Neuroimaging studies in schizophrenia: an overview of research from Asia.

PubMed

Narayanaswamy, Janardhanan C; Venkatasubramanian, Ganesan; Gangadhar, Bangalore N

2012-10-01

Neuroimaging studies in schizophrenia help clarify the neural substrates underlying the pathogenesis of this neuropsychiatric disorder. Contemporary brain imaging in schizophrenia is predominated by magnetic resonance imaging (MRI)-based research approaches. This review focuses on the various imaging studies from India and their relevance to the understanding of brain abnormalities in schizophrenia. The existing studies are predominantly comprised of structural MRI reports involving region-of-interest and voxel-based morphometry approaches, magnetic resonance spectroscopy and single-photon emission computed tomography/positron emission tomography (SPECT/PET) studies. Most of these studies are significant in that they have evaluated antipsychotic-naïve schizophrenia patients--a relatively difficult population to obtain in contemporary research. Findings of these studies offer robust support to the existence of significant brain abnormalities at very early stages of the disorder. In addition, theoretically relevant relationships between these brain abnormalities and developmental aberrations suggest possible neurodevelopmental basis for these brain deficits.

Effects of Age and Symptomatology on Cortical Thickness in Autism Spectrum Disorders

ERIC Educational Resources Information Center

Doyle-Thomas, Krissy A. R.; Duerden, Emma G.; Taylor, Margot J.; Lerch, Jason P.; Soorya, Latha V.; Wang, A. Ting; Fan, Jin; Hollander, Eric; Anagnostou, Evdokia

2013-01-01

Several brain regions show structural and functional abnormalities in individuals with autism spectrum disorders (ASD), but the developmental trajectory of abnormalities in these structures and how they may relate to social and communicative impairments are still unclear. We assessed the effects of age on cortical thickness in individuals with…

Statistical distribution of blood serotonin as a predictor of early autistic brain abnormalities

PubMed Central

Janušonis, Skirmantas

2005-01-01

Background A wide range of abnormalities has been reported in autistic brains, but these abnormalities may be the result of an earlier underlying developmental alteration that may no longer be evident by the time autism is diagnosed. The most consistent biological finding in autistic individuals has been their statistically elevated levels of 5-hydroxytryptamine (5-HT, serotonin) in blood platelets (platelet hyperserotonemia). The early developmental alteration of the autistic brain and the autistic platelet hyperserotonemia may be caused by the same biological factor expressed in the brain and outside the brain, respectively. Unlike the brain, blood platelets are short-lived and continue to be produced throughout the life span, suggesting that this factor may continue to operate outside the brain years after the brain is formed. The statistical distributions of the platelet 5-HT levels in normal and autistic groups have characteristic features and may contain information about the nature of this yet unidentified factor. Results The identity of this factor was studied by using a novel, quantitative approach that was applied to published distributions of the platelet 5-HT levels in normal and autistic groups. It was shown that the published data are consistent with the hypothesis that a factor that interferes with brain development in autism may also regulate the release of 5-HT from gut enterochromaffin cells. Numerical analysis revealed that this factor may be non-functional in autistic individuals. Conclusion At least some biological factors, the abnormal function of which leads to the development of the autistic brain, may regulate the release of 5-HT from the gut years after birth. If the present model is correct, it will allow future efforts to be focused on a limited number of gene candidates, some of which have not been suspected to be involved in autism (such as the 5-HT4 receptor gene) based on currently available clinical and experimental studies. PMID:16029508

Statistical distribution of blood serotonin as a predictor of early autistic brain abnormalities.

