Sickle cell disease as a neurodevelopmental disorder

Sickle cell disease (SCD) is a blood disorder; however, the central nervous system (CNS) is one of the organs frequently affected by the disease. Brain disease can begin early in life and often leads to neurocognitive dysfunction. Approximately one-fourth to one-third of children with SCD have some form of CNS effects from the disease, which typically manifest as deficits in specific cognitive domains and academic difficulties. We discuss SCD as a neurodevelopmental disorder by reviewing the mechanisms of neurological morbidity in SCD, the timing of these mechanisms, the types of cognitive and behavioral morbidity that is typical, and the interaction of social-environmental context with disease processes. The impact of the disease on families shares many features similar to other neurodevelopmental disorders; however, social-environmental factors related to low socioeconomic status, worry and concerns about social stigma, and recurrent, unpredictable medical complications can be sources of relatively higher stress in SCD. Greater public awareness of the neurocognitive effects of SCD and their impact on child outcomes is a critical step toward improved treatment, adaptation to illness, and quality of life.     

Neuropsychological Functioning and Antiretroviral Treatment in HIV/AIDS: A Review

This article presents a review of studies that have investigated the neuropsychological effects of antiretroviral treatment (ART) for HIV-1 infection. It provides a brief overview of the era of monotherapy, dual-therapy, and an extended overview of the current era of combination antiretroviral therapy (CART). This review highlights that while CART has had a dramatic effect on the incidence and the severity of HIV-associated neurocognitive disorders (HAND), HAND, in its mild form, still remains prevalent. New causes of this sustained prevalence are poor CNS penetration of some antiretroviral agents, drug resistance, poor adherence, potential neurotoxicity, co-morbidities such as the long-term CART side effects in relation to cardio-vascular disease, and chronic HIV brain infection that may facilitate the expression of new forms of neurodegenerative processes. The review emphasizes the need to address methodological limitations of published studies and the need for large and representative cross-disciplinary longitudinal investigations across the HIV illness span.     

Assessment of gestational age and neuromaturation

Neuromaturation is the functional development of the central nervous system (CNS). It is by its very nature a dynamic process, a continuous interaction between the genome and first the intrauterine environment, then the extrauterine environment. Understanding neuromaturation and being able to measure it is fundamental to infant neurodevelopmental assessment. Fetal and preterm neuromaturation has become easier to observe with the advent of prenatal ultrasonography and neonatal intensive care units. A number of measures of degree of fetal maturation have been developed and used to estimate gestational age (GA) at birth. The most reliable measures of GA are prenatal measures, especially from the first trimester. Postnatal GA measurements tend to be least accurate at the extremes of gestation, that is, in extremely preterm and post-term infants. Observations of measures of neuromaturation in infants born to mothers with pregnancy complications, including intrauterine growth restriction, multiple gestation, and chronic hypertension, have led to the discovery that stressed pregnancies may accelerate fetal pulmonary and CNS maturation. This acceleration of neuromaturation does not occur before 30 weeks' gestation and has a cost with respect to cognitive limitations manifested in childhood. The ability to measure fetal and preterm neuromaturation provides an assessment of neurodevelopmental progress that can be used to reassure parents or identify at risk infants who would benefit from limited comprehensive follow-up and early intervention services. In addition, measures of neuromaturation have the potential to provide insight into mechanisms of CNS injury and recovery, much-needed early feedback in intervention or treatment trials and a measure of early CNS function for research into the relationships between CNS structure and function.     

Neuropsychology and temporal lobe epilepsy

The purpose of this article is to review aspects of the neuropsychology of temporal lobe epilepsy. Evidence will be presented to demonstrate that the cognitive consequences of this focal seizure disorder can be more generalized in nature than expected. Consistent with the extratemporal neurocognitive findings, careful quantitative magnetic resonance imaging volumetrics have shown that structural brain changes may be detected outside the temporal lobes. Many factors can potentially affect cognition and brain structure. We focus on the potential neurodevelopmental impact of early-onset temporal lobe epilepsy on brain structure and cognition positing that this disorder can have both immediate and lifespan implications for cognition and psychosocial status.     

