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The causes of cerebral palsy. Recent evidence.

Cerebral palsy (CP), unlike many other neurodevelopmental disorders, is associated with abnormalities of pregnancy and birth, particularly 'birth asphyxia' and low birthweight. Associations, however, need not be causal, and some prenatally damaged infants manifest clinical signs suggestive of birth asphyxia in the perinatal period. The lack of a clinically reliable indicator of impaired fetal-placental gas exchange limits our confidence that birth asphyxia plays a true causal role in cerebral palsy. Premature delivery is the single most important antecedent of cerebral palsy, and the increase in survival of very small infants resulting from newborn intensive care may augment this contribution in the future. Cranial ultrasound imaging can describe patterns of neonatal brain damage in the low birthweight infant that are highly predictive of later cerebral palsy. Future research on the causes of cerebral palsy may benefit from improvements in the neurological assessment of the fetus prior to labor and from a clearer understanding of the role of endocrine factors, particularly thyroid disorders, in neurologic development.

Asphyxia Neonatorum↗

Parvalbumin in the human anterior cingulate cortex: morphological heterogeneity of inhibitory interneurons.

The calcium-binding protein parvalbumin (PV) is a marker for a certain subset of GABAergic cortical interneurons. In the present study, indirect immunocytochemistry with an antibody against PV was performed on serial sections of human anterior cingulate cortex (Brodmann's area 24), an important relay centre of the limbic system. PV-positive structures are distributed in a layer- and cell type-specific manner. Based on morphological features and laminar distribution pattern, PV-immunoreactive interneurons are subdivided into eight different classes. PV immunoreactivity within the neuropil comprises dendritic and axonal processes. Area 24 contains two densely immunolabelled neuropil bands in layers III and Vb. Axon cartridges are preferably located in layers V and VI. The results provide a "PV immunoarchitecture' as a basis for further studies of PV immunoreactivity under pathological conditions. PV is assumed to play a role in maintaining calcium homeostasis in nerve cells, and to modulate neuronal excitability and resistance to biochemical damage. On the other hand, PV immunoreactivity has recently been shown to undergo characteristic changes during different stages of brain maturation. Therefore, examination of PV-positive structures will provide new insights into cortical circuitry in neurodegenerative as well as neurodevelopmental disorders.

Adult↗

Language and Williams syndrome: how intact is "intact"?

It has been claimed that Williams syndrome (WS), a rare neurodevelopmental disorder, is characterized by serious cognitive deficits alongside intact language. The syndrome is often used as a prime example of the modularity of an innate faculty for morphosyntactic rules. We challenge this claim and hypothesize that morphosyntax, although surprisingly good given WS level of mental retardation, is by no means intact. We make an initial test of this hypothesis through an analysis of the receptive language of a group of English-speaking WS individuals on a standardized morphosyntactic test. We then present an experimental study of expressive language that examines grammatical gender assignment in French-speaking WS patients. Despite a Verbal Mental Age selected to be higher than the chronological age of the young control group, these people with WS continue even in adulthood to show clear-cut deficits in their production of an aspect of morphosyntax that normal children acquire effortlessly very early. The results of the 2 studies, one focusing on receptive language and the other on expressive language, challenge the notion that comprehension and use of morphosyntactic rules in WS individuals are intact. The Within-domain dissociations regarding the use of grammatical gender assignment across several sentence clements and their difficulties in understanding embedded sentences-two quintessentially linguistic skills-suggest that we must rethink the notion of spared, modular, language capacities in Williams syndrome. We conclude that WS language follows a different path to normal acquisition and may turn out to be more like second language learning.

Adolescent↗

The influence of systemic lupus erythematosus on fetal development: cognitive, behavioral, and health trends.