PubMed

Janusonis, Skirmantas

2005-07-19

A wide range of abnormalities has been reported in autistic brains, but these abnormalities may be the result of an earlier underlying developmental alteration that may no longer be evident by the time autism is diagnosed. The most consistent biological finding in autistic individuals has been their statistically elevated levels of 5-hydroxytryptamine (5-HT, serotonin) in blood platelets (platelet hyperserotonemia). The early developmental alteration of the autistic brain and the autistic platelet hyperserotonemia may be caused by the same biological factor expressed in the brain and outside the brain, respectively. Unlike the brain, blood platelets are short-lived and continue to be produced throughout the life span, suggesting that this factor may continue to operate outside the brain years after the brain is formed. The statistical distributions of the platelet 5-HT levels in normal and autistic groups have characteristic features and may contain information about the nature of this yet unidentified factor. The identity of this factor was studied by using a novel, quantitative approach that was applied to published distributions of the platelet 5-HT levels in normal and autistic groups. It was shown that the published data are consistent with the hypothesis that a factor that interferes with brain development in autism may also regulate the release of 5-HT from gut enterochromaffin cells. Numerical analysis revealed that this factor may be non-functional in autistic individuals. At least some biological factors, the abnormal function of which leads to the development of the autistic brain, may regulate the release of 5-HT from the gut years after birth. If the present model is correct, it will allow future efforts to be focused on a limited number of gene candidates, some of which have not been suspected to be involved in autism (such as the 5-HT4 receptor gene) based on currently available clinical and experimental studies.

Neonatal brain resting-state functional connectivity imaging modalities.

PubMed

Mohammadi-Nejad, Ali-Reza; Mahmoudzadeh, Mahdi; Hassanpour, Mahlegha S; Wallois, Fabrice; Muzik, Otto; Papadelis, Christos; Hansen, Anne; Soltanian-Zadeh, Hamid; Gelovani, Juri; Nasiriavanaki, Mohammadreza

2018-06-01

Infancy is the most critical period in human brain development. Studies demonstrate that subtle brain abnormalities during this state of life may greatly affect the developmental processes of the newborn infants. One of the rapidly developing methods for early characterization of abnormal brain development is functional connectivity of the brain at rest. While the majority of resting-state studies have been conducted using magnetic resonance imaging (MRI), there is clear evidence that resting-state functional connectivity (rs-FC) can also be evaluated using other imaging modalities. The aim of this review is to compare the advantages and limitations of different modalities used for the mapping of infants' brain functional connectivity at rest. In addition, we introduce photoacoustic tomography, a novel functional neuroimaging modality, as a complementary modality for functional mapping of infants' brain.

Functional-Lesion Investigation of Developmental Stuttering with Positron Emission Tomography.

ERIC Educational Resources Information Center

Ingham, Roger J.; And Others

1996-01-01

Analysis of use of positron emission tomographic measurements of resting-state regional cerebral blood flow in 29 men, 10 of whom stuttered, did not support the idea that developmental stuttering is associated with abnormalities of blood flow at rest. Findings did suggest an essentially normal functional brain terrain with a small number of minor…

Present and future of developmental neuropsychopharmacology.

PubMed

Arango, Celso

2015-05-01

The field of child and adolescent psychiatry has always lagged behind adult psychiatry. With recent evidence that the vast majority of mental disorders, even when they emerge in adulthood, cause abnormal neurodevelopment and resultant emphasis on prevention and early intervention, there is a need to put child psychiatry at the top of the agenda in mental health research. This should also be the case for developmental neuropsychopharmacology. The target of drug discovery should shift toward a population younger than the one that is typically included in clinical trials. This is not only a matter of trying to replicate what has been found in individuals with mature brains; it is about searching for new strategies that address developing brains while the therapeutic window for their effect is still open. At present, major concerns in developmental psychopharmacology are over-prescription rates and use of psychotropic medications for conditions with a particularly underdeveloped evidence base, as well as adverse effects, especially potentially life-shortening cardiometabolic effects and suicidal ideation. The future of research in this area should focus on the use of drugs for primary and secondary prevention that would modify abnormal brain development. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Scleroderma en coup de sabre with recurrent episodes of brain hemorrhage.

