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PubMedDate not supplied

[Inconsistent motor dominance in schizophrenic patients. Evidence in favor of neurodevelopmental changes].

INTRODUCTION: Motor left lateralization preference and lateralization inconsistencies have often been reported in schizophrenia and interpreted as an expression of a neurodevelopmental deficit in this disorder. However, the reported findings are contradictory and plagued by methodological errors. METHOD: The aim of this work is to examine functional motor lateralization preferences and lateralization inconsistencies in a sample on 78 schizophrenic patients by using a reliable method and comparing them with a nonclinical sample as a control group. We also study the potential associations between lateralization and several clinical, neuropsychological and neuroimage variables. RESULTS: No significant differences are found between schizophrenics and the control group in functional motor preferences. Other relevant finding are: absence of correlation between crural, ocular and hand preference; an association between the severity of negative symptoms and lateralization inconsistency; and an earlier clinical onset and a smaller brain volume in right-handed schizophrenics with ocular crossed lateralization as compared with right-handed schizophrenics with consistent ocular lateralization. CONCLUSION: These findings back up the hypothesis of a neurodevelopmental deficit in schizophrenia.

Adolescent↗

PubMed2004

Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders.

Disrupted In Schizophrenia 1 (DISC1) was identified as a potential susceptibility gene for schizophrenia due to its disruption by a balanced t(1;11) (q42;q14) translocation, which has been shown to cosegregate with major psychiatric disease in a large Scottish family. We have demonstrated that DISC1 exists in a neurodevelopmentally regulated protein complex with Nudel. The complex is abundant at E17 and in early postnatal life but is greatly reduced in the adult. Nudel has previously been shown to bind Lis1, a gene underlying lissencephaly in humans. Critically, we show that the predicted peptide product resulting from the Scottish translocation removes the interaction domain for Nudel. DISC1 interacts with Nudel through a leucine zipper domain and binds to a novel DISC1-interaction domain on Nudel, which is independent from the Lis1 binding site. We show that Nudel is able to act as a bridge between DISC1 and Lis1 to allow formation of a trimolecular complex. Nudel has been implicated to play a role in neuronal migration, together with the developmental variation in the abundance of the DISC1-Nudel complex, may implicate a defective DISC1-Nudel complex as a neurodevelopmental cause of schizophrenia.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1999

Reduced synaptophysin immunoreactivity in the dentate gyrus of prepulse inhibition-impaired isolation-reared rats.

Isolation rearing of rat pups from weaning produces neurochemical and behavioural changes that may have relevance to the neurodevelopmental basis of neuropsychiatric disorders such as schizophrenia. Although limited, studies have begun to probe for neuroanatomical changes produced by isolation rearing. In the present study, rat pups were reared in isolation, i.e., housed one per cage, from weaning. After 8 weeks of isolation, 'isolates' were compared to their socially reared controls (housed three per cage) in two behavioural paradigms: locomotor activity in a novel open field and prepulse inhibition (PPI) of the acoustic startle response. Subsequently, all rats were sacrificed and their brains removed. The hippocampus was sectioned and analysed immunohistochemically using an antibody to the synapse-specific protein synaptophysin, to gain an estimate of the synaptic content of selected hippocampal subfields. Isolates demonstrated locomotor hyperactivity and deficits in PPI relative to socially reared controls. Analysis of synaptophysin immunoreactivity suggested that isolates had significantly reduced synaptic content in the hippocampal dentate gyrus molecular layer, with smaller, non-significant reductions in the CA1 and CA3 regions. This pattern of change may be consistent with reduced neuronal input to the dentate gyrus via the entorhinal cortex, suggesting developmental changes in hippocampal-cortical circuitry. These preliminary studies extend the characterisation of isolation rearing as a model for the investigation of neurodevelopmental diseases such as schizophrenia.

