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Results for “Neurodevelopmental Disorders”

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PubMed2004

Do women with fragile X syndrome have problems in switching attention: preliminary findings from ERP and fMRI.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that represents the most common known cause of developmental delay. Recent neuropsychological findings indicate that females with FXS present with a specific pattern of cognitive deficits and that these difficulties primarily involve skills requiring executive control. The present study is the first to examine the extent to which neural activity of females with FXS can be observed on a task that specifically taps two core deficits, namely switching and response inhibition. Brain activity was measured using both event-related electrical potentials (ERPs) and event-related functional MRI (fMRI) neuroimaging in separate studies using the same cognitive paradigm. Compared to controls, females with FXS were significantly slower and made more errors on trials that required an immediate response (Go) to stimulus onset but were comparable on trials that required a delayed response (Wait) to stimulus onset. At the brain level, several areas showed significantly greater activation for females with FXS compared with controls, including the cingulate cortex and left and right ventral prefrontal areas. In contrast, no areas were found to show significantly greater activation for controls compared with females with FXS.

Adult↗

PubMed2005

The emerging fragile X premutation phenotype: evidence from the domain of social cognition.

Fragile X syndrome is a neurodevelopmental disorder that is caused by large methylated expansions of a CGG repeat (>200) region upstream of the FMR1 gene that results in the lack of expression of the fragile X mental retardation protein (FMRP). Affected individuals display a neurobehavioral phenotype that includes a significant impairment in social cognition alongside deficits in attentional control, inhibition and working memory. In contrast, relatively little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation ("carrier-status") (approximately 55-200 repeats). Here, we focus on one aspect of cognition that has been well documented in the fragile X full mutation, namely social cognition. The results suggest that premutation males display a pattern of deficit similar in profile, albeit milder in presentation, to that of the full mutation. However, little evidence emerged for a correlation between CGG repeat length and severity of phenotypic outcomes. The findings are discussed in the context of functional neuroimaging and brain-behaviour-molecular correlates. We speculate that the deficiencies in social cognition are attributable to impairment of neural pathways modulated by the cerebellum.

Adolescent↗

PubMed2005

Idiom comprehension deficits in relation to corpus callosum agenesis and hypoplasia in children with spina bifida meningomyelocele.

Idioms are phrases with figurative meanings that are not directly derived from the literal meanings of the words in the phrase. Idiom comprehension varies with: literality, whether the idiom is literally plausible; compositionality, whether individual words contribute to a figurative meaning; and contextual bias. We studied idiom comprehension in children with spina bifida meningomyelocele (SBM), a neurodevelopmental disorder associated with problems in discourse comprehension and agenesis and hypoplasia of the corpus callosum. Compared to age peers, children with SBM understood decomposable idioms (which are processed more like literal language) but not non-decomposable idioms (which require contextual analyses for acquisition). The impairment in non-decomposable idioms was related to congenital agenesis of the corpus callosum, which suggests that the consequences of impaired interhemispheric communication, whether congenital or acquired in adulthood, are borne more by configurational than by compositional language.

Adolescent↗

PubMed2006

Communal nesting, an early social enrichment, increases the adult anxiety-like response and shapes the role of social context in modulating the emotional behavior.

Early experiences affect brain function and behavior at adulthood. Being reared in a communal nest (CN), consisting in a single nest where three mothers keep their pups together and share care-giving behavior from birth to weaning (postnatal day 25), provides a highly stimulating social environment to the developing pup. CN characterizes the natural ecological niche of many rodent species including the mouse. Here we show that, at adulthood, compared to mice reared in standard laboratory conditions (SN), CN reared mice displayed increased anxiety-like behavior, performing more thigmotaxis in the open field and spending less time in the open arms of the plus-maze. Furthermore, we showed that social context (being alone or with a familiar conspecific in the test apparatus) affects the emotional response in both the plus-maze and open field test and that the relevance of social context changes according to the early social experiences. In particular, CN mice display higher levels of anxiety-like behavior, compared to SN mice, only when alone but not in the presence of a familiar conspecific. Overall, in line with previous findings, the present study suggests that CN mice have a more elaborate social and emotional behavior compared to SN mice and thus may be more appropriate to investigate socio-emotional impairments, in particular in the case of mouse models of neurodevelopmental disorders, such as autism, or anxiety and mood disorders.

