THE CONCEPT OF ABNORMAL HEMISPHERIC ORGANIZATION IN ADDICTION RESEARCH

W. Sperling*, H. Frank1, P. Martus2, R. Mader1, A. Barocka, H. Walter1 and O. M. Lesch1

Department of Psychiatry, Friedrich Alexander University of Erlangen–Nuremberg, Germany,
1 Anton Proksch Institute Vienna, Austria and
2 Department of Medical Informatics, Biometry and Epidemiology, University of Nuremberg–Erlangen, Germany

Received 14 January 2000; in revised form 23 March 2000; accepted 29 March 2000


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In addition to the established areas of endogenous psychoses, the concept of abnormal hemispheric organization in the field of psychiatry is also generating ever greater interest in the area of research into addiction. On the basis of the demonstrably higher rate of developmental risk factors (pre-, peri-, postnatal), in particular the marker left-handedness (LH) has been interpreted as an indication of induced hemispheric ‘malcontrol’ in endogenous psychoses. In various studies, elevated rates of LH have also been shown in alcoholics. Alcoholism could be related to biological factors associated with anomalous cerebral dominance. In a joint study carried out by the Anton Proksch Institut in Vienna (Austria), and the University of Erlangen–Nuremberg (Germany) involving a total of 250 alcohol-dependent inpatients, the hypothesis of deviant laterality in the presence of an elevated frequency of developmental risk factors has been confirmed exclusively in male alcoholics. A comparison of subtypes has also revealed that Type IV in the Lesch typology, and Type II in the Cloninger classification, are more vulnerable subtypes. These results clearly show that there are differences to be found within the overall group of alcoholics, and underscore the need for subtyping and gender-specific studies.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The development of major psychiatric disorders is very complex. It is difficult to pinpoint single characteristics associated with vulnerability to major psychiatric disorders. Among the most prominent and potentially powerful factors are genetic predispositions and evidence of early neurological damage, with the concurrence of these two apparently increasing the risk more than the sum of either alone. One corollary potentially related to both genetics and evidence of early neurologic damage is left-handedness (LH).

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, 1979Go; Geschwind and Behand, 1984Go; Mednick and Machon, 1988Go; McNamara et al., 1994Go). 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, 1982Go; Lesch et al., 1988Go; Lesch, 1990; Olsen, 1995Go; Lesch and Walter, 1996Go). LH in alcoholism might also be related to high-risk drinking associated with a high relapse rate and learning disorders (Lesch and Walter, 1996Go). 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, 1988Go).

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 1Go), which are briefly described as follows.


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Table 1. Alcohol classification systems according to Cloninger et al. (1988) and Lesch et al. (1988)
 
Lesch's Type I alcoholics suffer, often at an early stage, from marked withdrawal symptoms. After a lengthy period of abstinence, the patients have no particular desire for alcohol and manifest no abnormalities in terms of psychosocial behaviour; nor are any major personality disorders to be found. If however, usually depending on the social situation, small amounts of alcohol are consumed, an uncontrollable craving is developed. Aetiologically a primary vulnerability within the metabolism of alcohol is suspected.

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.


    SUBJECTS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The joint investigations were carried out between 1993 and 1998. The Anton Proksch Institute is specialized exclusively in the treatment of alcohol-dependent patients, and offers complete care of alcoholics from the acute phase (acute intoxication, delirium) via detoxification to resocialization measures during abstinence; it is unique within Europe. A total of 250 alcohol-dependent patients, 125 women, 125 men (age range: 19–69 years, mean age ± SD 43.8 ± 23.4 years) were admitted to the study and a gender- and age-matched group of healthy subjects served as a control group.

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, 1987Go). 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 1Go). 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, 1985Go) involving 13 scores (see Table 2Go). 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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Table 2. Handedness questionnaire according to Shimizu (Shimizu and Endo, 1985Go)
 
A history of obstetric complications for each patient and each normal subject was obtained from a detailed highly structured interview with the mother. During the interview, the mother was asked to describe her health status during each trimester of pregnancy.

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., 1987Go).

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.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 3Go shows the subtype classification of alcoholics according to gender. In the Lesch classification, Type II predominated, both in alcohol-dependent women and alcohol-dependent men. Marked gender-specific differences were, however, found in the intra-group distribution of Types III and IV. Thus, male alcohol-dependants were more often Type IV, whereas female alcoholics were more often Type III.


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Table 3. Distribution of Cloninger Types I and II and Lesch Types I–IV in alcoholics
 
Despite predominant RH in both the alcohol-dependent and control groups, the percentage of NRH patients among alcohol-dependent patients was significantly higher (P < 0.05) than among controls (see Table 4Go). For a more accurate understanding of this different distribution, however, a gender-specific presentation of the distribution of handedness is necessary.