PubMed

Takahashi, Takehiro; Asano, Yoshihide; Oka, Tomonori; Miyagaki, Tomomitsu; Tamaki, Zenshiro; Nonaka, Senshu; Sato, Shinichi

2016-02-01

We report a 39-year-old man referred to our facility with linear sclerotic lesions along the several Blaschko's lines of the scalp. A year before the referral, he had had an episode of brain hemorrhage, although there was no evidence of vascular malformation or any other risk factors of brain hemorrhage for his young age. On the diagnosis of scleroderma en coup de sabre, prednisolone intake was initiated, and the skin lesions were well controlled. However, in the course of our follow up, he had another episode of brain hemorrhage, again without any evidence of cerebral vascular abnormalities. Organic intracranial abnormalities in this disease are well-documented, but there have been few reports on comorbid recurrent brain hemorrhages. We herein discuss the possible relationship of the skin lesions with the brain hemorrhages in our case, taking notice of the implication of developmental abnormalities behind these apparently independent phenomena inside and outside the cranium. © 2015 Japanese Dermatological Association.

Roles of mTOR Signaling in Brain Development.

PubMed

Lee, Da Yong

2015-09-01

mTOR is a serine/threonine kinase composed of multiple protein components. Intracellular signaling of mTOR complexes is involved in many of physiological functions including cell survival, proliferation and differentiation through the regulation of protein synthesis in multiple cell types. During brain development, mTOR-mediated signaling pathway plays a crucial role in the process of neuronal and glial differentiation and the maintenance of the stemness of neural stem cells. The abnormalities in the activity of mTOR and its downstream signaling molecules in neural stem cells result in severe defects of brain developmental processes causing a significant number of brain disorders, such as pediatric brain tumors, autism, seizure, learning disability and mental retardation. Understanding the implication of mTOR activity in neural stem cells would be able to provide an important clue in the development of future brain developmental disorder therapies.

Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia.

PubMed

Kesby, James P; Cui, Xiaoying; Burne, Thomas H J; Eyles, Darryl W

2013-01-01

Schizophrenia is a heterogeneous group of disorders with unknown etiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine (DA) neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesized that abnormal DA signaling in the adult patient may result from altered DA signaling during fetal brain development. Environmental and genetic risk factors can be modeled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the etiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD) deficiency. DVD-deficient adult rats display an altered behavioral profile in response to DA releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis, and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters DA metabolism in the developing brain. We speculate such alterations in fetal brain development may change the trajectory of DA neuron ontogeny to induce the behavioral abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in DA ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

A Model for Predicting Cognitive and Emotional Health from Structural and Functional Neurocircuitry Following Traumatic Brain Injury

DTIC Science & Technology

2017-10-01

Neuroimaging 2006 Reviewer, Journal of Abnormal Psychology 2006 Reviewer, Psychopharmacology 2006 Reviewer, Developmental Science 2006 Reviewer...This study will address this problem by collecting measures of white matter integrity and concomitant neuropsychological status at five time points...hypothesize that structural white matter tract disintegrity will underlie abnormalities in functional connectivity, neurocognitive performance and

Magnetic resonance imaging (MRI) evaluation of developmental delay in pediatric patients.

PubMed

Ali, Althaf S; Syed, Naziya P; Murthy, G S N; Nori, Madhavi; Abkari, Anand; Pooja, B K; Venkateswarlu, J

