Incoherence of neuroimaging studies of attention deficit/hyperactivity disorder.

Neuroimaging studies have been conducted with increasing frequency in recent years in attempts to identify structural and functional abnormalities in the brains of persons with attention deficit/hyperactivity disorder. Although the results of these studies are frequently cited in support of a biologic etiology for this disorder, inconsistencies among studies raise questions about the reliability of the findings. The present review shows that no specific abnormality in brain structure or function has been convincingly demonstrated by neuroimaging studies. Implications regarding stimulant treatment for attention deficit/hyperactivity disorder are discussed.

Manipulation of central GABAergic and dopaminergic systems alters stress responding in the rat.

Activation of central GABA(A) systems with muscimol has been shown to facilitate stress responding and GABA is known to modulate central dopaminergic activity. To evaluate the possibility that this effect of muscimol may depend upon a dopamine mechanism we have tested the effect of intracerebroventricular coadministration of muscimol and the selective D(1) antagonist SCH 23390 on behaviors evoked by tail pinch stress. When injected by themselves muscimol (1.75 nmol) facilitated stress-evoked oral behavior while SCH 23390 (6-600 nmol) produced a dose-related suppression of oral behavior. Coadministration of muscimol and doses of SCH 23390 selected for producing no (6 and 30 nmol), or marginal (60 nmol), effects on stress responding resulted in a dose-related reversal of the increase in orality seen with muscimol alone. The results are consistent with the notion that stressful stimuli activate central GABA(A) systems which, in turn, enhance dopaminergic neurotransmission.

The Tulane Electrical Brain Stimulation Program a historical case study in medical ethics.

In 1950 physicians at Tulane University School of Medicine began a program of research on the use of electrical brain stimulation that would span three decades and involve approximately 100 patients. Initially, electrical brain stimulation was used to treat of schizophrenia, but later it was applied to a variety of other conditions. Throughout its history the Tulane research was well publicized in both the professional and lay literature, and for almost twenty years, with rare exception, these accounts were laudatory. However, in the early 1970s this work began to draw sharp public criticism. Despite its public and controversial nature, the Tulane electrical brain stimulation program has received relatively little attention from historians. This review recounts the history of the Tulane program with particular emphasis on the ethical propriety of the work. Factors that shaped the historical context in which the Tulane experiments were conducted are discussed.

Central GABA activation and behaviors evoked by tail-pinch stress in the rat.

Experiments were conducted to evaluate the possibility that central GABA(A) receptors are involved in the stress response of rats. Separate groups of animals were implanted bilaterally with cannulae in the lateral cerebral ventricle, substantia nigra, and anterior to the rostral margin of the substantia nigra. Microinjections of the GABA(A) agonist muscimol into each of these areas augmented the stress response evoked by moderate tail pinch. Although consistent changes in the amount of food eaten in response to stress were not observed, stress-evoked gnawing was significantly increased by muscimol at all three sites. Additionally, intraventricular muscimol resulted in an enhancement of stress-evoked oral stereotypy, revolution (escape behavior), and vocalization. The data suggest that a GABAergic component exists in the central mediation of stress. The results are discussed in regard to possible interactions between GABA and central dopamine systems.

Effects of maternal intelligence, marital status, income, and home environment on cognitive development of low birthweight infants.

OBJECTIVE: To examine direct and mediated effects of maternal IQ, marital status, family income, and quality of the home environment on the cognitive development of low birthweight infants. METHODS: Secondary analyses on a large dataset using hierarchical regression identified factors correlated with cognitive outcomes in children at 3 years of age who were born at low birthweight. RESULTS: Maternal IQ was a critical variable, because it was highly correlated with child IQ and because maternal intelligence influenced patterns of relationships among other predictor variables including marital status, income level, and home environment on child IQ. Analyses revealed that effects of these variables on child IQ interacted with maternal IQ. CONCLUSIONS: Early childhood intervention programs should target those low birthweight infants most at risk for impaired cognitive development. Children at greatest risk are those living with unmarried, low IQ mothers.

Dietary treatment of destructive behavior associated with hyperphenylalaninemia.