Animals↗

PubMed2006

Quantitative trait locus analysis of nonverbal communication in autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental syndrome marked by impairments in social interactive functioning and communication skills, and the presence of repetitive and restrictive behaviors. Twin and linkage studies provide evidence that ASD is heritable and genetically complex. Genetic analyses of familial quantitative traits in those with ASD may help to reveal underlying risk genes. We report a quantitative trait locus (QTL) analysis of nonverbal communication (NVC) in 228 families from the autism genetics resource exchange (AGRE) ascertained for at least two siblings with ASD. QTL at 1p13-q12, 4q21-25, 7q35, 8q23-24, and 16p12-13 indicate that genes at these loci may contribute to the variation in NVC among those with ASD. Using the criteria of Lander and Kruglyak, the QTL at 1p13-q12 is 'suggestive', while the other four are 'possible'. To assess whether these QTL are likely to harbor genes contributing specifically to the deficits in NVC, linkage analysis of ASD sibships with the most severe NVC scores was conducted. The sibships were identified by ordered-subset analyses (OSA), and families with the most severe NVC scores displayed lod scores of 3.4 at 8q23-24 and 3.8 at 16p12-13, indicating that these two regions are likely to harbor gene(s) contributing to ASD by predisposing to deficits in NVC.

Adolescent↗

PubMed1988

[Long-term prognosis for premature infants].

Recent advances in perinatology have been associated with a decrease in perinatal mortality among very low birth weight (VLBW) infants. However, only comprehensive follow-up programmes allow obstetricians and neonatologists to measure short-term and long-term effects of neonatal intensive care. In our experience, sequential brain ultrasonography together with serial neurological assessments during the neonatal period play an important role in the prediction of later neurodevelopmental outcome. Major sequelae are closely related to periventricular leukomalacia and extensive parenchymal haemorrhage. With improving knowledge of the physiopathology of cerebral damage, more effective preventive measures are now being taken. Nowadays, the incidence of major handicaps (5%) is steadily decreasing among VLBW survivors. Only a few comprehensive studies have regularly followed up preterm infants until school age. Our results showed that 17% of VLBW infants had minor neurodevelopmental abnormalities (visuomotor or motor disorders and language disorders) at 8 years of age. School failure was frequently found among children who presented the association of several neurodevelopmental abnormalities. Most of these developmental problems can be detected in preschool age, and early recognition may allow better counselling of parents and appropriate intervention. An optimistic attitude regarding the outcome in VLBW infants without cerebral lesions or associated neurodevelopmental abnormalities is certainly justified at the present time. These results emphasize the importance of optimal perinatal intensive care for VLBW infants.

Brain Damage, Chronic↗

PubMed2026

Individual differences in brain dynamics across a social cognition network induced by cortico-cerebellar tDCS in adults with autism spectrum disorder (ASD).

Autism spectrum disorder (ASD) is a neurodevelopmental condition with core diagnostic domains of social communication impairments, restricted interests and repetitive behaviors. Idiosyncratic brain organization is a potential hallmark of ASD. Previous transcranial direct current stimulation (tDCS) studies often targeted dorsolateral prefrontal cortex, with changes oin brain dynamics averaged across the cohort. We utilized a magnetoencephalographic (MEG) array to characterize individual differences in brain dynamics induced by cortico-cerebellar tDCS across nodes of a social cognition network. A randomized, sham-controlled, double-blind, within-subject clinical trial was conducted in a cohort of 24 young adults with ASD or high autistic traits. Two separate sessions of computerized social learning activities were combined with verum/sham tDCS, with anodal electrode over right temporoparietal junction (TPJ) and cathode on right deltoid. Following stimulation, theta- and alpha-band activity were evaluated within nodes of a social cognition network: bilateral TPJ, fusiform, medial prefrontal cortex and Crus I/II of cerebellum. Idiosyncratic participant-specific up- and down-regulation of theta- and alpha-band activity occurred across the network. Activity in right Crus I/II, a region inundated by the stimulation current, strongly correlated with the change of activity summed across all cerebral cortical nodes in theta- but not alpha-band. Intrinsic theta-band activity is believed to mediate input/output relationships in cerebellar cortex and to drive synaptic plasticity. These results suggest that theta-band stimulation of cerebellar cortex might be an effective therapy for individuals on the autism spectrum who present with cerebellar hyperactivity.

