Functional brain electrical activity mapping in boys with attention-deficit/hyperactivity disorder.

BACKGROUND: Symptoms of attention-deficit/hyperactivity disorder (ADHD) have been associated with frontal lobe deficits. We used a novel brain electrical imaging method to investigate rapid and continuous changes in brain activity during the continuous performance task (CPT) in normal boys and in boys with ADHD. The amplitude and latency topography of the steady-state visually evoked potential (SSVEP) were examined while subjects performed the "X" version of the CPT (CPT-X; the reference task) and the "A-X" version of the CPT (CPT-AX). METHODS: Seventeen boys meeting DSM-III-R criteria for ADHD and 17 age-matched controls participated in the study. Brain electrical activity was recorded from 64 scalp sites. During the reference task, subjects pressed a microswitch on the unpredictable appearance of the letter X. During the CPT-AX, subjects were required to press the microswitch on the appearance of the letter X only if an A had preceded it. RESULTS: In the interval between the appearances of the A and the X of the correct trials of the CPT-AX, control boys showed transient reductions in SSVEP latency at right prefrontal sites. By contrast, boys with ADHD showed no change or an increase in prefrontal SSVEP latency at right prefrontal sites. CONCLUSION: Our results suggest increased speed of prefrontal neural processing in children without ADHD following a priming stimulus, and a deficit in such processes in children with ADHD.

Genetics in the analysis of behaviour.

Behaviour genetics has developed rapidly in the last two decades and has now gone far beyond the stage of merely measuring the extent to which individual differences on a particular behaviour can be attributed to genetic factors. This paper discusses the uses to which genetics can be put in efficient experimental design, in determining the generality of results and, most importantly, in the simultaneous analysis of several behaviours and their relationship to each other and to physical and biochemical parameters. Because the principles of genetics apply to all organisms, the first animal discussed is Drosophila, the vinegar fly, which is a vital tool in genetics but which has met with scant attention among psychologists. Drosophila has some unique advantages such as the sex mosaic technique for studying sexual behaviour, but most of the discussion concerns learning and the extent to which parallels can be found between Drosophila and the vertebrates, both in terms of process and of genetic control. It is demonstrated how strain differences and the response to artificial selection can distinguish between learning and other components of behaviour. Drosophila are also used to explain how the type of genetic control can suggest the way in which natural selection acts upon the particular behaviour and further examples from rodents are discussed to show that this is a general result across species. There are many inbred strains and selection lines of mice and rats and examples from a wide range of behaviours illustrate the advantages of using such stocks. The concept of the 'behavioural phenotype' is explained, where genetic differences on a wide range of behaviours are considered, rather than just focusing on one behaviour or one response to a particular drug or environmental treatment. Many different aspects of open-field behaviour, learning and mother-infant interaction are used as examples of this concept. The extent of genotype-environmental interaction is considered, since the possibility that each genotype will have a unique response to a brief discussion of human behaviour genetics, since here again the concern is not just with the trivial question of measuring 'heritability', but rather with how such information can be used to understand behaviour. The final suggestion is that psychology may gain by having more contact not only with geneticists, but also with the ecologists concerned with the significance of behavioural differences in the wild.

Who should fund and control the direction of human behavior genetics? Review of Nuffield Council on Bioethics 2002 report, genetics and human behaviour: the ethical context.

In this (Nuffield Council on Bioethics 2002), the third in its series on ethics and related issues in genetics (see also Nuffield Council on Bioethics 1993 and Nuffield Council on Bioethics 1998), the Nuffield Council has focused on four'normal' behaviors; intelligence, personality, antisocial behavior and sexual orientation. This is a narrow range of behaviors and one where their discussion of the potential impact of predictive genetic testing is probably inappropriate. They also take an unduly narrow view of the purposes of behavior genetics in the 21st century. It is not simply to estimate heritability but to understand more about the structure of behavior and the processes which underlie it. Their narrow focus and their negative approach to the history and achievements of genetics is reflected in their less than positive support for future behavior genetic research. Behavior geneticists need to do more to publicize what their field has achieved in order to counter the very extensive antibehavior genetics initiatives which are almost unique in science. At the same time, organizations such as the Nuffield Council need to consider carefully the impact their deliberations may have on research funding.