In 1985, Gualtieri and Hicks proposed the immunoreactive theory to explain the higher prevalence of childhood neurodevelopmental disorders in males. The theory claimed that male fetuses are more antigenic to mothers, resulting in increased immunologic attack on the developing central nervous system, and increased probability of atypical brain development. Individuals with systemic lupus erythematosus (SLE) provide a unique situation in which to investigate this theory. We evaluated the parent-reported prevalence of five developmental problems (stuttering, other speech problems, hyperactivity, attention deficit, and reading problems) in two groups: 154 individuals ages 8-20 years born to women with SLE, drawn from six cities, and 154 controls of comparable age and sex whose mothers did not have SLE. Controls were drawn from a comparison group ascertained from randomly selected schools in one of the cities. Questions about handedness, immune disorders, and pregnancy and birth complications were also evaluated. Children of SLE mothers were shown to have more evidence of developmental difficulties, immune related disorders, and nonrighthandedness. For developmental problems, these findings were most marked in male children of SLE mothers. These results suggest that maternal immunoreactivity, as represented by women with SLE, may present a special risk factor for subsequent learning difficulties in their children, particularly males.

Adolescent↗

Neurobiology and neurochemistry of Rett syndrome.

Rett syndrome (RS) represents a neurodevelopmental disorder of uncertain pathogenesis, featuring an apparent arrest in neural maturation during the perinatal period. Recent findings highlight the intensive ongoing research activities surrounding the neurobiology and neurochemistry of this unique disorder. Abnormalities in multiple neurotransmitter/receptor systems (dopaminergic, glutamatergic, and cholinergic), whether primary or secondary, underscore the pervasive effects of this maturational arrest. The possible role of neurotrophic factors is supported by significantly reduced nerve growth factor levels in cerebrospinal fluid. Similarly, gangliosides and other neuronal markers are perturbed in RS and may represent another critical area of study. The availability of a suitable animal model would accelerate the pace of these important investigations.

Biomarkers↗

Effect of prenatal ethanol exposure on the developmental profile of the NMDA receptor subunits in rat forebrain and hippocampus.

The effects of prenatal ethanol exposure on the NMDAR1 protein expression (postnatal days 1 and 7) and on the developmental profile of the NMDAR2A and NMDAR2B subunits in rat forebrain and hippocampus were investigated. Forebrain and hippocampal membrane proteins were isolated from pups of various ages (postnatal days 1 to 21) from prenatally ethanol exposed, pair-fed and ad libitum control groups. A semiquantitative immunoblot procedure was used with antibodies raised against the NMDAR1, NMDAR2A, and the NMDAR2B subunits to assess the NMDA subunit protein expression in the samples. NMDAR1 protein expression was unaffected by prenatal ethanol exposure at postnatal day 1 or 7 in both the forebrain and hippocampus. NMDAR2A protein expression levels rose rapidly in both forebrain and hippocampus during the time frame of study. Prenatal ethanol exposure caused a significant reduction in protein expression levels of the NMDAR2A in forebrain through postnatal day 14. NMDAR2B protein expression levels were high throughout the study in both forebrain and hippocampus. Prenatal ethanol exposure significantly reduced protein expression of the NMDAR2B in the forebrain (through postnatal day 14) and hippocampus (up to day 7). The results suggest that there may be a link between the depressed expression of the NMDAR2 subunits and the neurodevelopmental disorders associated with fetal ethanol exposure.

Animals↗

Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome.

Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from a deletion/mutation in maternal chromosome 15q11-13. The genes in 15q11-13 contributing to the full array of the clinical phenotype are not fully identified. This study examines whether a loss or reduction in the GABAA receptor beta3 subunit (GABRB3) gene, contained within the AS deletion region, may contribute to the overall severity of AS. Disrupting the gabrb3 gene in mice produces electroencephalographic abnormalities, seizures, and behavior that parallel those seen in AS. The seizures that are observed in these mice showed a pharmacological response profile to antiepileptic medications similar to that observed in AS. Additionally, these mice exhibited learning and memory deficits, poor motor skills on a repetitive task, hyperactivity, and a disturbed rest-activity cycle, features all common to AS. The loss of the single gene, gabrb3, in these mice is sufficient to cause phenotypic traits that have marked similarities to the clinical features of AS, indicating that impaired expression of the GABRB3 gene in humans probably contributes to the overall phenotype of Angelman syndrome. At least one other gene, the E6-associated protein ubiquitin-protein ligase (UBE3A) gene, has been implicated in AS, so the relative contribution of the GABRB3 gene alone or in combination with other genes remains to be established.

Age Factors↗

Sensorineural hearing loss in ECMO survivors. Extracorporeal membraneous oxygenation.