2015-01-01

Developmental delay is defined as significant delay in one or more developmental domains. Magnetic Resonance Imaging (MRI) is the best modality to investigate such patients. Evaluation of a child with developmental delay is important not only because it allows early diagnosis and treatment but also helpful for parental counseling regarding the outcome of their child and to identify any possible risk of recurrence in the siblings. Thus this study was undertaken to evaluate the developmental delay in Indian children which will help the clinicians in providing an estimation of the child's ultimate developmental potential and organize specific treatment requirement and also relieve parental apprehension. To study the prevalence of normal and abnormal MRI in pediatric patients presenting with developmental delay and further categorize the abnormal MRI based on its morphological features. It is a prospective, observational & descriptive study of MRI Brain in 81 paediatric patients (46 Males and 35 Females), aged between three months to 12 years; presenting with developmental delay in Deccan College of Medical Sciences, Hyderabad; over a period of three years (Sept 2011 to Sept 2014). MRI brain was done on 1.5T Siemens Magnetom Essenza & 0.35T Magnetom C with appropriate sequences and planes after making the child sleep/sedated/ anesthetized. Various anatomical structures like Ventricles, Corpus callosum, etc were systematically assessed. The MRI findings were divided into various aetiological subgroups. Normal MRI findings were seen in 32% cases and 68% had abnormal findings of which the proportion of Traumatic/ Neurovascular Diseases, Congenital & Developmental, Metabolic and Degenerative, neoplastic and non specific were 31%, 17%, 10%, 2.5% and 7.5% respectively. The ventricles and white matter mainly the corpus callosum were the most commonly affected anatomical structures. The diagnostic yield was found to be 68% and higher yield was seen in patients presenting with developmental delay plus. The clinical diagnosis of developmental delay should not be the end point, but rather a springboard for an effective search for causal factors. MRI is the best investigation with a high yield in such patients.

Magnetic Resonance Imaging (MRI) Evaluation of Developmental Delay in Pediatric Patients

PubMed Central

Syed, Naziya P.; Murthy, G.S.N.; Nori, Madhavi; Abkari, Anand; Pooja, B.K.; Venkateswarlu, J.

2015-01-01

Introduction: Developmental delay is defined as significant delay in one or more developmental domains. Magnetic Resonance Imaging (MRI) is the best modality to investigate such patients. Evaluation of a child with developmental delay is important not only because it allows early diagnosis and treatment but also helpful for parental counseling regarding the outcome of their child and to identify any possible risk of recurrence in the siblings. Thus this study was undertaken to evaluate the developmental delay in Indian children which will help the clinicians in providing an estimation of the child’s ultimate developmental potential and organize specific treatment requirement and also relieve parental apprehension. Aims and Objectives: To study the prevalence of normal and abnormal MRI in pediatric patients presenting with developmental delay and further categorize the abnormal MRI based on its morphological features. Materials and Methods: It is a prospective, observational & descriptive study of MRI Brain in 81 paediatric patients (46 Males and 35 Females), aged between three months to 12 years; presenting with developmental delay in Deccan College of Medical Sciences, Hyderabad; over a period of three years (Sept 2011 to Sept 2014). MRI brain was done on 1.5T Siemens Magnetom Essenza & 0.35T Magnetom C with appropriate sequences and planes after making the child sleep/sedated/ anesthetized. Various anatomical structures like Ventricles, Corpus callosum, etc were systematically assessed. The MRI findings were divided into various aetiological subgroups. Results: Normal MRI findings were seen in 32% cases and 68% had abnormal findings of which the proportion of Traumatic/ Neurovascular Diseases, Congenital & Developmental, Metabolic and Degenerative, neoplastic and non specific were 31%, 17%, 10%, 2.5% and 7.5% respectively. The ventricles and white matter mainly the corpus callosum were the most commonly affected anatomical structures. The diagnostic yield was found to be 68% and higher yield was seen in patients presenting with developmental delay plus. Conclusion: The clinical diagnosis of developmental delay should not be the end point, but rather a springboard for an effective search for causal factors. MRI is the best investigation with a high yield in such patients. PMID:25738057

High Fat Diet Induced Developmental Defects in the Mouse: Oocyte Meiotic Aneuploidy and Fetal Growth Retardation/Brain Defects

PubMed Central

Purcell, Scott H.; Chi, Maggie; Jimenez, Patricia T.; Grindler, Natalia; Schedl, Tim; Moley, Kelle H.