Twin birth is not a risk factor for seizures.

There is a belief that perinatal factors are a major cause of epilepsy. We studied a community-based sample of twins, a group with a marked excess of adverse perinatal events. The observed number of non-twin siblings with seizures did not differ from that predicted by the age-specific cumulative incidence rate of seizures (4.2% at age 10 years) in the twins. The types of epilepsies in the twins were largely benign and self-limited and not those associated with brain damage. Zygosity, birth order, and birth weight did not predict affected status. Within affected sibships, the frequency of seizures in co-twins of dizygotic probands (9%) was not different from the frequency in non-twin siblings (12%) but was much less than the frequency in co-twins of monozygotic probands (38%; p < 0.001), reflecting a major genetic component to certain epilepsies. These data show that twins do not have an increased risk of seizures and strongly suggest that perinatal factors have little bearing on the etiology of the common epilepsies in the community.

Neuropsychological dimensions of the fragile X syndrome: support for a non-dominant hemisphere dysfunction hypothesis.

This study contends that males with the fragile X syndrome feature problems in the visuospatial sphere as compared with Down syndrome males matched on vocabulary ability. Fragile X males suffer impairments of constructional functions, as demonstrated by their poor performance on block construction tests and on drawing tasks. These problems exist in association with visuoperceptive impairments, including the inability to reliably estimate angular relationships (Judgement of Line Orientation). They have shortened Digit and Corsi spans, and may feature some deficits in left hand co-ordination. The observation of a pervasive non-verbal deficit may also apply to carrier females, who despite functioning at an overall higher level, feature a similar pattern of deficits. It is possible that the deficit in non-dominant hemisphere functioning may be a pathognomonic feature of the chromosomal abnormality.

Selective breeding for increased cholinergic function: biometrical genetic analysis of muscarinic responses.

Biometric genetic analyses of behavioral and physiologic responses known to be related to muscarinic cholinergic receptors (hypothermia, hypoactivity, inhibited avoidance, and reduced responding for water) were studied in genetic crosses and backcrosses of the Flinders sensitive line (FSL) and Flinders resistant line (FRL) of rats. The FSL rats were more sensitive to the direct muscarinic agonists, arecoline and oxotremorine, and to the indirect agonist, physostigmine, than any other group. The next most sensitive group was the F1 x FSL backcross, followed by the F2, F1, F1 x FRL backcross, and the FRL, in that order. These differences between the genetic groups could be accounted for completely by either solely additive or additive plus dominance genetic factors. When dominance genetic factors contributed to the differences among groups (6 out of 15), the F1 responded like the FRL rats. The variance of the responses measured made it impossible to obtain reliable estimates of the number of genes involved in many instances; when such estimates were possible, several genes (greater than or equal to 3) appeared to be involved. We conclude that muscarinic sensitivity in rats is under genetic control, with the greatest contribution coming from additive genetic factors. Because the FSL rat appears to be a genetic animal model of depression, the finding of several genes influencing muscarinic responses may help account for the difficulties investigators have had in locating a single major gene or biological marker for human depressive disorders.

Does IQ decline with age in fragile-X? A methodological critique.

The recent claims for a decline in intelligence test performance in males and females with fragile-X (fra(X)) syndrome have implications both clinically and in evaluating the underlying neurological basis. This commentary identifies three key issues in evaluating evidence for a decline and in planning future, more co-ordinated efforts. These are (1) problems in combining data across different intelligence tests and/or different ages with potentially incompatible norms, task demands, and models of the structure of intelligence; (2) limitations in applying to low ability persons tests designed to discriminate best around the population average; and (3) specific cognitive deficits and behavioral problems in fra(X) individuals which may be confounded with the task demands of particular IQ tests at particular ages. While the decline in ability may be a real phenomenon rather than an artifact, recommendations are made about the psychometric requirements for a larger and more definitive collaborative study.

Individual variation and specific cognitive deficits in the fra(X) syndrome.