Behavior disorders frequently are associated with mental retardation. The most common interventions involve psychotropics, behavior modification, or both. Etiologically based treatments, derived from an understanding of underlying disease pathogeneses, are infrequent. However, several genetic diseases are associated with elevated rates of destructive responding. The hyperphenylalaninemias provide an excellent model for alternative interventions that have clear biological plausibility. A literature review is undertaken that provides the biochemical rationale for treatment with a low-phenylalanine diet. Several phenylalanine dietary control studies designed to manage aberrant responding among patients with hyperphenylalaninemia are summarized. Together they provide strong evidence that dietary phenylalanine restriction is the treatment of choice among patients ranging from classic phenylketonuria to milder hyperphenylalaninemia. Corroborating evidence derived from phenylalanine loading, magnetic resonance imaging, and dietary amino acid supplementation studies is presented.

"Big" versus "little" science: comparative analysis of program projects and individual research grants.

Controversy about the amount and nature of funding for mental retardation research has persisted since the creation of NICHD. An issue that has aroused considerable debate, within the mental retardation research community as well as beyond, is distribution of funds between large group research grants, such as the program project (PO1) and the individual grant (RO1). Currently within the Mental Retardation and Developmental Disabilities Branch, more money is allocated to the PO1 mechanism than the RO1. We compared the two types of grants, focusing on success rates, productivity, costs, impact, publication practices, and outcome and conducted a comparative analysis of biomedical and behavioral research. Other related issues were considered, including review processes and cost-effectiveness.

Effects in the rat of intranigral morphine and DAGO on eating and gnawing induced by stress.

Stress produced by pinching the tail is known to increase feeding behavior in rats, and endogenous opioids have been implicated in the mediation of this effect. We have reported previously that a nonspecific opioid antagonist and a mu-selective antagonist decrease this stress-induced eating (SIE) when they are microinjected into the substantia nigra (SN). The present study investigated the possibility that activation of opioid receptors in the SN might also alter SIE. Because oral stereotypy and nociception are affected by opioid mechanisms in the SN, measurements of gnawing and of tail flick and hot plate response latencies were also made. Bilateral injection of morphine (0.1-20 nmol) and the mu-selective agonist D-Ala2,N-Me-Phe4,Gly5-ol-enkephalin (DAGO; 0.03-1 nmol) increased response latency on the hot plate test and decreased gnawing produced by tail pinch. Tail flick latency and SIE were not affected. It is concluded that activation of opioid receptors in the SN does not produce an alteration in SIE as has been seen with opioid antagonists.

A critique of the application of sensory integration therapy to children with learning disabilities.

Sensory integration (SI) therapy is a controversial--though popular--treatment for the remediation of motor and academic problems. It has been applied primarily to children with learning disabilities, under the assumption that such children (or at least a subgroup of them) have problems in sensory integration to which some or all of their learning difficulties can be ascribed. The present article critically examines the related issues of whether children with learning disabilities differentially exhibit concomitant problems in sensory integration, and whether such children are helped in any way by means specific to SI therapy. An overview of theoretical contentions and empirical findings pertaining to the first issue is presented, followed by a detailed review of recent studies in the SI therapy research literature, in an effort to resolve the second issue. Results of this critique raise serious doubts as to the validity or utility of SI therapy as an appropriate, indicated treatment for the clinical population in question--and, by extension, for any other groups diagnosed as having "sensory integrative dysfunction." It is concluded that the current fund of research findings may well be sufficient to declare SI therapy not merely an unproven, but a demonstrably ineffective, primary or adjunctive remedial treatment for learning disabilities and other disorders.

The antinociceptive and motivational effects of intranigral injection of opioid agonists.

The antinociceptive potency of morphine and the morphine metabolite morphine-6-glucuronide (M6G) was examined after injection into the substantia nigra and periaqueductal gray (PAG) of rats. Both drugs produced antinociception in both sites. The antinociceptive potency of M6G was significantly greater than morphine in the nigra. There was no difference in the antinociceptive potency of M6G in the nigra and PAG. M6G and other opioids were also examined for motivational effects after intranigral injection. A high dose of intranigral morphine (10.0 nmol) produced a conditioned place preference. No significant motivational effects were produced by 1.0 nmol of M6G, D-Ala2, N-Me-Phe4,Gly5-ol-enkephalin (DAGO), D-Pen2,D-Pen5-enkephalin (DPDPE), or U-50,488H. It is concluded that the substantia nigra plays an important role in opioid antinociception. The role of the nigra in opioid reward is questionable.

Motivational orientation and span of apprehension in children with mental retardation.

