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protein is prevalent in chronic alcoholics, ADINOLFI’S writings on the vulnerability of the fetal brain to immune attack, and the precedents of maternal immune attack upon the fetus provided by BEHAN et al. and SCOTT et al., when taken together point to the possibility of an immune mechanism in the etiology of FAS which should be actively explored.

JOHN WARREN FOSTER Theoretical Foundations of

Education Program, College of Education, Arizona State University, Tempe, Arizona 85281.

References 1 . Abel, E. L. (1982) ‘Consumption of alcohol

during pregnancy: a review of effects on growth and development of offspring.’ Human Biology, 54, 42 1-453.

2. Abel, E. L. (1985) Fetal Alcohol Exposure and Effects: A Comprehensive Bibliography. Westport, Connecticut: Greenwood Press.

3. Brown, N. A., Goulding, E. H., Fabio, S. (1979) ‘Ethanol embryotoxicity: direct effects on mammalian embryos in vitro.’ Science, 206, 573-575.

4. Higuchi, Y., Matsumoto, N. (1984) ‘Embryo- toxicity of ethanol and and acetaldehyde: direct effects on mouse embryo in vitro.’ Congenital Anomalies, 24, 9-28.

5 . Jankovic, B. D., Jukulic, S., Horvat, J . (1982) ‘Hypersensitivity to human brain S-100 protein in chronic alcoholics.’ Clinical and Experi- mental Immunology, 49, 598-602.

Left-handedness and Lea rn I ng Left-handedness has for a long time been regarded as a risk factor for learning disabilities. Admittedly we live in a right- handed world and certain tasks will be awkward for the left-handed. For a start, writing from left to right must present problems, as well as the use of certain implements, although an increasing number are now made specially for left- handers. On the other side, there may be advantages, as suggested by Geschwind (BBC television programme). This author

6. Sarker, S. , Chang, H. C., Porreco, R. P. , Jones, 0. W. (1980) ‘Neural origin cells in amniotic fluid.’ American Journal of Obstetrics and Gynecology, 136, 67-72.

7 . Lincer, P., Moscona, A. A. (1982) ‘Distribution of S-100 in avian neural retina.’ Develop- mental Neuroscience, 4, 433-441.

8. Beer, A. E., Billingham, R. E. (1976) The Immunology of Reproduction. New York: Prentice-Hall.

9. Adinolfi, M., Wood, C. B. S. (1969) ‘Ontogenesis of immunoglobulins and components of complement in man.’ In Adinolfi, M. (Ed.) Immunology and Development. Clinics in Developmental Medicine, no. 34. London: S.I.M.P. with Heinernan Medical.

10. Adinolfi, M. (1976) ‘Neurological handicap and permeability of the blood-cerebrospinal fluid barrier during fetal life to maternal antibodies and hormones.’ Developmental Medicine and Child Neurology, 18, 243-246.

1 1 . Wolin, S. L., Steitz, J . A. (1984) ‘The Ro small cytoplasmic ribonucleoproteins: identification of the antigenic protein and its binding site on the Ro RNAs.’ Proceedings of the National Academy of Science USA, 81, 1996-2000.

12. Behan, W. M. H., Behan, P. O., Geschwind, N. (1985) ‘Anti-Ro antibody in mothers of dyslexic children.’ Developmental Medicine and Child Neurology, 21, 538-542.

3. Scott, J . S. , Maddison, P. J . , Taylor, P . V., Escher, E., Scott, O., Skinner, R. P. (1983) ‘Connective-tissue disease antibodies to ribonucleoprotein and congenital heart block.’ New England Journal of Medicine, 309,

4. Majewski, F., Goecke, T, (1981) ‘Alcohol embryopathy: studies in Germany.’ In Abel, E. L. (Ed.) Fetal Alcohol Syndrome. Volume 2: Human Studies. Boca Raton, Florida: CRC

209-2 12.

