinations, use of medications or drugs.
Maternal infectious disease. Nasal catarrh or cough lasting for at least 2 weeks, common cold, febrile cold, bronchitis, influenza, pneumonia, sinusitis, otitis media, tonsillitis, gastroenteritis, urinary infection (cystitis, pyelonephritis), localized pyogenic infections (abscess, phlegmon), salmonella, rubella, measles, mumps, varicella, hepatitis, herpes zoster, venereal diseases, osteomyelitis, meningitis, sepsis.
Intrapartum. Gestational age <37 weeks, >42 weeks, birth weight <2500 g, narrow pelvis during delivery, unfavourable fetal position, premature rupture of membranes, bleeding during labour, placental ablation, cord complications, meconium staining, instrumental delivery (vacuum, forceps, Caesarean section).
Postpartum. Respiratory disturbances (asphyxiation, blue baby, resuscitation, baby in incubator), cardiac arrest, hyperbilirubinaemia, CNS (convulsions, opisthotonus, lethargy, poor suckling), infections after birth. Further questions included the use of medications, drugs, smoking, drinking, stress, possible exposure to environmental hazards, medical treatments, including those for concurrent disorders. If an obstetric complication or infectious disease was reported, the mother was questioned closely about its duration, symptoms and treatment to determine the most likely diagnosis.
Confirmed and possible complications according to the scale of Lewis (1987) were recorded, but only one definite complication (each subject) was counted in the analysis. The interviewers were blind to the diagnoses.
Exclusion criteria were: (1) patients with endogenous psychoses (depressive or anxiety states during the withdrawal stage within the first 3 weeks after detoxification were not considered to represent comorbidity); (2) patients with cerebral damage, non-alcohol-related damage, cerebral tumours, and true cerebral epileptic states; (3) patients undergoing neuroleptic treatment, which has been shown to have a distorting effect on laterality (Oepen et al., 1987).
Statistics
The main scientific questions of our study concerned the gender-related association between handedness and alcoholism and between developmental risk factors and alcoholism. Additionally, the association between the Lesch classification and handedness was investigated. Risk factors were pre-, peri- and postnatal developmental events. According to the study design, all analyses had to be adjusted for gender. In a first group of logistic regression analyses, the association between handedness, pre-, peri- and postnatal events and alcoholism was examined separately. In a second logistic regression analysis, at least one developmental risk factor/no developmental risk factor was analysed simultaneously with handedness. Owing to the fact that in all analyses strong interactions were found between gender and risk factors as well as between gender and handedness (see below), we have presented our final model separately for male and female subjects.
In all logistic regression analyses, P-values and observed odds ratios are given. These odds ratios approximate the relative risk of LH, as compared with RH, and of subjects affected by risk factors, as compared with non-affected subjects. In all statistical tests, the level of significance was set at 0.05 (two-sided). All analyses were performed using SPSS for Windows 9.0.
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RESULTS |
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The risk analysis (prenatal, perinatal, postnatal) revealed 106 events in the group of alcohol-dependent patients, and 41 events in the controls (see Table 5). Most common prenatal risk events were alcohol abuse (n = 14), maternal viral disease during pregnancy (e.g. influenza, herpes, chlamydia, n = 21), Caesarean section and forceps delivery for perinatal risk events (n = 24), parental separation for postnatal risk events (n = 40). Pre-, peri- and postnatal developmental risk factors were statistically significantly more common in alcoholics than in controls (P < 0.05). Prenatal risk events predominated in the second trimester in the group of alcoholic patients.
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DISCUSSION |
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The lumping together of the highly heterogeneous addictive patients into one group of drinkers, with no consideration being given to their individual predisposition and developmental determinants, cannot do justice to understanding the complex problems involved in addictive illnesses. Here, the classification systems proposed by Cloninger and Lesch offer major advantages, since they differ from other systems, in particular in their subtle subtyping.
Within the resulting subgroups, our patients were found to have gender-specific differences, particularly in the case of Lesch Type III and Type IV alcohol-dependent patients. In one category (Type IV) (characterized in particular by prior cerebral damage), alcoholic men clearly predominated a result that was in accord with the results of another study (Lesch et al., 1988).
A gender effect was observed within the Lesch Type III category, in which women clearly predominated. The alcoholism seen in this subtype is characterized by comorbidity taking the form of temporary affective symptoms, and the drinking style is of the self-medication type. A comparison of the overall groups (alcoholics/controls) revealed a clear difference in handedness, with increased rates of NRH in alcohol-dependent individuals. An accurate evaluation of these results, however, was possible only for gender in the alcohol group. This showed a clear predominance of male NRH. The risk factor analysis also revealed a preponderance of male NRH. On the basis of our results, a genetic linkage between alcoholism and laterality appears more probable in males than in females.
In the case of addiction, the vulnerability marker NRH proved to be unequivocally male gender-specific. With regard to subtype-specific vulnerability, both the Lesch and the Cloninger classifications revealed a significantly increased presence of vulnerability markers for acquired or genetically determined cerebral risks [Cloninger Type II (Cloninger et al., 1988) and Lesch Type IV (Lesch et al., 1988
)], in comparison with the other subtypes. In summary, therefore, the following conclusions may be drawn from the data we obtained.
NRH and developmental risk factors are found significantly more often in male alcoholics than in alcoholic women and non-alcoholic controls. These vulnerability results indicate that different gender-specific manifestations occur, an observation that may also apply to other psychiatric illnesses. An evaluation of our data also reveals similarities to other high-risk groups, since increased percentages of NRH and developmental risk factors are also found in schizophrenic subjects (Geschwind and Behand, 1984; Lewis, 1987
; London, 1987
; Mednick and Machon, 1988
; Barr et al., 1990
; Lesch and Walter, 1996
). Of apparent particular relevance in this connection is the fact that an increase in prenatal developmental risk factors occurs just in the vulnerable phase of the second trimester of pregnancy, which has already been under repeated discussion with regard to disorders of neuronal migration in schizophrenics (Bogerts et al., 1990
; Beckmann and Jakob, 1994
).
In this context it must also be considered whether prenatal alcohol exposure (especially in the second trimester) alters the normal development of behavioural laterality. It has been demonstrated in rat models that high-doses of alcohol have a neurotoxic effect on the developing brain and increase the frequency of LH in offspring (Zimmerberg and Riley, 1986, 1988
). In humans, it has been demonstrated that even a moderate intake of alcohol in pregnancy increases the frequency of LH in the children of alcoholics. An earlier study (Olsen, 1995
) showed that 9.1% of the children were LH, with a higher prevalence among boys (11.8%). These results showed a slightly higher frequency of LH among children exposed to alcohol in the womb, but the findings were not statistically significant (Olsen, 1995
). To this extent, the question must be asked whether the disordered cerebral organization based on developmental risk factors includes an entity-going beyond vulnerability model, particularly since this question also needs to be expanded to cover other psychiatric high-risk groups.
The demonstration of a subtype-specific vulnerability in alcoholism research suggests differences in the natural history of the disease in terms of the qualitative and quantitative severity of withdrawal symptoms and the long-term course. Initial relevant results are now available. The major question of interest for clinical application, however, is that of therapeutic relevance.
In particular with respect to the continuing advances, also in the field of prevention of addiction (anticraving), the differentiated concept of vulnerability will probably result in a basic reorientation in the treatment of alcoholism, with consideration being given to accompanying parameters such as prior cerebral damage and psychopathological factors.
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FOOTNOTES |
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