Mental retardation has been associated with fra(X) but comprehensive psychological evaluation has rarely been applied to 2 major behavioral questions 1) the extent of individual variation in IQ among fra(X) males and the possibility of some fra(X) males being of normal IQ; and 2) whether there is a depression in general IQ or whether specific abilities are impaired. The problems of developing an effective battery of tests for assessing fra(X) are discussed. These questions were examined in 54 individuals, comprising fra(X) males, their obligate carrier mothers and those sisters shown to have the fra(X). Among noninstitutionalised males nonverbal IQ as measured on a Block Design test ranged from 100 to 0, and vocabulary scores while generally higher, ranged from 79-33. The males scored low on a digit span memory task, while performance on a memory of objects task was adequate. Despite lower overall scores, a similar pattern and variability emerged in institutionalised males. Daughters were extremely variable in performance and the mothers performed much better, supporting the view that women who have children are a selected subset of fra(X) syndrome individuals. The performance of one male is discussed in detail. His vocabulary and nonverbal IQ scores were normal, despite his having other specific cognitive deficits. The pattern of abilities and behavior seen in fra(X) may result in an overestimation of intelligence and underestimation of penetrance when based on clinical impressions rather than formal psychological assessment. The implications of this for molecular and for population genetic approaches to fra(X) are discussed.

Problems in ascertainment of transmitting males in Martin-Bell syndrome.

The difficulty of assigning families affected with the Martin-Bell syndrome (MBS) into the category of male transmission is emphasised and illustrated by examples of 3 MBS families. These examples demonstrate how the ability to detect transmitting males depends on the number of generations available for investigation, and also on the "spread" of clinical investigation across many branches of the family regardless of what appears to be an unremarkable family history. Some unusual properties of male transmission are shown, and the problem of selective ascertainment of the particular MBS male individuals in different generations in a set of pedigrees is discussed.

Transmitting males and carrier females in fragile X--revisited.

Fragile X "transmitting males" have customarily been defined as phenotypically normal hemizygotes, who show very few or no fragile sites, and who transmit the fragile X premutation to phenotypically normal daughters. However, an objective justification of this definition was lacking. The discovery of an unstable CCG repeat as the genetic basis of fragile X further emphasized the apparent distinction between the "normal transmitting males" with short repeat and expression of the FMR1 gene, and the affected males with larger repeats (delta > 0.6 kb) and a complete lack of FMR1 transcription. We have recently shown that the transition between these two groups in phenotypic expression of fragile X is gradual, mainly on account of methylation mosaicism. However, there were insufficient data on the phenotype within the short repeat (0.0 < delta < 0.6) range. In this paper we approach this problem by comparing some clinical, anthropometric, and psychometric data from a sample of normal transmitting males with those from their non-fragile X male relatives. Moreover, female carriers with short repeat are compared for the same traits with their non-fragile X female relatives. The results have shown that both males and females with a short repeat differed significantly from normal on several psychometric and physical measurements, and males only showed differences in typical facial traits. Further studies of genotype-phenotype correlations within the short repeat range, including the estimate of FMR1 gene function and a more exact estimate of repeat size, is required before genetic explanation for the clinical findings can be provided.(ABSTRACT TRUNCATED AT 250 WORDS)

Fragile X family with unusual digital and facial abnormalities, cleft lip and palate, and epilepsy.

We present a fragile X family with unusual clinical manifestations. These findings, which often occur in the X-linked FG syndrome, include minor limb anomalies, cleft lip and palate, characteristic facial appearance, gastrointestinal problems and epilepsy, and intellectual disability. In a total sample of 54 fra(X) families, the frequency of minor limb anomalies was estimated to be 32% in the affected males and 19% in the female heterozygotes. These anomalies tend to occur in several members of the same family, where some craniofacial abnormalities reported as characteristic of the FG syndrome have also been encountered. Possible mechanisms for the occurrence of these unusual manifestations in the fra(X) families are discussed.

Phenotypic variation in male-transmitted fragile X: genetic inferences.