Press. pp. 65-88. 15 . Veghelyi, P. V., Osztovics, M. (1979) ‘Fetal

alcohol syndrome in a child whose parents had stopped drinking.’ Lancet, 2, 35-36.

has a personal interest in the Kerrs, who were said to be predominantly left- handed, as many of his ancestors belonged to this clan. Their advantage was the building of the spiral staircases in their castles the wrong way around, so they could more easily slay their right- handed enemies. (However, they must have been better in defence than attack, as there is an old Scottish ballad about a battle in the 17th century in which four Kerr brothers ran away, and as a result were all disinherited by their father.)

In the past left-handers have often been considered as a homogenous group and studied accordingly. However, some children are strongly left-handed from an early age, and usually left-footed and

eyed as well. Also there is often a family history of left-handedness. Others take a long time to decide which hand they prefer, and even then perform some tasks with one hand and some with the other. There is often so-called ‘crossed’ laterality, with hand and foot showing a different preference. It may well be that some of these chiidren are not natural left-handers but have preferred to use their left hand because their right hand is clumsy, so it proves easier to use the left.

Left-handers, who may find it easier to think in three dimensions because of their right-sided cerebral dominance, are said to make good architects; and perhaps for the same visual perceptual reasons, top- ranking tennis players. However, it must be stressed that only a certain number of left-handers show evidence of right- hemisphere dominance, so there may be many other reasons for being exceptionally good at some ’particular task.

BISHOP’ reviews theories relating laterality to developmental disorders, The idea that all left-handers are brain- damaged has received no convincing support, but what about the significance of crossed laterality? This is certainly one of the items recorded in many preschool medical examinations. 16 studies were reviewed and only two showed a weak relationship between crossed dominance and reading retardation. As confirmed by BISHOP, such crossed dominance is common and should not be regarded as an atypical finding; and there is no special relationship between handedness and the dominant eye. Also, there is really no definite evidence that atypical speech representation is detrimental to normal development. There is the theory that cerebral lateralisation is a progressive process, so that mixed handedness is due to a developmental lag, but lack of clear hand-preference is more likely to be due to immaturity of motor or cognitive development than to immaturity of cerebral lateralisation. Strong hand- preference seems to depend on the level of skill required for a particular task, so the more untrained activities are the more mixed or confused dominance is likely to be. However, in that case adults with no particular hand-preference should show

immaturity of learning, which does not seem to be the case. BISHOP in her review emphasises that one must distinguish between two kinds of mixed handedness: some people are stable and will continue as mixed-handers into adulthood, while others go through a period of inconsistency of hand usage in early childhood but then develop a stable preference for one side.

Then BISHOP considers evidence which suggests that there are ‘normal’ and ‘pathological’ left-handers. Impairment of arm and hand function due to an interference with the development of one or other cerebral hemisphere may result in a particular choice of handedness, because it is easier to use one hand than the other. If it can be presumed that such impairment is equally likely to affect the right or left side and the left hand is affected, most people will remain right- handed (left-handers make up about 10 per cent of the general population) and only a few who would have been left- handed will switch to the other hand because the left hand is clumsy. However, most of those with an impaired right hand will, for the same reason, choose to use their left hand and become pathological left-handers. This means that unilateral brain-damage will lead to a raised incidence of left-handedness and the proportion of ‘pathological’ handedness will be much higher among left-handers. It does seem reasonable to suggest that pathological left-handedness can occur in those without gross motor impairment, and BISHOP’ suggested that one way to test this hypothesis was by examining the function of the non-preferred hand. She has found, indeed, that there is no evidence that left-handers as a group are clumsier than right-handers, but that among children selected on the basis of clumsiness of the non-preferred hand, there is a raised incidence of left-handers. BISHOP’ found that among children with no ‘neurological’ history or mental retardation about 5 per cent of left handers are ‘pathological’, while among those with such a history and cognitive deficits the proportion is much higher. Also, there was a high incidence of speech problems in left-handed children with poor non-preferred hand scores, 65 7

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2 presumably due to left cerebral- hemisphere lesions causing the disruption

area on that side3. The results certainly show that pathological left-handedness is not restricted to children with obvious hemiplegia.

GILLBERG et aL4 studied 45 left- handed children (22 boys and 23 girls) and a control group of right-handers (20 boys and 26 girls). The age-range was 9.4 to 10.2 years, and none suffered from any major neurological handicap or from mental handicap.