Cognitive training programs for childhood cancer patients and survivors: A critical review and future directions

A robust literature has developed documenting neurocognitive late effects in survivors of leukemia and central nervous system (CNS) tumors, the most frequent cancer diagnoses of childhood. Patterns of late effects include deficits in attention and concentration, working memory, processing speed, and executive function, as well as other domains. As childhood cancer survivors are living longer, ameliorating deficits both in broad and specific neurocognitive domains has been increasingly recognized as an endeavor of paramount importance. Interventions to improve cognitive functioning were first applied to the field of pediatric oncology in the 1990s, based on strategies used effectively with adults who had sustained a traumatic brain injury (TBI). Compilation and modification of these techniques has led to the development of structured cognitive training programs, with the effectiveness and feasibility of such interventions currently an active area of research. Consequently, the purpose of this critical review is to: (1) review cognitive training programs intended to remediate or prevent neurocognitive deficits in pediatric cancer patients and survivors, (2) critically analyze training program strengths and weaknesses to inform practice, and (3) provide recommendations for future directions of clinical care and research.     

Risky families: family social environments and the mental and physical health of offspring

Risky families are characterized by conflict and aggression and by relationships that are cold, unsupportive, and neglectful. These family characteristics create vulnerabilities and/or interact with genetically based vulnerabilities in offspring that produce disruptions in psychosocial functioning (specifically emotion processing and social competence), disruptions in stress-responsive biological regulatory systems, including sympathetic-adrenomedullary and hypothalamic-pituitary-adrenocortical functioning, and poor health behaviors, especially substance abuse. This integrated biobehavioral profile leads to consequent accumulating risk for mental health disorders, major chronic diseases, and early mortality. We conclude that childhood family environments represent vital links for understanding mental and physical health across the life span.     

Neurocognitive outcomes in pediatric HIV

Cognitive impairment has long been associated with the natural history of HIV among vertically infected children. In children, HIV may have a direct or indirect impact on the developing brain, may lead to global or highly specific consequences, and may be responsible for minor cognitive consequences or, conversely, long-term and severe disability. This differential impact is related to multiple factors that influence the individual expression of the virus in any given child. This review provides an overview of the relevant literature on neurocognitive outcomes for infants, children, and youth vertically infected with HIV, with attention to those factors impacting neurocognitive outcome within a developmental framework. Research findings in both the era preceding and following the introduction of combined therapies are reviewed, since many of the issues identified prior to state-of-the-art treatment currently available in the United States and other developed countries still apply in much of the developing world. Intervention issues and directions for future research are also discussed.     

Neurocognitive profiles of preterm infants randomly assigned to lower or higher hematocrit thresholds for transfusion

Objective: Preterm infants are frequently transfused with red blood cells based on standardized guidelines or clinical concerns that anemia taxes infants' physiological compensatory mechanisms and thereby threatens their health and well-being. The impact of various transfusion guidelines on long-term neurocognitive outcome is not known. The purpose of this study is to evaluate long-term neurocognitive outcome on children born prematurely and treated at birth with different transfusion guidelines.

Methods: Neurocognitive outcomes were examined at school age for 56 preterm infants randomly assigned to a liberal (n?=?33) or restrictive (n?=?23) transfusion strategy. Tests of intelligence, achievement, language, visual-spatial/motor, and memory skills were administered. Between-group differences were assessed.

Results: Those in the liberal transfusion group performed more poorly than those in the restrictive group on measures of associative verbal fluency, visual memory, and reading.

Conclusions: Findings highlight possible long-term neurodevelopmental consequences of maintaining higher hematocrit levels.     

Feasibility of Conducting Long-Term Follow-Up of Children and Infants Treated for CNS Tumors on the Same Cooperative Group Clinical Trial Protocol

Given the barriers to conducting long-term assessment of neurocognitive and psychosocial functioning of those treated in infancy for central nervous system (CNS) tumors, a multi-site feasibility study was conducted. The primary objective was to demonstrate that it is feasible to identify, locate and assess the functioning of children treated on the same protocol 10-years post-treatment. Six sites obtained institutional approval, identified and recruited subjects, and obtained comprehensive neurocognitive and psychosocial data. All feasibility objectives were met. Barriers to participation included length of time for Institutional Review Board submission and review, clinical demands, limited eligible participants at individual institutions, difficulty locating long-term subjects and stipend/reimbursement concerns. Results indicate that long-term studies are feasible and essential given the need to address long-term issues of children treated at a young age for CNS tumors, especially as they relate to later academic and vocational planning, but require significant coordination and commitment of cooperative group and institutional resources.     

Social brain development and the affective consequences of ostracism in adolescence

Recent structural and functional imaging studies have provided evidence for continued development of brain regions involved in social cognition during adolescence. In this paper, we review this rapidly expanding area of neuroscience and describe models of neurocognitive development that have emerged recently. One implication of these models is that neural development underlies commonly observed adolescent phenomena such as susceptibility to peer influence and sensitivity to peer rejection. Experimental behavioural evidence of rejection sensitivity in adolescence is currently sparse. Here, we describe a study that directly compared the affective consequences of an experimental ostracism manipulation (Cyberball) in female adolescents and adults. The ostracism condition led to significantly greater affective consequences in the adolescents compared with adults. This suggests that the ability to regulate distress resulting from ostracism continues to develop between adolescence and adulthood. The results are discussed in the context of models of neurocognitive development.     