2012-01-01

Background Maternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, fetal loss, congenital abnormalities and neonatal conditions. Furthermore, the proportion of reproductive-aged woman that are obese in the population is increasing sharply. From current studies it is not clear if the origin of the reproductive complications is attributable to problems that arise in the oocyte or the uterine environment. Methodology/Principal Findings We examined the developmental basis of the reproductive phenotypes in obese animals by employing a high fat diet mouse model of obesity. We analyzed very early embryonic and fetal phenotypes, which can be parsed into three abnormal developmental processes that occur in obese mothers. The first is oocyte meiotic aneuploidy that then leads to early embryonic loss. The second is an abnormal process distinct from meiotic aneuploidy that also leads to early embryonic loss. The third is fetal growth retardation and brain developmental abnormalities, which based on embryo transfer experiments are not due to the obese uterine environment but instead must be from a defect that arises prior to the blastocyst stage. Conclusions/Significance Our results suggest that reproductive complications in obese females are, at least in part, from oocyte maternal effects. This conclusion is consistent with IVF studies where the increased pregnancy failure rate in obese women returns to the normal rate if donor oocytes are used instead of autologous oocytes. We postulate that preconceptional weight gain adversely affects pregnancy outcomes and fetal development. In light of our findings, preconceptional counseling may be indicated as the preferable, earlier target for intervention in obese women desiring pregnancy and healthy outcomes. PMID:23152876

Mutations in α-Tubulin Cause Abnormal Neuronal Migration in Mice and Lissencephaly in Humans

PubMed Central

Keays, David A.; Tian, Guoling; Poirier, Karine; Huang, Guo-Jen; Siebold, Christian; Cleak, James; Oliver, Peter L.; Fray, Martin; Harvey, Robert J.; Molnár, Zoltán; Piñon, Maria C.; Dear, Neil; Valdar, William; Brown, Steve D.M.; Davies, Kay E.; Rawlins, J. Nicholas P.; Cowan, Nicholas J.; Nolan, Patrick; Chelly, Jamel; Flint, Jonathan

2007-01-01

Summary The development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of α-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders. PMID:17218254

Primary cortical folding in the human newborn: an early marker of later functional development.

PubMed

Dubois, J; Benders, M; Borradori-Tolsa, C; Cachia, A; Lazeyras, F; Ha-Vinh Leuchter, R; Sizonenko, S V; Warfield, S K; Mangin, J F; Hüppi, P S

2008-08-01

In the human brain, the morphology of cortical gyri and sulci is complex and variable among individuals, and it may reflect pathological functioning with specific abnormalities observed in certain developmental and neuropsychiatric disorders. Since cortical folding occurs early during brain development, these structural abnormalities might be present long before the appearance of functional symptoms. So far, the precise mechanisms responsible for such alteration in the convolution pattern during intra-uterine or post-natal development are still poorly understood. Here we compared anatomical and functional brain development in vivo among 45 premature newborns who experienced different intra-uterine environments: 22 normal singletons, 12 twins and 11 newborns with intrauterine growth restriction (IUGR). Using magnetic resonance imaging (MRI) and dedicated post-processing tools, we investigated early disturbances in cortical formation at birth, over the developmental period critical for the emergence of convolutions (26-36 weeks of gestational age), and defined early 'endophenotypes' of sulcal development. We demonstrated that twins have a delayed but harmonious maturation, with reduced surface and sulcation index compared to singletons, whereas the gyrification of IUGR newborns is discordant to the normal developmental trajectory, with a more pronounced reduction of surface in relation to the sulcation index compared to normal newborns. Furthermore, we showed that these structural measurements of the brain at birth are predictors of infants' outcome at term equivalent age, for MRI-based cerebral volumes and neurobehavioural development evaluated with the assessment of preterm infant's behaviour (APIB).

MYELIN, COPPER, AND THE CUPRIZONE MODEL OF SCHIZOPHRENIA

PubMed Central

Herring, Nicole R.; Konradi, Christine

2010-01-01

In recent years increasing evidence is pointing toward white matter abnormalities in schizophrenia and other psychiatric disorders. The present paper will provide an overview over the role of myelin in cognition and brain function, and its potential involvement in brain disorders. Furthermore, we will examine one particular experimental model for the study of dysmyelination, created by the administration of the toxin cuprizone. Cuprizone, a copper chelator, causes white matter abnormalities in rodents. The administration of cuprizone during specific developmental periods allows for the targeting of specific brain areas for dysmyelination. Thus, cuprizone can be used to study the pathogenesis and pathophysiology of myelin deficiencies in the central nervous system, and its effect on behaviors relevant to psychiatric disorders. PMID:21196354

Brain Growth Rate Abnormalities Visualized in Adolescents with Autism

PubMed Central

Hua, Xue; Thompson, Paul M.; Leow, Alex D.; Madsen, Sarah K.; Caplan, Rochelle; Alger, Jeffry R.; O’Neill, Joseph; Joshi, Kishori; Smalley, Susan L.; Toga, Arthur W.; Levitt, Jennifer G.