Among the 45 left-handers, 20 were regarded as ‘pathological left-handers’, due to their poor performance with their right hands, while only 10 right-handers out of 46 showed significantly poor performance with their left hands. ‘Normal’ left-handers had significantly more left-handed relatives than right- handers, while ‘pathological’ left-handers had about the same number as ‘normal’ right-handers. The latter group had significantly more prenatal, perinatal and postnatal problems than the control group, and significantly lower marks for spelling, writing and reading; as well as having more learning disorders requiring special education. The differences in school achievements and in behavioural problems, which were also more frequent among the ‘pathological’ children, were mainly accounted for by left-handed boys, suggesting that left-handedness in boys is more often a symptom of a pathological shift of handedness than is left-handedness in girls. These studies emphasize that left handedness may be due to a number of causes, and only some are left-handed because of damage to the brain or impairment of its development; and therefore likely to manifest disorders of learning.

It can no longer be maintained that verbal and manual dominance are two aspects of the same function, although there are obvious links. As far as language is concerned, representation may range from almost total left-sided dominance through equal dominance to moderate right-sided dominance, the first being the most frequent. Therefore it may be better to talk about cerebral preponderance than

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Genetic factors are likely to be of importance in deciding on lateralisation of functions when it is not just a matter of chance. ANNETT’S Right Shift theory is a particularly attractive one6. While admitting that acquired cerebral lesions may sometimes be the deciding factor in the choice of preferred hand, she maintains that, apart from this, her genetic theory can explain many of the findings. This suggests that the population is divided into those who are right-handed, those who are left-handed and those who prefer one hand for some tasks and the other hand for others. The human distribution resembles that of other mammals in all essential respects, except that it is shifted to the right. This shift can be a by-product of a factor that induces speech representation in the left cerebral hemisphere; which may well be genetic.

In the genetic model proposed there is a single allele (7s + ) at one locus which induces a shift to the left hemisphere of speech function. The alternative alleles at that locus are neutral or indifferent to laterality (7s-), and it is assumed the gene is dominant, in that left- hemiphere speech is likely to be induced when the gene is present on one or both chromosomes. Right-hemisphere or bilateral speech is assumed to occur only in the 7s- - . How the gene works is unknown, but it may depend on the relative rates of maturation of the right and left cerebral hemispheres. If the 7s + gene facilitates language development by organising this function mainly within one hemisphere, it is likely to be more efficient. As a possible alternative, lateralisation of language to the left hemisphere may be induced by some factor that slows down or otherwise impairs the growth of the right hemisphere. The 7s+ + genotype may therefore be disadvantageous, while left- handers have an absolute advantage in hand skills.

The persistence of left-handedness in spite of the 7s + gene being dominant can be due to balanced polymorphism, the most favoured genotype being 7s + - , other alternatives having possible disadvantages and advantages.

The main r6le of the T S + gene is to

facilitate the development of a speech output-input loop system on the left side of the brain. Then the close proximity of the mouth and hand areas in the sensorimotor cortical strip suggests that any advantage to the left hemisphere mouth-area would be likely to give an incidental advantage to the right hand. Alternatively, there may be inhibited growth of the sensorimotor cortex for the left hand. Whatever the answer, an inequality is introduced which biases the random chance of superiority on either side in favour of left-hemisphere speech, and preference for the right hand. When the gene is absent, the output-input loop involves either or both hemispheres by chance.

In a detailed review of cerebral lateralisation, GESCHWIND and GALABURDA7-9 raise a number of interesting arguments. Only a few aspects of the various hypotheses suggested can be considered from such a long discourse. Perhaps the main theme is to challenge the theory of a genetically determined pattern of asymmetry, although there is common ground with some aspects of ANNETT’S theory. In their opinion, however, this and other genetic theories have serious shortcomings. Their thesis is that while genes make a contribution, many influences outside the gene pool of the fetus can alter lateralisation patterns. The stated intent of their hypothesis is to account for the facts that left-handedness is more common in men than women; that the developmental disorders of language, speech and cognition predominate among males; that women on average are superior in verbal talents, while men on average tend to be better at spatial functions; that left-handers of both sexes and those with learning disabilities often exhibit superior right-hemisphere functions; that left-handedness and ambidexterity are more frequent in the developmental disorders of childhood; and that certain diseases, for example immune disorders, are more common in non right-handers.