Epigenetics in the mature mammalian brain: effects on behavior and synaptic transmission

The role of epigenetic mechanisms in control of gene expression during mammalian development is well established. Associations between specific DNA or histone modifications and numerous neurodevelopmental and neurodegenerative disorders implies significant consequences of epigenetic dysregulation in both the developing and mature brain, the latter of which is the general focus of this review. Accumulating evidence suggests that epigenetic changes are involved in normal cognitive processes in addition to neurological and psychiatric disorders. Recent investigations into the regulation of epigenetic modifications in the adult brain have revealed novel and surprisingly dynamic mechanisms for controlling learning and memory-related behaviors as well as long-term synaptic plasticity. DNA methylation and histone acetylation have also been implicated in the modulation of basal synaptic transmission and the balance between excitation and inhibition in various brain regions. Studies have begun to uncover some of the alterations in gene expression that appear to mediate many of these effects, but an understanding of the precise mechanisms involved is still lacking. Nevertheless, the fundamental importance of epigenetic processes in influencing neuronal activity is becoming increasingly evident.     

Coping with chronic childhood diseases: Implications for counselling children and adolescents

Children with chronic diseases have to cope with a number of potentially stressful situations. Some relate specifically to the disease and treatment, and others, relating to school and home, are shared with all children. Research has tended to focus on environmental or personal variables that influence ‘adjustment’ to the disease. In contrast, work in general developmental psychology is concerned with identifying changes in children's appraisal of what constitutes a stressful situation, and describing appropriate coping skills. It is argued that this latter approach should be integrated with work concerned with coping in childhood illness. Implications for clinical practice are considered.     

The Abecedarian Approach to Social,Educational, and Health Disparities

This paper places the Abecedarian Approach in theoretical and historical context and reviews the results from three randomized controlled trials that have tested an experimental protocol designed to prevent cognitive disabilities and their social consequences. Results affirm that cognitive disabilities can be prevented in early childhood and subsequent academic achievement enhanced via a multipronged comprehensive approach that contains individualized and responsive early childhood education starting in early infancy, coupled with pediatric health care, good nutrition, and family-oriented social services. Additional important findings reveal that the most vulnerable children benefited the most and that cognitive gains were not at the expense of children’s socioemotional development or relationship to family. In general, mothers derived benefits in education and employment and teenage mothers especially benefited from their children participating in the early education treatment group. On the whole, the overall pattern of results supports a multidisciplinary, individualized, and long-term longitudinal perspective on human development and prevention science. Recent structural and functional brain imaging in the fifth decade of life shows persistent effects of intensive early educational treatment. Independent recent cost–benefit analysis in adulthood reveals a 7.3:1 return on investment with a 13.7% average annual rate of return. The paper concludes with a discussion of implications of the Abecedarian Approach to today’s high-risk population in the USA     

Brain Activity and Cognitive Transition during Childhood: A Longitudinal Event-Related Brain Potential Study

This study examined the relation between brain activation and cognitive development using event-related brain potentials (ERPs) and a longitudinal design. Five-year-old girls performed a visual recognition (‘oddball’) task and an experimental analogue of the Piagetian conservation of liquid quantity task at three experimental sessions, with one year between consecutive sessions. The data revealed age-related changes in neurocognitive mechanisms common to both tasks. In comparing children before and after a Piagetian transition on a traditional clinical conservation test the data revealed a major shift in performance and ERPs to the experimental analogue of the liquid quantity task. These findings are consistent with a previously performed cross-sectional study and provide strong support for the hypothesis that cognitive transition is related to new neurocognitive mechanisms emerging during childhood. Possible implications of these findings for child neuropsychology are discussed.     

Advanced microscopic imaging methods to investigate cortical development and the etiology of mental retardation

Studies on human patients and animal models of disease have shown that disruptions in prenatal and early postnatal brain development are a root cause of mental retardation. Since proper brain development is achieved by a strict spatiotemporal control of neurogenesis, cell migration, and patterning of synapses, abnormalities in one or more of these events during prenatal development can lead to cognitive dysfunction after birth. Many of underlying causes of mental retardation must therefore be studied in developing brains. To aid in this research, live imaging using laser scanning microscopy (LSM) has recently allowed neuroscientists to delve deeply into the complex three-dimensional environment of the living brain to record dynamic cellular events over time. This review will highlight recent examples of how LSM is being applied to elucidate both normal and abnormal cortical development.     