Humans↗

PubMed2026

Clinical Utility of Trio Exome Sequencing in Rwandan Children With Autism Spectrum Disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental condition with substantial genetic and phenotypic heterogeneity. However, populations of African ancestry remain underrepresented in genomic studies, limiting understanding of ASD genetic architecture. This study aimed to characterize rare, clinically relevant genetic variants in a Rwandan pediatric ASD cohort using trio-based whole-exome sequencing (WES). METHODS: Trio-based WES was performed in 31 Rwandan pediatric patients with ASD (aged 2-18 years) and their parents. Variants were analyzed using a trio-based workflow and classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Eleven candidate variants were identified in 9 of 31 patients, including four likely pathogenic variants and seven variants of uncertain significance. This resulted in a diagnostic yield of 12.9% (4/31), expanded to 29.0% when phenotypically concordant variants of uncertain significance were considered. Most likely pathogenic variants were identified in individuals with syndromic ASD who presented with intellectual disability, epilepsy, and global developmental delay. Likely pathogenic findings included two single nucleotide variants in GABRB3, SYNGAP1, and two copy-number variants involving the GNAS locus and chromosome 1p35.3-p35.2. CONCLUSIONS: The diagnostic yield observed in this cohort is consistent with previous trio-based WES studies of ASD. The findings support the clinical utility of WES for the genetic evaluation of ASD and underscore the need for expanded genomic studies in African populations.

Humans↗

PubMed2025

Prematurity and Genetic Liability for Autism Spectrum Disorder.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by diverse presentations and a strong genetic component. Environmental factors, such as prematurity, have also been linked to increased liability for ASD, though the interaction between genetic predisposition and prematurity remains unclear. This study aims to investigate the impact of genetic liability and preterm birth on ASD conditions. METHODS: We analyzed phenotype and genetic data from two large ASD cohorts, the Simons Foundation Powering Autism Research for Knowledge (SPARK) and Simons Simplex Collection (SSC), encompassing 78,559 individuals for phenotype analysis, 12,519 individuals with genome sequencing data, and 8,104 individuals with exome sequencing data. Statistical significance of differences in clinical measures was evaluated between individuals with different ASD and preterm status. We assessed the rare variants burden using generalized estimating equations (GEE) models and polygenic load using ASD-associated polygenic risk score (PRS). Furthermore, we developed a machine learning model to predict ASD in preterm children using phenotype and genetic features available at birth. RESULTS: Individuals with both preterm birth and ASD exhibit more severe phenotypic outcomes despite similar levels of genetic liability for ASD across the term and preterm groups. Notably, preterm ASD individuals showed an elevated rate of de novo variants identified in exome sequencing (GEE model, p=0.005) in comparison to the non-ASD preterm group. Additionally, a GEE model showed that a higher ASD PRS, preterm birth, and male sex were positively associated with a higher predicted probability for ASD, reaching a probability close to 90% in SPARK. Lastly, we developed a machine learning model using phenotype and genetic features available at birth with limited predictive power (AUROC = 0.65). CONCLUSIONS: Preterm birth may exacerbate the multimorbidity present in ASD, which was not due to the ASD genetic factors. However, increased genetic factors may elevate the likelihood of a preterm child being diagnosed with ASD. Additionally, a polygenic load of ASD-associated variants had an additive role with preterm birth in the predicted probability for ASD, especially for boys. We propose that incorporating genetic assessment into neonatal care could benefit early ASD identification and intervention for preterm infants.

Autism Spectrum Disorder↗

PubMed1997

The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys. Rapid communication.