As they say’, their hypothesis is that the basic pattern of most brains includes a larger left side, and certain influences in the course of pregnancy tend to slow development of the left side of the brain.

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towards symmetry, and occasionally to 3 asymmetry, favouring the right side. r\l

image of ANNETT’S; a strongly left- hemisphere basic dominance pattern and

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2 increasing symmetry and therefore random dominance. 2 Much evidence is reviewed which .2:

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supports the hypothesis that left- handedness is determined by events in (u

.E utero. It is suggested that variations in the * 9 asymmetry of neurological function

reflects influences of an endocrine or - immune nature acting during the development of the nervous system. Slowed growth within certain zones of the left cerebral hemisphere may result in enlargement of other cortical areas, in particular the homologous contralateral area and unaffected areas on the same side. Hormonal influences on laterality may be particularly important. Major effects of testosterone on neuronal development have been demonstrated, and it is postulated that such hormones slow the growth of the convexity of the left cerebral hemisphere in utero; and this will be greater in the male because the fetal testes secrete this hormone. This would also account for the higher frequency of sinistrality and of learning disorders in men. There is certainly evidence from animal studies that testosterone can selectively affect the development of parts of the cortex on one or other side of the brain8. Testosterone also affects the growth of other tissues, in brain, or part of the brain, the more liable particular the growth of structures involved in immunity such as the thymus gland. This may be a link between sinistrality and immune disorders.

These influences could also be related to a greater risk of the altered immune processes leading to diseases in early infancy, particularly infections, which may damage the more immature left cerebral hemisphere’.

The initial asymmetry may have resulted phylogenetically from the advantages of brain asymmetry and the resulting ability to learn and adapt, and the effect this may have had on survival.

Their hypothesis is essentially a mirror

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2 In terms of human evolution, early development of the right hemisphere could have been essential for survival, with its major r81e in spatial function, particularly external space and the orientation of the body within this space, as well as its major r81e in emotion and attention'. It could be that the inherited asymmetries of the brain are carried by cytoplasmic genes associated with mitochondria" and, to repeat, as far as the GESCHWIND and GALABURDA theory is concerned, whatever the genetic endowment this will be modified by a number of different external factors.

The effects of lesions will be different at various ages-prenatal and perhaps early postnatal life, childhood, adolescence and adult life. The earlier development of parts of the right hemisphere concerned with perceptual functions in the first year or two of life implies that it may be less subject to disrupting influences in early infancy if it is accepted that the more immature the brain, or part of the brain, the more liable it is to suffer from noxious agents. The converse will be true when language function is predominant in later childhood and the left cerebral hemisphere in most people becomes relatively more mature". There are many and varied asymmetries in the human brain which must underlie the diversity of the population, and these are present from early fetal life. Also, structural asymmetries of the brain are by no means confined to vertebrates and occur in any number of invertebrates.

There are few neuropathological studies of the brain in developmental dyslexia but in some of these the findings can be attributed to alterations to the cortex, and to the related subcortical structures, of a developmental nature. GALABURDA and colleagues12 report on the neuro-anatomical findings in the brains of four males with developmental dyslexia. The patients' ages ranged between 14 and 32 years, and dyslexia had been diagnosed during life. All four brains showed developmental anomalies of the cerebral cortex: these consisted of neuronal ectopias and architectonic dysplasias, located mainly in the perisylvian regions, predominating on the

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left side. Also, all the brains showed a symmetry of the planum temporale, instead of the more usual larger planum on the left side. The lesions seen are developmental anomalies acquired some time before birth, possibly at a time that coincides with peak rates of neuronal migration from the germinal zones to the cerebral cortex. It is postulated that the pathological changes accounted for the dyslexia, or that lesions inhibiting the growth of language-related structures during development may be accompanied by improved growth of other structures, which may help to explain the better development of non-linguistic functions among many with dyslexia.