Age Factors↗

PubMed2005

Reelin signaling is impaired in autism.

BACKGROUND: Autism is a severe neurodevelopmental disorder with genetic and environmental etiologies. Recent genetic linkage studies implicate Reelin glycoprotein in causation of autism. To further investigate these studies, brain levels of Reelin protein and mRNA and mRNAs for VLDLR, Dab-1, and GSK3 were investigated. METHODS: Postmortem superior frontal, parietal, and cerebellar cortices of age, gender, and postmortem interval-matched autistic and control subjects were subjected to SDS-PAGE and Western blotting of Reelin protein. Quantitative reverse transcriptase polymerase chain reaction analysis of Reelin, VLDL-R, Dab-1, and GSK3 mRNA species in superior frontal and cerebellar cortices of autistic and control subjects were also performed. RESULTS: Reelin 410, 330, and 180 kDa/beta-actin values were reduced significantly in frontal and cerebellar, and nonsignificantly in parietal, areas of autistic brains versus control subjects, respectively. The mRNAs for Reln and Dab-1 were reduced significantly whereas the mRNA for Reln receptor VLDLR was elevated significantly in superior frontal and cerebellar areas of autistic brains versus control brains, respectively. CONCLUSIONS: Reductions in Reelin protein and mRNA and Dab 1 mRNA and elevations in Reln receptor VLDLR mRNA demonstrate impairments in the Reelin signaling system in autism, accounting for some of the brain structural and cognitive deficits observed in the disorder.

Actins↗

PubMed2005

Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice.

BACKGROUND: Mutations in the methyl-CpG binding protein 2 (MeCP2) gene cause Rett syndrome (RTT), a neurodevelopmental disorder that is accompanied by a broad array of behavioral phenotypes, mainly affecting females. Methyl-CpG binding protein 2 is a transcriptional repressor that is widely expressed in all tissues. METHODS: To investigate whether the postnatal loss of MeCP2 in the forebrain is sufficient to produce the behavioral phenotypes observed in RTT, we have generated conditional MeCP2 knockout mice. RESULTS: These mice display behavioral abnormalities similar to RTT phenotypes, including hindlimb clasping, impaired motor coordination, increased anxiety, and abnormal social behavior with other mice. These mice, however, have normal locomotor activity and unimpaired context-dependent fear conditioning, suggesting that the behavioral deficits observed are the result of loss of MeCP2 function in postnatal forebrain and not the result of generalized global deficits. CONCLUSIONS: These data highlight the important role of MeCP2 in the forebrain and suggest that even partial loss of MeCP2 expression in these brain regions is sufficient to recapitulate features of RTT.

Animals↗

PubMed2006

Omega-3 fatty acids supplementation in children with autism: a double-blind randomized, placebo-controlled pilot study.

BACKGROUND: There is increasing evidence that fatty acid deficiencies or imbalances may contribute to childhood neurodevelopmental disorders. METHODS: We conducted a randomized, double-blind, placebo-controlled 6-week pilot trial investigating the effects of 1.5 g/d of omega-3 fatty acids (.84 g/d eicosapentaenoic acid, .7 g/d docosahexaenoic acid) supplementation in 13 children (aged 5 to 17 years) with autistic disorders accompanied by severe tantrums, aggression, or self-injurious behavior. The outcome measure was the Aberrant Behavior Checklist (ABC) at 6 weeks. RESULTS: We observed an advantage of omega-3 fatty acids compared with placebo for hyperactivity and stereotypy, each with a large effect size. Repeated-measures ANOVA indicated a trend toward superiority of omega-3 fatty acids over placebo for hyperactivity. No clinically relevant adverse effects were elicited in either group. CONCLUSIONS: The results of this study provide preliminary evidence that omega-3 fatty acids may be an effective treatment for children with autism.