Survivors of extracorporeal membraneous oxygenation (ECMO) treatment are at risk for serious neurodevelopmental disorders or neurologic sequelae, but little has been reported about the prevalence of sensorineural hearing loss in these patients. Of 123 ECMO survivors born between 1987 and 1996, at least 30 survivors have confirmed sensorineural hearing loss. Progressive hearing loss has been confirmed in 10 subjects.

Evoked Potentials, Auditory, Brain Stem↗

FISH analysis in both classical and atypical cases of Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder, characterized by distinct facial changes, growth deficiency, mental retardation, supravalvular aortic stenosis (SVAS)/peripheral pulmonary stenosis, and associated at times with infantile hypercalcemia. A pilot study has been carried out to assess the reliability of the detection of hemizygosity at the elastin locus by fluorescence in situ hybridization (FISH) analysis as a diagnostic test in both classical and atypical WBS. Eight subjects with classical WBS and four others in whom a diagnosis could not be confirmed on clinical criteria alone were enrolled. In the classical WBS group, five (5/8) had a visible interstitial 7q11.22-11.23 deletion detected by high-resolution banding, and all (8/8) had a submicroscopic deletion of the elastin locus on chromosome 7 by FISH analysis. In the atypical WBS group, only one (1/4) had elastin deletion. The other three, with isolated SVAS, had normal development and minimal signs of WBS. Furthermore, the patients with microscopic 7q11.22-11.23 deletion have more associated features of WBS than those without visible interstitial deletions by high-resolution banding. These results, therefore, emphasize the importance of a combined high-resolution and molecular cytogenetic (i.e., FISH) approach to diagnosis and suggest that the degree to which microscopic/submicroscopic deletions of chromosome 7 extending in beyond the elastin locus may explain some of the phenotypical variability found in WBS.

Child↗

Sleep-wake function in children with neurodevelopmental and psychiatric disorders.

Sleep disturbance is commonly described in children with developmental problems of a primarily physical or psychiatric nature. Its persistence is likely to adversely affect cognition, mood, behavior, and family functioning. Therefore, accurate diagnosis of the underlying sleep disorder, with prompt and effective treatment, can be considered essential for overall care. Reports of sleep disturbance in various neurodevelopmental and psychiatric disorders of childhood are outlined. The origins of the disturbance in each condition may lie in the disorder itself, the child's circumstances, or reflect comorbidity. Each contributory factor has implications for treatment strategies and outcome. Much remains to be discovered about childhood sleep disorders. However, sufficient information is already known to significantly improve their recognition and management if professional education in such matters improves.

Adolescent↗

Prothrombotic disorders and abnormal neurodevelopmental outcome in infants with neonatal cerebral infarction.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the occurrence of prothrombotic disorders in a well-characterized cohort of infants with neonatal stroke and to document any association of prothrombotic disorders with the type of infarct seen on magnetic resonance imaging (MRI) and clinical outcome. METHODS: Twenty-four infants with perinatal cerebral infarction confirmed by neonatal MRI were enrolled in the study. All the infants and, when possible, both parents were tested to identify inherited and acquired prothrombotic disorders. RESULTS: None of the infants had a significant bleeding diathesis, but 10 (42%) had at least 1 prothrombotic risk factor. Five children showed heterozygosity for factor V Leiden, and 6 had high factor VIIIc concentrations. There was a striking association between the occurrence of these abnormalities and both the presence of cerebral hemorrhage on MRI and poor neurologic outcome. Eight of the 11 patients (73%) with hemiplegia or global developmental delay had factor V Leiden and/or raised factor VIIIc, whereas only 1 of the 13 patients (8%) with normal outcome had any prothrombotic risk factors. In particular, all 5 infants with factor V Leiden had hemiplegia, compared with only 4 of the 19 infants without factor V Leiden (21%). CONCLUSIONS: These data suggest that the presence of prothrombotic risk factors and, in particular, of the factor V Leiden mutation, is significantly associated with poor outcome after perinatal cerebral infarction.

Activated Protein C Resistance↗

Age- and sex-dependent laterality of rat hippocampal cholinergic system in relation to animal models of neurodevelopmental and neurodegenerative disorders.