Children diagnosed as mildly mentally retarded were examined with respect to performance on Estes's (1965) span-of-apprehension task. Based on their scores on the Simplified Version of the Intellectual Achievement Responsibility scale, we divided subjects into a "learned-helpless" group and a "mastery-oriented" group. Motivational orientation had a significant effect on performance, with the mastery-oriented subjects demonstrating higher detection accuracies than the learned-helpless subjects. These results have implications regarding not only centrally mediated attentional functioning in children with mental retardation, but also interpretation of certain previous findings with the span-of-apprehension task.

Efficacy and specificity of pharmacological therapies for behavioral disorders in persons with mental retardation.

This review assesses the efficacy and specificity of psychotropic medications used to control aberrant behavior in persons with mental retardation. It is concluded that neuroleptics, the most widely used psychotropic agents in this population, suppress aberrant behavior, but do so by suppressing behavior generally. An exception to this conclusion is that it may be possible to selectively suppress stereotyped behavior with neuroleptics. In addition, the empirical evidence indicates that, in some persons with mental retardation, opioid antagonists and methylphenidate are useful therapies for self-injurious behavior and hyperactivity, respectively. Lithium and beta-blockers are potentially useful for treating aggression.

Span of apprehension in mentally retarded children: an initial investigation.

The present investigation is the first to apply Estes' (1965) span of apprehension task to the study of attentional functioning in mentally retarded persons. Detection accuracies of 25 children diagnosed as mildly mentally retarded and 25 non-retarded children were compared under conditions of 100-ms exposure duration, and either two, four, six or eight distractor letters. Significant main effects of subject group and distractor number were found, with no interaction. These results provide converging evidence in support of previous positions that posit a structural deficit in mentally retarded individuals with respect to centrally mediated processing.

Further studies of the role of opioid receptors in the nigra in the morphine withdrawal syndrome.

Bilateral injection of naloxone (3.0-30.0 nmol) into the substantia nigra of morphine-dependent rats produced a withdrawal syndrome consisting of wet-dog shakes, teeth chattering, irritability to touch, diarrhea and hypothermia. Intense wet-dog shakes and grooming were observed after intranigral injection of the mu selective antagonist D-Phe-Cys-Try-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 3.0-30.0 nmol) in morphine-dependent animals. Body temperature after 30.0 nmol CTOP was significantly increased. A significant positive correlation between body temperature and wet-dog shakes was observed in morphine-dependent animals that received CTOP. Intranigral injection of beta-funaltrexamine (beta-FNA, 10.0 nmol), an irreversible mu antagonist, produced no signs of withdrawal in morphine-dependent animals. However, intranigral injection of beta-FNA (1.0-3.0 nmol) suppressed the antinociceptive effect of the mu-selective agonist, D-Ala2,N-Me-Phe4,Gly5-ol-enkephalin (DAGO, 1.0 nmol). The withdrawal syndrome produced by CTOP (10.0 nmol) was not suppressed by the administration of U50,488H (10.0 nmol), a kappa agonist, suggesting that the absence of an effect of beta-FNA was not due to its kappa agonist activity. Neither the delta-selective antagonist, naltrindole (NTI, 10.0 nmol) nor the kappa-selective antagonist, nor-binaltorphimine (nor-BNI, 10.0 nmol) produced withdrawal. Only wet-dog shakes were observed when CTOP, NTI and nor-BNI (5 nmol each) were administered together into the nigra. These studies suggest an involvement of mu receptors in the nigra in the wet-dog shakes and thermoregulatory dysfunction that occur during withdrawal of morphine. However, the subtypes of opioid receptors in the nigra, that mediate the other signs of morphine withdrawal remain obscure.

Microinjection of opioid antagonists into the substantia nigra reduces stress-induced eating in rats.

Stress produced by pinching the tail has been shown to cause satiated animals to eat and to display oral stereotypies. Endogenous opioids and central dopamine systems have been implicated in the mediation of these effects. In order to test the possibility that the substantia nigra (SN) might be involved, the amount of food intake and gnawing produced by mild tail pinch were assessed following bilateral microinjections of opioid antagonists into the SN. Evaluations of nociceptive thresholds were also conducted using tail flick and hot plate tests. Eating induced by tail pinch was reduced by microinjections of the non-selective opioid antagonist naloxone (3, 10, 20 and 30 nmol) and by the mu-selective antagonist Cys2, Tyr3, Orn5, Pen7 Amide (CTOP) (1, 3 and 10 nmol). These effects on eating occurred in the absence of effects on gnawing. kappa- and delta-antagonists (10 nmol) had no effect on eating or gnawing. Naloxone did not alter either tail flick or hot-plate response latencies. The highest dose of CTOP increased response latency on the hot-plate test only. The results are interpreted as suggesting that the SN may be an important central site of action for opioid antagonists in reducing stress-induced eating. The possibility that the SN may be a central site mediating the effects of dopamine on this phenomenon is also discussed.