2014-01-01

Autism spectrum disorder (ASD) is a heterogeneous disorder of brain development with wide-ranging cognitive deficits. Typically diagnosed before age 3, ASD is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared to those of typically developing children and adolescents. Using tensor-based morphometry (TBM), we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and 7 typically developing boys (mean age/inter-scan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole-brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (p = 0.03, corrected), especially in the parietal (p = 0.008), temporal (p = 0.03) and occipital lobes (p =0.02). We also visualized abnormal overgrowth in autism in some gray matter structures, such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. TBM revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects. PMID:22021093

Brain growth rate abnormalities visualized in adolescents with autism.

PubMed

Hua, Xue; Thompson, Paul M; Leow, Alex D; Madsen, Sarah K; Caplan, Rochelle; Alger, Jeffry R; O'Neill, Joseph; Joshi, Kishori; Smalley, Susan L; Toga, Arthur W; Levitt, Jennifer G

2013-02-01

Autism spectrum disorder is a heterogeneous disorder of brain development with wide ranging cognitive deficits. Typically diagnosed before age 3, autism spectrum disorder is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared with those of typically developing children and adolescents. Using tensor-based morphometry, we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and seven typically developing boys (mean age/interscan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (P = 0.03, corrected), especially in the parietal (P = 0.008), temporal (P = 0.03), and occipital lobes (P = 0.02). We also visualized abnormal overgrowth in autism in gray matter structures such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. Tensor-based morphometry revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects. Copyright © 2011 Wiley Periodicals, Inc.

Annual Research Review: Growth connectomics – the organization and reorganization of brain networks during normal and abnormal development

PubMed Central

Vértes, Petra E; Bullmore, Edward T

2015-01-01

Background We first give a brief introduction to graph theoretical analysis and its application to the study of brain network topology or connectomics. Within this framework, we review the existing empirical data on developmental changes in brain network organization across a range of experimental modalities (including structural and functional MRI, diffusion tensor imaging, magnetoencephalography and electroencephalography in humans). Synthesis We discuss preliminary evidence and current hypotheses for how the emergence of network properties correlates with concomitant cognitive and behavioural changes associated with development. We highlight some of the technical and conceptual challenges to be addressed by future developments in this rapidly moving field. Given the parallels previously discovered between neural systems across species and over a range of spatial scales, we also review some recent advances in developmental network studies at the cellular scale. We highlight the opportunities presented by such studies and how they may complement neuroimaging in advancing our understanding of brain development. Finally, we note that many brain and mind disorders are thought to be neurodevelopmental in origin and that charting the trajectory of brain network changes associated with healthy development also sets the stage for understanding abnormal network development. Conclusions We therefore briefly review the clinical relevance of network metrics as potential diagnostic markers and some recent efforts in computational modelling of brain networks which might contribute to a more mechanistic understanding of neurodevelopmental disorders in future. PMID:25441756

A family affair: brain abnormalities in siblings of patients with schizophrenia.