GESCHWIND and GALABURDA' rightly indicate that major disorders of neuronal migration and assembly producing gross lesions are described in detail by neuropathologists, but minor develop- mental defects tend to be ignored. As already mentioned, GESCHWIND and BEHANI3 have also found an increased number of left-handers among those with disorders of the immune system, which they attribute to the same type of delay, perhaps related to hormonal influences, affecting this system as well as the brain; and also among those with migraine, which may sometimes have an allergic path~genesis '~ although others do not confirm thisI5. GESCHWIND and BEHAN'~ agree that further research is needed in this field, and it seems a fertile one, particularly to identify acquired factors which may influence cerebral dominance.

The increased interest in those who prefer to use their left hand has already clarified some of the problems. It has certainly shown that they are indeed a heterogenous group, and only if the left- handedness is a symptom of some disturbance of cerebral function are other symptoms of such a disturbance, for instance difficulties in learning, likely to occur. These are the children who seem to be at risk and who should be identified early in their school-life so that their progress can be monitored.

Rather than recording crossed laterality, doctors working in schools may be better employed testing the function of the non-preferred hand, especially of left- handers, for example with a square-

tracing task’. More information is needed about the progress of these children and the types of learning problems they may develop; since if the non-preferred hand is abnormally clumsy, this is a sign of impaired cerebral function.

Booth Hall Children’s Hospital, Charlestown Road, Blackley, Manchester M9 2AA.

References

NEIL GORDON

1. BishoD. D. V. M. (1983) ‘How sinister is sinisirality?’ Journal’of the Royal College of Physicians, 17, 161-172.

2. Bishop, D. V. M. (1980) ‘Handedness, clumsiness and cognitive ability.’ Develop- mental Medicine and Child Neurology, 22,

3. Bishop, D. V. M. (1984) ‘Using non-preferred hand skill to investigate pathological left- handedness in an unselected population.’ Developmental Medicine and Child Neurology, 26, 2 14-226.

4. Gillberg, C., Waldenstrom, E., Rasmussen, P. (1984) ‘Handedness in Swedish 10-year-olds. Some background and associated factors.’ Journal of Child Psychology and Psychiatry,

5. Joynt, R. J. (1985) ‘Cerebral dominance.’ Archives of Neurology, 42, 427.

6. Annett, M. (1985) Left, Right Hand and Brain: the Right Shift Theory. London: Lawrence Erlbaum.

569-579.

25, 421-432.

7. Geschwind, N., Galaburda, A. M. (1985a) ‘Cerebral lateralization. Biological mechan- isms, associations and pathology. I: A hypothesis and a program for research.’ Archives of Neurology, 42, 428-459.

8 . Geschwind, N., Galaburda, A. M. (198%) ‘Cerebral lateralization. Biological mechan- isms, associations and pathology. 11: A hypothesis and a program for research.’ Archives of Neurology, 42, 521-552.

9. Geschwind, N., Galaburda, A. M. (1985~) ‘Cerebral lateralization. Biological mechan- isms, associations and pathology. 111: A hypothesis and a program for research.’ Archives of Neurology, 42, 634-654.

10. Corballis, M. C., Morgan, M. J . (1978) ‘On th: biological basis of human laterality. Behavioral Bruin Science, 2, 261-336.

11. Ounsted, C., Taylor, D. C. (1972) Gender Differences: Their Ontogeny and Significance. Edinburgh: Churchill Livingstone.

12. Galaburda, A. M., Sherman, G. F., Rosen, G. D., Aboitiz, F., Geschwind, N. (1985) ‘Developmental dyslexia: four consecutive patients with cortical anomalies.’ Annals of Neurology, 18, 222-233.

13. Geschwind, N., Behan, P. (1982) ‘Left- handedness: association with immune disease, migraine and developmental learning disorders.’ Proceedings of the National Academy of Sciences, V.S.A., 19, 5097-5100.

14. Egger, J., Carter, C. M., Wilson, J., Turner, M. W., Soothill, J. F. (1983) ‘Is migraine food allergy?’ Lancet, 2, 865-869.

15. Blau, J . N. (1985) ‘Migraine and left- handedness.’ Lancet, 2, 757.

16. Geschwind, N., Behan, P. (1984) ‘Hormones, handedness and immunity.’ Immunolofgy Today, 5, 190-191.

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