Neurocognitive and functional outcomes in persons recovering from West Nile virus illness

Long‐term neurocognitive and functional impairments following West Nile virus (WNV) disease are poorly understood. We assessed quality‐of‐life indices and neurocognitive performance in a cohort of 54 persons recovering from one of three WNV disease syndromes (fever [WNF], meningitis [WNM], or encephalitis [WNE]) approximately 1.5 years following acute illness. We compared findings between the three syndromic groups; the study cohort and a demographically similar group of 55 controls from a study of chronic fatigue syndrome (CFS); and the study cohort and a ‘normative’ control population based on cognitive test data. Persistent symptoms, diminished quality of life, and functional impairment were reported by 50% of WNF patients, and 75% each of WNM and WNE patients. Overall, objective neurocognitive performance did not differ significantly between the three syndromic groups, or between the study cohort and the CFS controls or the normative controls. In some neurocognitive subtests, the study cohort scored below the 15th percentile when compared with normative control data. Most persons who returned to independent living following hospitalization for WNV illness had persistent subjective complaints, but had normal cognitive function. However, a minority displayed subtle neurocognitive deficits more than 18 months following acute disease.     

Lay concepts of health and illness from a developmental perspective

Abstract

The concepts of children, adolescents and their mothers with regard to different aspects of health and illness in general and five specific diseases were explored in this study. An exploration with fully standardised questions and open answers was subjected to a content analysis. A reliable rating system was developed to score the sophistication of the answers. The study included 99 Ss of the age groups 5, 8, 12 and 16 years, as well as 48 mothers of the children. Many children and adolescents were able to define health positively (well-being) and not merely as the absence of illness. The definition of illness in general was frequently composed of somatic symptoms and disorders, feeling poorly and things one would like to accomplish but can't. The causality explanations of illness in general were dominated by contagion. The concepts of the older children and the mothers were richer, more elaborated, less concrete and less action-oriented than those of the younger children. However, abstract formulations and complex aspects of illness were very rarely expressed. In addition, concepts regarding the characteristics (definition, symptoms, causality, treatment and prevention) of five diseases (cold, measles, heart infarction, cancer and AIDS) were measured. The pattern of results was strongly influenced by age. By and large, the development of most disease concepts was linear with significant differences between age groups. Conversely, within a given age group, significant differences were found in the cognitive level of disease characteristics, either with respect to the same disease or between different diseases (“horizontal shifts”).     

A systems neuroscience approach to autism: biological,cognitive, and clinical perspectives

Autism is a behaviorally defined disorder characterized by a broad constellation of symptoms. Numerous studies directed to the biological substrate demonstrate clear effects of neurodevelopmental differences that will likely point to the etiology, course, and long-term outcomes of the disorder. Consistently replicated research on the neural underpinnings of autism is reviewed. In general, results suggest several main conclusions: First, autism is a heterogeneous disorder and is likely to have multiple possible etiologies; second, structural brain studies have indicated a variety of diffuse anatomical differences, reflective of an early developmental change in the growth or pruning of neural tissue, rather than localized lesions; similarly, neurochemical studies suggest early, neuromodulatory discrepancies rather than gross or localized abnormalities; and finally, there are a number of limitations on studies of brain activity that to date preclude definitive answers to questions of how the brain functions differently in autism. The large number of active research programs investigating the cognitive neuroscience of autism spectrum disorders, in combination with the exciting development of new methodologies and tools in this area, indicates the drama and excitement of work in this area.     

Discrepancies between standardized measures of cognitive level and Halstead-Reitan impairment indices as inferences of brain damage following head injuries

z scores for measures of intelligence, memory, educational achievement, and neuropsychological impairment were obtained for 193 patients who had sustained impacts of mechanical energy to their skulls. Two sets of normative data, adjusted for age and sex and not adjusted for these variables, were employed to compute indices of neurocognitive proficiency (the inverse of impairment). 80% or 76 of the 96 patients whose Halstead-Reitan Indices were greater than 0.4 displayed scores for neurocognitive proficiency that were two or more standard deviations below the averages of their scores for intelligence, memory, and educational achievement. None of the patents whose Impairment Indices were 0.4 or less displayed this discrepancy. There were no statistically significant differences between these two groups of patients with respect to the presence of unconsciousness following the injury or the duration of posttraumatic memory disruptions. The results indicate that quantitative scores for neuropsychological impairments are still the most accurate criteria to discern brain dysfunction within the mild to moderate range.