Adolescent↗

PubMed2007

Three-dimensional laser surface imaging and geometric morphometrics resolve frontonasal dysmorphology in schizophrenia.

BACKGROUND: Although a role for early developmental disturbance(s) in schizophrenia is postulated, it has proved difficult to identify hard, biological evidence. The brain and face emerge in embryologic intimacy, such that in neurodevelopmental disorders, brain dysmorphogenesis is accompanied by facial dysmorphogenesis. METHODS: Three-dimensional (3D) laser surface imaging was used to capture the facial surface of patients and control subjects in 37 male and 32 female patients who satisfied DSM-IV criteria for schizophrenia in comparison with 58 male and 34 female control subjects. Surface images were analyzed using geometric morphometrics and 3D visualizations to identify domains of facial shape that distinguish patients from control subjects. RESULTS: Both male and, particularly, female patients evidenced significant facial dysmorphology. There was narrowing and reduction of the mid to lower face and frontonasal prominences, including reduced width and posterior displacement of the mouth, lips, and chin; increased width of the upper face, mandible, and skull base, with lateral displacement of the cheeks, eyes, and orbits; and anterior displacement of the superior margins of the orbits. CONCLUSIONS: The frontonasal prominence, which enjoys the most intimate embryologic relationship with the anterior brain and also orchestrates aspects of development in maxillary and mandibular domains, evidences a characteristic topography of dysmorphogenesis in schizophrenia.

Adult↗

PubMed2006

The use of an unpleasant sound as an unconditional stimulus in a human aversive Pavlovian conditioning procedure.

Ethical considerations can limit the use of traditional unconditional stimuli (US), such as electric shock and loud tones, when used in a human aversive Pavlovian conditioning procedure. The risk of the US causing pain or excessive anxiety is a particular concern when testing sensitive populations such as children, the elderly, and those with psychological or neurodevelopmental disorders. Two experiments used a differential conditioning procedure to determine whether an unpleasant sound (metal scraping on slate) could support the acquisition and extinction of conditioned responses to the same extent as either electric shock or a 100 dB(A) tone US. Experiment 1 (N=48) demonstrated equivalent or superior conditioning effects for the signal-based learning measures of US expectancy, skin conductance responses, and heart rate. Experiment 2 (N=57) yielded similar outcomes in the affective-based learning measures of startle blink modulation and pleasantness ratings. The results support the use of an unpleasant sound as a US in human Pavlovian conditioning experiments.

Acoustic Stimulation↗

PubMed2005

Genotype and early development in Rett syndrome: the value of international data.

BACKGROUND: Rett syndrome is a neurodevelopmental disorder mostly affecting females and caused by mutations in the MECP2 gene. Originally the syndrome was characterised as having a normal prenatal and perinatal period with later regression. Previous work has speculated that the girl with Rett syndrome may not be normal at birth. AIMS: to examine whether early development between birth and ten months varies by genotype in Rett syndrome. METHODS: cases were sourced from two databases, the Australian Rett Syndrome Database (est. 1993) and the newly formed InterRett - IRSA Rett Phenotype Database. Data available on 320 cases included information provided by parents on perinatal problems, early developmental behaviour and mobility. Problem scores, mobility scores and a total composite score for each mutation were generated and compared. RESULTS: overall, 58% of respondents noted unusual behaviour during the first six months and 70.6% from the period between 6 and 10 months of life. Statistically significant differences were detected between some of the common mutations. Infants with R294X (P=0.05) and R133C (P=0.03) were less likely than those with R255X to have problems in the perinatal period. The most severe profile overall for early development was associated with mutations R255X and R270X. CONCLUSION: This is the largest study to date examining the effects of individual mutations in Rett syndrome. With the ongoing case ascertainment and expansion of InterRett, sample size will increase rapidly and provide improved statistical power for future analyses. Results from this study will contribute to understanding the mechanism of early development in Rett syndrome and determining if and at which time(s) early intervention might be feasible.

Adolescent↗

PubMed2006

MECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients.