Three families with confirmed and one family with suspected male transmission of the fragile X are presented, with psychological and physical assessment of all available members. The psychological tests used were the Peabody Picture Vocabulary test and Block Design which measured verbal and non-verbal abilities, respectively. Physical status was assessed by recording dysmorphic features and by anthropometric measurements. This study demonstrated that there are appreciable differences in mental and physical status within sibships of daughters of male carriers, as well as recognizable physical alterations and intellectual impairment in the transmitting males. These findings contradict the concept that there are two distinct categories of fragile X carriers: phenotypically normal as opposed to affected. They suggest instead that the defect may be graded and emphasize the importance of intellectual deficits and physical alterations in defining the fragile X phenotype, both in low-penetrant males and female heterozygotes.

Biochemical and ultrastructural integrity of the saphenous vein conduit during coronary artery bypass grafting. Preliminary results of the effect of papaverine.

Factors associated with early and late graft patency related to aorta-coronary artery bypass grafting with a reversed segment of saphenous vein are clinically important. The present investigation examines the biochemical and electron microscopic integrity of this venous conduit intraoperatively with regard to pharmacologic manipulation with papaverine. Portions of saphenous vein were analyzed in 22 patients undergoing coronary artery bypass operations. Levels of a stable derivative of prostacyclin, 6-keto-PGF1 alpha, were measured by radioimmunoassay. Scanning as well as transmission electron microscopy was also performed. In particular, the efficacy of local vein treatment with papaverine, a phosphodiesterase inhibitor, was evaluated. We found that levels of 6-keto-PGF1 alpha in venous effluent showed a biphasic response with initial elevation followed by a relative depression after papaverine exposure. There were no such changes observed in veins subjected to a balanced electrolyte solution (Plasma-Lyte). In addition, levels of the platelet-inhibitory substance 6-keto-PGF1 alpha in venous tissue were less in papaverine-treated veins than those found in veins treated only with the balanced electrolyte solution (Plasma-Lyte). Furthermore, evidence for ultrastructural damage was also somewhat greater in the papaverine-treated group. An alternative method of dilating the saphenous vein after harvesting, which involves the creation of the proximal aorta-coronary anastomosis first and gentle finger manipulation subsequently, appeared to minimize venous injury. Under present clinical conditions, it appears that some amount of injury is inevitable during harvesting and suturing of the human saphenous vein during coronary bypass grafting.

In vitro and in vivo activity of a novel series of radical trapping agents in model systems of CNS oxidative damage.

Many laboratory and clinical studies suggest that oxygen radical formation and resultant cell damage contribute to CNS injury following stroke and neurotrauma. Accordingly, antioxidants represent a viable therapeutic approach for management of CNS oxidative damage. Recently, several investigators have reported that the spin trap PBN protects against stroked-induced damage and reduces aging-associated neurological deficits. We have prepared and tested a cyclic analog of PBN, MDL 101,002, in a number of in vitro and in vivo assays designed to assess its neuroprotective properties. MDL 101,002 was found to be an effective .OH trap, to inhibit lipid peroxidation, and to decrease infarct size in a gerbil model of stroke. These results further indicate that oxidative damage arising from stroke contributes to infarct formation, and that spin traps are effective in ameliorating ischemia and reperfusion-induced CNS injury.

Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study.

OBJECTIVE: To investigate heritability and continuum versus categorical approaches to attention-deficit hyperactivity disorder (ADHD), using a large-scale twin sample. METHOD: A cohort of 1,938 families with twins and siblings aged 4 to 12 years, recruited from the Australian National Health and Medical Research Council Twin Registry, was assessed for ADHD using a DSM-III-R-based maternal rating scale. Probandwise concordance rates and correlations in monozygotic and dizygotic twins and siblings were calculated, and heritability was examined using the De Fries and Fulker regression technique. RESULTS: There was a narrow (additive) heritability of 0.75 to 0.91 which was robust across familial relationships (twin, sibling, and twin-sibling) and across definitions of ADHD as part of a continuum or as a disorder with various symptom cutoffs. There was no evidence for nonadditive genetic variation or for shared family environmental effects. CONCLUSIONS: These findings suggest that ADHD is best viewed as the extreme of a behavior that varies genetically throughout the entire population rather than as a disorder with discrete determinants. This has implications for the classification of ADHD and for the identification of genes for this behavior, as well as implications for diagnosis and treatment.