By conferring allele-specific transcriptional activity on the 5-HT transporter gene promoter in humans, the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) influences a constellation of personality traits related to anxiety and increases the risk for neurodevelopmental, neurodegenerative, and psychiatric disorders. Here we have analyzed the presence and variability of the 5-HTTLPR in several species of primates including humans, and other mammals. PCR, Southern blot, and sequence analyses of the 5-HT transporter gene's 5'-flanking region in different mammalian species confirmed the presence of the 5-HTTLPR in platyrrhini and catarrhini (hominoids, cercopithecoids) but not in prosimian primates and other mammals. Since the 5-HTTLPR is unique to humans and simian primates, a progenitor 5-HTTLPR sequence may have been introduced into the genome some 40 Mio, years ago. In humans the majority of alleles are composed of either 14 or 16 repeat elements, while alleles with 18 or 20 repeat elements are rare. In contrast, great apes including orang-utan, gorilla, and chimpanzee display a high prevalence of alleles with 18 and 20 repeat elements. In hominoids all alleles originate from variation at a single locus (polymorphic locus 1). In the 5-HTTLPR of rhesus monkeys (rh5-HTTLPR) we found an alternative locus for length variation (polymorphic locus 2) generated by a 21 bp insertion/deletion event. The existence of a distinct biallelic variation of the 5-HTTLPR in rhesus monkeys but similar allele and genotype frequencies in this species and humans supports the notion that there may be a relationship between functional 5-HT transporter expression, anxiety-related traits, and the complexity of socialization in human and non-human primate populations.

Alleles↗

PubMed1994

Ontogeny of [3H]-SCH23390 and [3H]-YM09151-2 binding sites in human fetal forebrain.

In order to determine the gestational age at which binding sites for the dopamine "D1-like" and "D2-like" receptor antagonists, [3H]-SCH23390 and [3H]-YM09151-2, respectively, can be reliably detected in the human and to identify any discrete anatomic distribution of these binding sites, fetal forebrain tissue sections from mid-first (n = 4) and mid-second (n = 4) trimester gestations were used for receptor autoradiography. Specific binding for both ligands was detectable at the earliest fetal age examined (gestational week 6). Age-related increases in maximum saturation binding were demonstrated for both ligands using tissue sections from basal forebrain. The Bmax for both [3H]-SCH23390 and [3H]-YM09151-2 binding increased ten-fold comparing gestational week 6 and gestational week 18 values. In the cortex at gestational day 120, [3H]-YM09151-2 specific binding could be seen at the gray-white matter boundary, which was more prominent by gestational day 140. In contrast, [3H]-SCH23390 specific binding to the cortex at gestational day 120 did not appear to differentiate specific areas and did not increase between gestational days 120 and 140. These preliminary observations in human fetal brain provide evidence that dopamine "D2-like" binding sites can be localized in a discrete cortical area in the course of normal human brain development. Characterizing these binding sites and the population of cells that demonstrates these binding sites may be relevant to neurodevelopmental hypotheses of psychiatric disorders.

Antipsychotic Agents↗

PubMed2005

Brain magnetic resonance study of Mecp2 deletion effects on anatomy and metabolism.

Rett syndrome, a neurodevelopmental X-linked disorder, represents the most important genetic cause of severe mental retardation in the female population and results from a mutation in the gene encoding methyl-CpG-binding protein 2 (MECP2). We report here the first characterization of Mecp2-null mice, by in vivo magnetic resonance imaging and spectroscopy, delineating the cerebral phenotype associated with the lack of Mecp2. We performed a morphometric study that revealed a size reduction of the whole brain and of structures involved in cognitive and motor functions (cerebellum and motor cortex). Significant metabolic anomalies, including reduced N-acetylaspartate, myo-inositol, and glutamine plus glutamate, and increased choline levels were evidenced. These findings indicate that not only neuronal but also glial metabolism is affected in Mecp2-null mice. Furthermore, we uncovered an important reduction of brain ATP level, a hitherto undetected anomaly of energy metabolism that may reflect and contribute to cerebral injury and dysfunction.