Mutations in the methyl-CpG-binding protein 2 (MECP2) gene located on Xq28, cause Rett syndrome (RTT) in female patients. Meanwhile, nonmosaic MECP2 mutations unknown in girls have been found in an increasing number of male patients with a normal 46, XY karyotype. They can cause a broad spectrum of neurodevelopmental disorders which often show a combination of mental retardation (MR) with neurological symptoms. We present the results of MECP2 analysis in a group of 72 male patients with an unexplained combination of MR and neurological features, and review the mutational reports published on male patients since the discovery of the MECP2 gene. Analysis included sequencing of exon 1 which thus far was mostly omitted from DNA screening. One pathogenic mutation has been found in a patient with Rett variant, in addition to an unclassified variant and a series of nonpathogenic changes. No changes have been found in exon 1. Criteria for testing of male patients are classic RTT, severe neonatal encephalopathy, and RTT variant which may be clinically underrecognized. Testing can also be considered in males with a combination of unexplained MR and (progressive) neurological manifestations although the yield of MECP2 analysis is probably low in this situation. Based on the literature, MECP2 testing in males with MR only is debatable.

Adolescent↗

PubMed2006

The development of visual- and auditory processing in Rett syndrome: an ERP study.

Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. It is characterized by a progressive loss of intellectual functioning and motor skills, and the development of stereotypic hand movements, that occur after a period of normal development. Event-related potentials were recorded to a passive auditory- and visual oddball task in 17 females with Rett syndrome aged between 2 and 60 years, and age-matched controls. Overall the participants with Rett syndrome had longer ERP latencies and smaller ERP amplitudes than the Control group suggesting slowed information processing and reduced brain activation. The Rett groups also failed to show typical developmental changes in event-related brain activity and revealed a marked decline in ERP task modulation with increasing age.

Acoustic Stimulation↗

PubMed2006

MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother.

Rett syndrome is a severe neurodevelopmental disorder affecting principally females and characterized by a normal postnatal development followed by stagnation and regression of acquired skills. We report a 4-year-old boy with a Rett syndrome phenotype and his unaffected mother both carrying a 44 bp truncating deletion mutation (c.1158del44 or p.388X) in the MECP2 gene. The presence of a skewed X inactivation in the mother provides a possible explanation for the absence of penetrance. The finding of a MECP2 mutation in an unaffected female complicates genetic counseling and further confirms that it is essential to look for mutations in the mothers of all patients with MECP2 mutations.

Adult↗

PubMed2006

Childhood autism and associated comorbidities.

Autism is a heterogeneous neurodevelopmental disorder with a variety of different etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of autism is still unclear. This review refers to all the genetic syndromes that have been described in children with pervasive developmental disorders (tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Gilles de la Tourette, Williams, etc.). Issues covered include prevalence and main characteristics of each syndrome, as well as the possible base of its association with autism in terms of contribution to the current knowledge on the etiology and genetic base of pervasive developmental disorders.

Autistic Disorder↗

PubMed2004

Neonatal neurosteroid administration alters parvalbumin expression and neuron number in medial dorsal thalamus of adult rats.

The neuroactive steroid 3alpha-hydroxy-5alpha-pregnane-20-one (allopregnanolone) is a potent endogenous modulator of GABAA receptor function. A single neonatal allopregnanolone administration (10 mg/kg, i.p.) was previously shown to alter the localization of parvalbumin-positive neurons in the prefrontal cortex at maturity. Cells in the prefrontal cortex receive the majority of their inputs from the medial dorsal nucleus of the thalamus. We investigated whether neonatal allopregnanolone administration alters the neuronal population of the medial dorsal nucleus of the thalamus. We show that the number of parvalbumin-expressing neurons is increased while the total neuron number is decreased in the medial dorsal nucleus after allopregnanolone administration. EAAT3 (excitatory amino acid transporter type 3, the neuron-specific glutamate reuptake transporter) immunoreactivity was unchanged in adjacent sections. These findings suggest that neonatal allopregnanolone administration disrupts the normal development of the prefrontal cortex and medial dorsal thalamus, indicating that neurosteroid levels are important for proper development of thalamocortical systems and may play a role in neurodevelopmental disorders such as schizophrenia.