Studies suggest age- and sex-dependent structural and functional patterns of human cerebral lateralization underlie hemisphere specialization and its alterations in schizophrenia. Recent works report sexual dimorphism of neurons in the hippocampal formation and specialization of hemispheres in rats. Our experiments indicate for the first time functional lateralization of the high-affinity choline uptake (HACU) system directly associated with a synthesis of acetylcholine in the hippocampus of Wistar rats. The markedly increased HACU activity was found in the left compared to the right hippocampus of adult male but not female animals. Lineweaver-Burk plot analysis revealed a statistically significant increase of Vmax in the left hippocampus of 14-day-old when compared to 7-day-old males. It appears that laterality of HACU occurs during late postnatal maturation, and its degree is markedly enhanced after puberty and attenuated during aging. Quinolinic acid (QUIN), an endogenous agonist of N-methyl-D-aspartate type glutamate receptors, was used in this study to evaluate the neurodevelopmental hypothesis of schizophrenia. It is known that elevated levels of QUIN accompany viral infections, increasing the risk of developing schizophrenia. Bilateral intracerebroventricular application of QUIN (250 nmoles/ventricle) to pups aged 12 days significantly impaired the cholinergic hippocampal system of adolescent male and female rats and reversed lateralization of male HACU. Morphological analysis indicated marked changes in brain lesion sizes (extensive 24 h and moderate 38 days after the operation). Asymmetry of lesions was observed in the majority of cases, but the left hemisphere was not generally more vulnerable to QUIN effects than the right side. Moreover, no lateral differences were found between lesioned hippocampi in the specific binding of [3H]hemicholinium-3 (10%-15% loss of binding sites when compared to sham-operated animals). In summary, our results indicate a symmetrical drop in the number of choline carriers of lesioned male rats but a asymmetrical decrease in the activity of remaing carriers, suggesting defects in processes of sexual brain differentiation, leading under normal conditions to the higher activity of carriers in the left hippocampus. The data demonstrate viral infection-mediated alterations in normal patterns of brain asymmetry and are discussed in relation to animal models of neurodevelopmental and neurodegenerative diseases.

Animals↗

Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders?

Serotonin (5-HT) is an important regulator of morphogenetic activities during early central nervous system development, including cell proliferation, migration, and differentiation. The 5-HT transporter (5-HTT) plays a pivotal role in brain 5-HT homeostasis. It is also the initial target for both antidepressant drugs and drugs of abuse, some of which are potent neurotoxins. A polymorphism in the 5'-flanking regulatory region of the 5-HTT gene that results in allelic variation of 5-HTT expression is associated with anxiety-related personality traits and may influence the risk of developing affective disorders. Progress in 5-HTT gene inactivation studies are also changing views of the relevance of adaptive 5-HT uptake function in brain development and plasticity as well as processes underlying drug dependence and neurodegeneration. Despite evidence for a potential role of the 5-HTT in the integration of synaptic connections in the mammalian brain during development, adult life, and old age, detailed knowledge of the molecular mechanisms involved in these fine-tuning processes is just beginning to emerge. Integration of various strategies, including molecular genetic, transgenic, and gene transfer techniques, will allow elucidation of the 5-HTT's role in brain development, plasticity, and degeneration as well as in affective illness, drug abuse, and dementia.

Adult↗

Development of an Internet-based real-time system for monitoring pharmacological interventions in children with neurodevelopmental and neuropsychiatric disorders.

Few children have a 'pure' diagnosis of neuropsychiatric disorders such as attention deficit hyperactivity disorder or autism. Most have complex, overlapping symptoms, and it is often these associated and common comorbidities that cause as much, if not more impairments, than the core symptoms. Prescribing decisions are therefore complex and made on the basis of eliciting a range of agreed 'target symptoms'. At present, however, there are no agreed systems that allow monitoring of all areas of potential change, and few services are able to monitor symptoms, side effects, impact on family life and individual children's quality of life systematically. At best many clinics use a plethora of paper-based standardized questionnaires, based on individual diagnoses. This article describes the development of a novel biomedical informatics system that has been designed to allow parents, professionals and children to use a web-based, real-time symptom monitoring system to enable more effective treatments, better pathways of shared care, and more equitable and efficient service delivery for this group of vulnerable children.

Attention↗

Neurodevelopmental study of writing disorders in middle childhood.