The effects of bilateral intranigral microinjection of selective opioid agonists on behavioral responses to noxious thermal stimuli.

This study examined the effects of bilateral intranigral microinjection of selective opioid agonists on the tail-flick and hot-plate antinociception tests. The principal findings are: (1) the mu-selective agonist D-Ala2, N-Me-Phe4, Gly5-ol-enkephalin (DAGO) had antinociceptive effects on both tests which were reversible by beta-funaltrexamine (beta-FNA: a mu-selective antagonist) and naloxone (a non-selective opioid antagonist); (2) the antinociceptive potency of DAGO injected into the nigra is comparable to its potency in the periaqueductal gray; (3) intranigral D-Pen2, D-Pen5-enkephalin (a delta-selective agonist), U-50, 488H and dynorphin A-(1-13) (kappa-selective agonists) had no antinociceptive effects; (4) antinociceptive effects were produced by the mixed delta/mu agonists D-Thr2-leucine enkephalin-Thr (DTLET) and D-Ser2-leucine enkephalin-Thr (DSLET); (5) the effect of DTLET on the hot-plate but not the tail-flick test was reversed by Cys2, Tyr3, Orn5, Pen7-amide (CTOP; a mu-selective antagonist), beta-FNA, and naloxone, but not by the delta-selective antagonist naltrindole. Based on the potent antinociceptive effects of DAGO, the complete lack of such effects by the highly selective delta and kappa agonists, and the antagonism of DTLET by CTOP and beta-FNA, it is concluded that the antinociceptive effects of intranigral opioid agonists are mediated by mu receptors.

Rhythmic motor behavior of preambulatory motor impaired, Down syndrome and nondisabled children: a comparative analysis.

The developmental course of rhythmic motor behavior was followed longitudinally for three groups of preambulatory children--normally developing, Down syndrome, and those with profound motor impairment. The groups differed in chronological age but were comparable with respect to motor age. The motor impaired subjects displayed significantly less rhythmic motor behavior than the nondisabled and Down syndrome groups. In comparing particular subtypes of rhythmic motor behavior, differences were found in both the average number of bouts and duration of subtypes among the groups. Longitudinal analyses of the data over the entire observation period revealed that the rhythmic motor behavior of the children with Down syndrome was more similar to that exhibited by the nondisabled children than was the rhythmic motor behavior of the children with motor impairment. However, there was considerable variability among the groups in several particular subtypes.

Generalized oddity performance in preschool children: a bimodal training procedure.

Oddity performance requires relational discriminative responding, which typically is difficult to establish in children with MAs below five. In Experiment 1, a combination intrasubject reversal and multiple baseline across subjects design was used to establish the internal validity of a bimodal intervention in establishing generalized oddity performance. Six of seven children demonstrated oddity responding when presented with stimuli that instantiated the oddity relation in the visual and auditory modalities simultaneously. Oddity performance was evaluated with both reversal assessments and assessments with new sets of stimuli. The newly acquired oddity performance was durable; the six children continued to respond discriminatively when returned to a visual-only task on which they previously had been unsuccessful. Utilizing a reversal assessment more stringent than that of Experiment 1, Experiment 2 replicated this effect. The present studies are the first to demonstrate the utility of bimodal training in establishing oddity performance. The bimodal procedure is discussed with respect to the theoretical positions of Gibson, Dinsmoor, and Dixon.

The influence of rotary vestibular stimulation upon motor development of nonhandicapped and Down syndrome infants.

The vestibular system plays a major role in the expression of early motor behavior. Previous research has cited extensive neural connections between the vestibular apparatus and the motor system. Accordingly, some therapists have implemented programs of supplemental vestibular stimulation to improve motor and cognitive abilities in children with delayed motor development. In the present study a quantifiable regimen of supplemental rotary vestibular stimulation was administered in a cross-over longitudinal design to nonhandicapped and Down syndrome infants. Time constants, considered a measure of habituation in the vestibular system, were derived from postrotary nystagmus. Results indicated that supplemental rotary vestibular stimulation produced no measurable gain in motor ability beyond that evident in control periods. In addition, it was determined that children exhibited greater gains in motor skills in the early phase of the study, regardless of experimental condition. A positive correlation was found between changes in time constant and motor development.