Adenosine Triphosphate↗

PubMed2006

Cavum septum pellucidum and adhesio interthalamica in schizophrenia: an MRI study.

Several studies have independently suggested that patients with schizophrenia are more likely to have an enlarged cavum septum pellucidum (CSP) and an absent adhesio interthalamica (AI), respectively. However, neither finding has been consistently replicated and it is unclear whether there is an association between these two midline brain abnormalities. Thus, we compared the prevalence of absent AI and the prevalence, size and volume of CSP in 38 patients with schizophrenia and 38 healthy controls using magnetic resonance imaging (MRI). There were no between group differences in the presence or volume of CSP; however, an enlarged CSP was commoner among patients than controls. There was also a positive correlation between CSP ratings and volumes. No differences in the presence or absence of the AI were found between patients and controls; however, an absent AI was commoner in male patients with schizophrenia than females. There was absolutely no overlap between the presence of a large CSP and an absence of AI. In conclusion, our findings are in line with several case series and other MRI investigations that have shown a higher incidence of putatively developmental brain abnormalities in patients with schizophrenia, particularly in males, and support the neurodevelopmental model of this disorder.

Adult↗

PubMedDate not supplied

Course of psychopathology, cognition and neurobiological abnormality in schizophrenia: developmental origins and amelioration by antipsychotics?

It is argued that schizophrenia has origins in events occurring during the first or early second trimester that are reflected in minor physical anomalies and which may at least in part predispose to later obstetric complications. This neurodevelopmental basis underlies certain neuromotor and psychosocial abnormalities of infancy and childhood, which are the early manifestations of what will be reconceptualised later as negative symptoms and (particularly frontal) cognitive dysfunction, but gives rise to positive symptoms only on the maturation of other systems necessary for their expression. This later emergence of psychosis may reflect an active morbid process that is associated with increased accrual of negative symptoms and of general (but not frontal) cognitive impairment that may be ameliorated by effective antipsychotic treatment. The psychological or biological basis of this heuristic process is poorly understood. Contemporary re-appraisal of any impact of antipsychotics on the long-term course of schizophrenia must take into account what is known of the origins of the disease process with which such drugs might interact. Much recent work continues to indicate that very early events, during the embryonic/fetal period, are important in, if not fundamental to, the genesis of schizophrenia; i.e. that there is a neurodevelopmental basis to the disorder. The present article seeks to establish a time-line relating early intrauterine adversity and dysmorphogenesis, through the onset of psychosis, to the chronic phase of the illness over adulthood; from this time-line, a schema is elaborated for a beneficial impact of antipsychotics on the course of psychopathology, cognition and, less clearly, neurobiological abnormality.

Antipsychotic Agents↗

PubMedDate not supplied

Prenatal exposure to methylazoxymethanol acetate in the rat alters neurotrophin levels and behavior: considerations for neurodevelopmental diseases.

We did a single injection of methylazoxymethanol acetate (MAM) in pregnant rats on gestational day (GD) 11 or 12 to investigate the long-lasting effects of early entorhinal cortex (EC) and hippocampus maldevelopment on behavior, brain nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels, and the neurotrophin receptor p75 and choline acetyltransferase (ChAT) immunoreactivity. Adult animals treated with MAM had compromised EC development and showed changes in locomotion and displacement activities. In addition, rats treated on GD 12 had increased concentration of NGF and BDNF in the EC and hippocampus if compared to control rats. Prenatal MAM administration did not affect significantly p75 and ChAT distribution in the EC and septum. Results are discussed in reference to the neurodevelopmental hypothesis of psychiatric disorders.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Schizophrenia and the ciliary neurotrophic factor (CNTF) gene: no evidence for association.

The ciliary neurotrophic factor (CNTF) gene is considered a candidate gene for schizophrenia, in view of the neurodevelopmental hypothesis of the disorder. Recently, controversial results regarding an association between psychiatric disorders; mainly schizophrenia, and a null mutation of the CNTF gene were reported. We investigated this mutation in 138 Japanese patients with schizophrenia and 140 healthy control subjects. No significant difference was observed in allele frequencies or genotype distribution between the patients and control subjects. Our results did not provide evidence for the involvement of the null mutation of the CNTF gene in the development of schizophrenia.