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Table 4. Handedness in alcoholics and controls according to gender
 
Alcohol-dependent males had a NRH rate of 44.0%, whereas for women, the figure was 6.4%. In the controls, no statistically significant differences were found between males and females.

The risk analysis (prenatal, perinatal, postnatal) revealed 106 events in the group of alcohol-dependent patients, and 41 events in the controls (see Table 5Go). 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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Table 5. Pre-, peri-, postnatal risk events in alcoholics and controls
 
A statistical comparison between Cloninger type and handedness is not useful because one of the defining items of the Cloninger classification is gender, which was strongly associated with handedness. Analogously, a statistical comparison between both the Lesch and Cloninger classification and risk factors is not adequate. Therefore, these results are given only descriptively. In the Lesch classification, however, the vast majority of LH was classified as Type IV (P < 0.001, Table 6Go). In the Lesch classification, RH predominated within Types I–III.


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Table 6. Handedness according to Cloninger/Lesch subtypes
 
Type IV alcoholics had a particularly high percentage of NRH and the highest rates of pre-, peri- and postnatal risk events. The above-mentioned hypothesis of a correlation between aberrant laterality (NRH) and developmental risk events was confirmed by our investigation. Thus in terms of pre-, peri- and postnatal risk events, NRH alcohol-dependent patients were more significantly affected than RH alcoholics (P < 0.001) (see Table 7Go). In the intra-group gender-specific distribution, only male NRH alcoholics had significantly more developmental risk factors than male RH alcoholics. In the control group, in contrast, no notable increases in developmental risk factors in NRH, as compared with RH, alcoholics were to be found.


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Table 7. Pre-, peri- and postnatal risk events dependent on handedness and gender in alcoholics and controls
 
In the multivariate logistic regression analysis, an overall significant association between handedness (P = 0.002, odds ratio 2.3) and developmental risk factors (P = 0.04, odds ratio 2.0) was found. This, however, does not adequately describe the effects found in our data. In male subjects the odds ratio was 4.2 for handedness (P < 0.001) and 2.9 for developmental risk factor (P = 0.02), whereas for female subjects the odds ratio was 0.6 (P = 0.23) for handedness and 1.2 (P = 0.68) for risk factors. In the male population, no synergistic effect was found between handedness and risk factors (P = 0.72), i.e. the risk of alcoholism in LH affected by developmental risk factors may be computed as 2.9 x 4.2 {approx} 12.2. In other words, vulnerability for alcoholism seems to be increased in male, but not in female, subjects in the presence of LH or developmental risk factors.


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The concept of abnormal hemispheric organization in psychiatry is based on the idea that the final manifestation of mental and/or physical changes is an additive effect of a range of influencing factors. So far, the latter have not been clearly defined. However, in this context, abnormal cerebral hemispheric organization showing correlations with pre-, peri- and postnatal developmental risk factors in different psychiatric diseases must be discussed. According to this concept, abnormal cerebral organization means a more frequently occurring combination of mental diseases and anomalies of peripheral laterality with simultaneous evidence of developmental risk factors. However, in the last instance, the triggering threshold for disease remains specific to the individual. To this extent, the data we have collected on vulnerability in alcohol-dependent patients are not to be interpreted in the sense of a sine qua non claim.

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., 1988Go).

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., 1988Go) and Lesch Type IV (Lesch et al., 1988Go)], 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, 1984Go; Lewis, 1987Go; London, 1987Go; Mednick and Machon, 1988Go; Barr et al., 1990Go; Lesch and Walter, 1996Go). 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., 1990Go; Beckmann and Jakob, 1994Go).

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, 1986Go, 1988Go). 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, 1995Go) 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, 1995Go). 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.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
* Author to whom correspondence should be addressed at: Department of Psychiatry, University of Nuremberg–Erlangen, Schwabachanlage 6–10, 91054 Erlangen, Germany. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
American Psychiatric Association (1987) Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised. American Psychiatric Association.

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Flor Henry, P. (1979) Laterality shifts of cerebral dominance, sinistrality and psychosis. In Hemispheric Asymmetries of Function in Psychopathology, Gruzelier, J. and Flor Henry, P. eds, pp. 3–19. Elsevier, Amsterdam.

Geschwind, N. and Behand, P. (1984) Laterality Hormones and Immunity. In Cerebral Dominance: The Biological Foundations, Geschwind, N. and Galaburda, A. M. eds, pp. 211–224. Harvard University Press, Cambridge, MA, USA.

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