Prophylactic scleral buckle for prevention of retinal detachment following vitrectomy for macular hole.

AIM: To review the rate of retinal detachment after macular hole surgery in patients who received vitrectomy and scleral buckle versus those who had vitrectomy alone. METHODS: All patient charts and hospital records were examined for patients who underwent vitrectomy surgery for macular hole between September 1993 and June 1997. A total of 326 patients were identified and all were followed for a minimum of 6 months. Clinical records were examined for details of the surgical procedure, visual acuity, hole closure status, adjuvant therapies used, and postoperative retinal attachment status. Relative risks (the ratio of the incidence rate in the exposed to that in the unexposed) with 95% confidence intervals and chi(2) tests were calculated to determine which variables were associated with retinal detachment. The primary outcome measure in this review was retinal attachment status. RESULTS: Of 326 eyes which underwent surgery for macular hole during the study period, scleral buckles were utilised in 152 (46.6%) patients. Analysis revealed a detachment rate of 13.2% in patients who did not receive a scleral buckle compared with 5.9% detachment rate in those who did. Analysis of these results indicated a 2.42 times greater risk of developing a retinal detachment in patients without a scleral buckle. Complications related to the use of scleral buckles occurred in two of 152 cases (1.3%) CONCLUSIONS: A reduction in the rate of retinal detachment was noted in patients receiving prophylactic scleral buckles. Those finding suggest a possible beneficial effect of this adjunctive procedure in preventing postoperative retinal detachments. The authors are currently preparing a multicentred, prospective, clinical trial to further study this hypothesis

The relevance of the health belief model to Australian smokers.

The Health Belief Model is one of the few models predicting health behavior which explicitly evaluates the role of cues to action from the doctor or others. Rarely have such cues to action been examined formally by the comparison of groups receiving different interventions. Initial and follow-up data covering a wide range of sociopsychological variables were gathered from typical smokers among family-practice patients participating in an Australian quit-smoking program. Patients were randomly assigned either to a control or experimental group, the latter receiving the Give-Up Smoking (GUS) kit, and quit-smoking advice from their doctor. Factor analysis of the initial data largely confirmed the clusters of the Health Belief Model. At follow-up, after the experimental and control group treatment, a totally different factor structure emerged, comprising some very specific sociopsychological variables and cues to action. Implications are discussed for the Health Belief Model relative to other health behavior models.

A multivariate regression analysis of adolescent multiple drug use in two western Canadian provinces.

This article reports on the results of a multiple regression analysis of an adolescent multiple drug use index on 17 predictor variables from the PRIDE CANADA Drug survey with 18,685 Grades 9 through 12 students in two Western Canadian provinces in 1995-96. The predictor variables represent eight familial, five school and peer, and four individual level attributes and behaviours. The regression analysis is used to estimate the combined effects along with the relative importance of the predictor variables on the students' self-reported use of 11 drugs combined into a multiple drug use index. Separate analyses are conducted for the male and female students. The results indicate that two of the most important predictor variables are the frequency with which both the female and male students report getting into trouble at school and the frequency of the students' participation in worship. The relative importance of these two variables and other variables in relation to the students' multiple use of drugs differ to some extent for the two genders.

Sex differences in familial correlations for visual and kinesthetic aftereffects.

72 subjects from 16 families performed a visual and kinesthetic aftereffect task where data were also obtained on the pretest variability and on the adjustment times. Considerable sex differences were found, such that for mothers pretest variability correlated positively with magnitude of kinesthetic and negatively with magnitude of visual aftereffect. Daughters showed more pretest variability on both tasks and much larger individual differences on the visual task than sons. These sex differences complicate any attempt at genetic analysis. However, there was some indication of X-linked inheritance in males for magnitude aftereffect and of autosomal inheritance of visual adjustment time in females.