Amino Acid Transport System X-AG↗

PubMed2006

Cerebral asymmetry in 14 year olds born very preterm.

The normal pattern of cerebral asymmetry may be altered in neurodevelopmental disorders such as autism and schizophrenia. Babies born very preterm have an increased risk of brain damage, and brain abnormalities which persist into adolescence. This study aimed to ascertain whether preterm birth affects the development of fronto-occipital asymmetry. Structural MRI (magnetic resonance imaging) scans from 14 year old individuals born very preterm (n = 61; mean age 14 years 11 months; 29 male) and age-matched full-term controls (n = 49; mean age 14 years 11 months; 31 male) underwent morphometric analysis, using well-validated stereological methods. Measurements of right and left prefrontal, premotor, sensorimotor and occipitoparietal regional volumes were made and asymmetry indices calculated. These factors underwent a reductive factor analysis. There were no significant between-group differences in fronto-occipital asymmetry between the preterm adolescents and their full-term counterparts. It seems unlikely, therefore, that preterm birth per se deviates the development of normal fronto-occipital asymmetry. Neonatal periventricular haemorrhage with ventricular dilatation revealed by ultrasound may be associated with reversal of asymmetry in the sensorimotor area.

Adolescent↗

PubMed2006

Intrauterine growth restriction due to uteroplacental vascular insufficiency leads to increased hypoxia-induced cerebral apoptosis in newborn piglets.

Uteroplacental vascular insufficiency in humans is a common cause of intrauterine growth restriction (IUGR) and is associated with an increased incidence of perinatal asphyxia and neurodevelopmental disorders compared to normal weight newborns. Experimental models that provide an opportunity to analyze the pathogenesis of these relationships are limited. Here, we used neonatal pigs from large litters in which there were piglets of normal birth weight (for controls) and of low birth weight (for uteroplacental vascular insufficiency). Hypoxia was induced in paired littermates by reducing the fraction of inspired oxygen to 4% for 25 min. Brain tissue was collected 4 h post-hypoxia. Cerebral levels of apoptosis were quantified morphologically and verified with caspase-3 activity and TUNEL. Expression of Bcl-2, Bcl-XL and Bax proteins was investigated using immunohistochemistry. Cellular positivity for Bcl-2 was consistently higher in the non-apoptotic white matter of the hypoxic IUGR animals compared with their littermates and reached significance at P < 0.05 in several pairs of littermates. Alterations in Bax showed a trend towards higher expression in the hypoxic IUGR littermates but rarely reached significance. The IUGR piglets showed a significantly greater amount of apoptosis in response to the hypoxia than the normal weight piglets, suggesting an increased vulnerability to apoptosis in the IUGR piglets.

Animals↗

PubMed2003

Brain anatomy and development in autism: review of structural MRI studies.

Autism is a neurodevelopmental disorder that severely disrupts social and cognitive functions. MRI is the method of choice for in vivo and non-invasively investigating human brain morphology in children and adolescents. The authors reviewed structural MRI studies that investigated structural brain anatomy and development in autistic patients. All original MRI research papers involving autistic patients, published from 1966 to May 2003, were reviewed in order to elucidate brain anatomy and development of autism and rated for completeness using a 12-item check-list. Increased total brain, parieto-temporal lobe, and cerebellar hemisphere volumes were the most replicated abnormalities in autism. Interestingly, recent findings suggested that the size of amygdala, hippocampus, and corpus callosum may also be abnormal. It is conceivable that abnormalities in neural network involving fronto-temporo-parietal cortex, limbic system, and cerebellum may underlie the pathophysiology of autism, and that such changes could result from abnormal brain development during early life. Nonetheless, available MRI studies were often conflicting and could have been limited by methodological issues. Future MRI investigations should include well-characterized groups of autistic and matched healthy individuals, while taking into consideration confounding factors such as IQ, and socioeconomic status.

Autistic Disorder↗