This study investigated patterns of neurodevelopmental dysfunction in children with writing disorders (WD). Records of children, ages 9 to 15 years, referred to a school problems clinic were examined. Using teacher questionnaire information, including ratings of writing legibility, mechanics, rate, linguistic sophistication, and spelling, 99 cases of WD were found. Sixty-three children without WD served as clinic controls. A cluster analysis revealed four discrete subtypes of WD and two non-WD control clusters. The four WD clusters were found to have different patterns of writing and reading characteristics. Neurodevelopmental tests discriminated among the clusters (F = 2.8, p less than .0001), and an examination of neurodevelopmental performance characteristics among the clusters showed different patterns of strengths and weaknesses. An empirically derived subtyping of WD is proposed: WD with fine motor and linguistic deficits, WD with visual-spatial deficits, WD with attention and memory deficits, and WD with sequencing deficits. This subtyping, if confirmed in a population study, may have important diagnostic and therapeutic implications.

Achievement↗

Impaired toilet training and bladder and bowel dysfunction in children with developmental coordination disorder - an underreported issue.

BACKGROUND & OBJECTIVE: Children with Developmental Coordination Disorder (DCD) face significant, yet often overlooked, challenges beyond motor impairments, including difficulties with toilet training and bladder and bowel dysfunctions (BBD). This study aims to explore whether children with DCD exhibit greater difficulties in these areas compared to typically developing children (TDC). METHOD: This cross-sectional case-control study included 84 children aged 5-8 years (42 DCD, 42 TDC), matched by school-grade and sex (33 boys and 9 girls per group). Parents completed the Vancouver Symptom Score for Dysfunctional Elimination Syndrome (VSSDES) to assess BBD symptoms, the Dutch DCD-questionnaire (DCD-Q) to evaluate motor coordination, and additional questions regarding toilet training, elimination diagnosis, and co-occurring conditions. Correlations and exploratory group differences were analysed. RESULTS: Parents of children with DCD reported significantly more toilet training difficulties than parents of controls (p < 0.001), including persistent accidents (47.6% vs. 9.5%), prolonged training (45.2% vs. 4.8%), and difficulties recognizing urination urgency (40.5% vs. 2.4%). The parental report of delayed attainment of bowel and bladder control (p < 0.05) and BBD rates (p < 0.001) was also significantly higher in children with DCD. Exploratory analyses indicated that the prevalence of these outcomes was not significantly different between children with DCD with and without co-occurring ADHD or autism, suggesting a possible primary association with DCD. Additionally, across both children with DCD and TDC, poorer motor skills were associated with more BBD symptoms (r = -0.474, p < 0.001). CONCLUSION: Children with DCD have a higher prevalence of toilet training difficulties and BBD compared to TDC, potentially affecting their psychosocial well-being. Greater awareness is crucial for timely and targeted care. Notably, the study's design, directly comparing children diagnosed with DCD to matched TDC, provides new insights into the prevalence of elimination difficulties in this population.

Humans↗

Attention deficit hyperactivity disorder, combined type, dysthymic disorder and anxiety disorders: differential patterns of neurodevelopmental deficits.

The associations between neurodevelopmental deficits (NDD) and (1) attention deficit hyperactivity disorder, combined type (ADHD-CT) and (2) internalising disorders have been replicated. To date, the specific association between standardized NDD and carefully defined ADHD-CT alone, dysthymic disorder alone and anxiety disorders alone has not been systematically investigated in children of primary school age. A cross-sectional study of NDD in 99 six- to 12-year-old children with categorically and dimensionally defined ADHD-CT alone, dysthymic disorder alone and anxiety disorders alone and 20 age-matched healthy children was undertaken. The ADHD-CT and dysthymic disorder groups had increased total neurological subtle signs, compared to the anxiety disorders group, which, in turn, had increased total neurological subtle signs compared with the healthy children. Interestingly, the dysthymic disorder children had increased conjugate eye gaze difficulties compared with the other three groups. The differences remained after controlling for full scale IQ. These findings suggest a neurobiological underpinning of dysthymic disorder, while confirming that of ADHD-CT in primary school age children. Future studies will explore whether the above more specific neurological subtle signs are developmental phase specific or independent associations.

Anxiety Disorders↗