Adult↗

PubMed1997

Neuropsychological profiles in schizophrenia: paranoid versus undifferentiated distinctions.

Research on schizophrenia has searched for subtype-specific cognitive dysfunction to elucidate the neurodevelopmental underpinnings of the disorder. The neuropsychological distinctions between 21 paranoid and 15 undifferentiated schizophrenics were studied. The paranoid group had significantly better Verbal IQ, executive functioning on the Wisconsin Card Sorting Test, and memory for spoken language on the Sentence Repetition Test compared to undifferentiated schizophrenics. While the paranoid subtype showed trends toward better performance on a wide variety of tasks, both subtypes showed impairments on tasks requiring continuous auditory attention and fine motor speed and coordination. Despite the paranoid subjects' more intact verbal skills, both groups showed significant deficits in verbal learning on the Rey Auditory Verbal Learning Test. This suggests that temporal-hippocampal system dysfunction may be a common denominator in both schizophrenic subtypes. These findings were not accounted for by subtype differences in the level of education, depression or severity of illness.

Adult↗

PubMed1998

Neurodevelopmental dysfunction and specific learning disabilities in school-aged twins.

The frequency of the developmental dysfunction and specific learning disabilities were assessed in the retrospective study in the group of 56 school-aged twins. The relationships between genetic, perinatal and social factors and learning disability were also determined. It was found that 12.5% of twins had learning disabilities. The most common neurodevelopmental dysfunction were language disorders, poor graphomotor fluency and poor fine motor dexterity. It was also found that educational difficulty were associated with prematurity, low Apgar scores, neonatal complications and familial predisposition.

Adolescent↗

PubMed2002

Changes in rhythmic suckle feeding patterns in term infants in the first month of life.

To quantify parameters of rhythmic suckle feeding in healthy term infants and to assess developmental changes during the first month of life, we recorded pharyngeal and nipple pressure in 16 infants at 1 to 4 days of age and again at 1 month. Over the first month of life in term infants, sucks and swallows become more rapid and increasingly organized into runs. Suck rate increased from 55/minute in the immediate postnatal period to 70/minute by the end of the first month (p<0.001). The percentage of sucks in runs of > or =3 increased from 72.7% (SD 12.8) to 87.9% (SD 9.1; p=0.001). Average length of suck runs also increased over the first month. Swallow rate increased slightly by the end of the first month, from about 46 to 50/minute (p=0.019), as did percentage of swallows in runs (76.8%, SD 14.9 versus 54.6%, SD 19.2; p=0.002). Efficiency of feeding, as measured by volume of nutrient per suck (0.17, SD 0.08 versus 0.30, SD 0.11 cc/suck; p=0.008) and per swallow (0.23, SD 0.11 versus 0.44, SD 0.19 cc/swallow; p=0.002), almost doubled over the first month. The rhythmic stability of swallow-swallow, suck-suck, and suck-swallow dyadic interval, quantified using the coefficient of variation of the interval, was similar at the two age points, indicating that rhythmic stability of suck and swallow, individually and interactively, appears to be established by term. Percentage of sucks and swallows in 1:1 ratios (dyads), decreased from 78.8% (SD 20.1) shortly after birth to 57.5% (SD 25.8) at 1 month of age (p=0.002), demonstrating that the predominant 1:1 ratio of suck to swallow is more variable at 1 month, with the addition of ratios of 2:1, 3:1, and so on, and suggesting that infants gain the ability to adjust feeding patterns to improve efficiency. Knowledge of normal development in term infants provides a gold standard against which rhythmic patterns in preterm and other high-risk infants can be measured, and may allow earlier identification of infants at risk of neurodevelopmental delay and feeding disorders.

Breast Feeding↗