PubMed

Moran, Marcel E; Hulshoff Pol, Hilleke; Gogtay, Nitin

2013-11-01

Schizophrenia is a severe mental disorder that has a strong genetic basis. Converging evidence suggests that schizophrenia is a progressive neurodevelopmental disorder, with earlier onset cases resulting in more profound brain abnormalities. Siblings of patients with schizophrenia provide an invaluable resource for differentiating between trait and state markers, thus highlighting possible endophenotypes for ongoing research. However, findings from sibling studies have not been systematically put together in a coherent story across the broader age span. We review here the cortical grey matter abnormalities in siblings of patients with schizophrenia from childhood to adulthood, by reviewing sibling studies from both childhood-onset schizophrenia, and the more common adult-onset schizophrenia. When reviewed together, studies suggest that siblings of patients with schizophrenia display significant brain abnormalities that highlight both similarities and differences between the adult and childhood populations, with shared developmental risk patterns, and segregating trajectories. Based on current research it appears that the cortical grey matter abnormalities in siblings are likely to be an age-dependent endophenotype, which normalize by the typical age of onset of schizophrenia unless there has been more genetic or symptom burdening. With increased genetic burdening (e.g. discordant twins of patients) the grey matter abnormalities in (twin) siblings are progressive in adulthood. This synthesis of the literature clarifies the importance of brain plasticity in the pathophysiology of the illness, indicating that probands may lack protective factors critical for healthy development.

A family affair: brain abnormalities in siblings of patients with schizophrenia

PubMed Central

Hulshoff Pol, Hilleke; Gogtay, Nitin

2013-01-01

Schizophrenia is a severe mental disorder that has a strong genetic basis. Converging evidence suggests that schizophrenia is a progressive neurodevelopmental disorder, with earlier onset cases resulting in more profound brain abnormalities. Siblings of patients with schizophrenia provide an invaluable resource for differentiating between trait and state markers, thus highlighting possible endophenotypes for ongoing research. However, findings from sibling studies have not been systematically put together in a coherent story across the broader age span. We review here the cortical grey matter abnormalities in siblings of patients with schizophrenia from childhood to adulthood, by reviewing sibling studies from both childhood-onset schizophrenia, and the more common adult-onset schizophrenia. When reviewed together, studies suggest that siblings of patients with schizophrenia display significant brain abnormalities that highlight both similarities and differences between the adult and childhood populations, with shared developmental risk patterns, and segregating trajectories. Based on current research it appears that the cortical grey matter abnormalities in siblings are likely to be an age-dependent endophenotype, which normalize by the typical age of onset of schizophrenia unless there has been more genetic or symptom burdening. With increased genetic burdening (e.g. discordant twins of patients) the grey matter abnormalities in (twin) siblings are progressive in adulthood. This synthesis of the literature clarifies the importance of brain plasticity in the pathophysiology of the illness, indicating that probands may lack protective factors critical for healthy development. PMID:23698280

Early Brain Vulnerability in Wolfram Syndrome

PubMed Central

Hershey, Tamara; Lugar, Heather M.; Shimony, Joshua S.; Rutlin, Jerrel; Koller, Jonathan M.; Perantie, Dana C.; Paciorkowski, Alex R.; Eisenstein, Sarah A.; Permutt, M. Alan

2012-01-01

Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development. PMID:22792385

Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice.

PubMed

Ansorge, Mark S; Morelli, Emanuela; Gingrich, Jay A

2008-01-02

Serotonin (5-HT) acts as a neurotransmitter, but also modulates brain maturation during early development. The demonstrated influence of genetic variants on brain function, personality traits, and susceptibility to neuropsychiatric disorders suggests a critical importance of developmental mechanisms. However, little is known about how and when developmentally perturbed 5-HT signaling affects circuitry and resulting behavior. The 5-HT transporter (5-HTT) is a key regulator of extracellular 5-HT levels and we used pharmacologic strategies to manipulate 5-HTT function during development and determine behavioral consequences. Transient exposure to the 5-HTT inhibitors fluoxetine, clomipramine, and citalopram from postnatal day 4 (P4) to P21 produced abnormal emotional behaviors in adult mice. Similar treatment with the norepinephrine transporter (NET) inhibitor, desipramine, did not adversely affect adult behavior, suggesting that 5-HT and norepinephrine (NE) do not share the same effects on brain development. Shifting our period of treatment/testing to P90/P185 failed to mimic the effect of earlier exposure, demonstrating that 5-HT effects on adult behavior are developmentally specific. We have hypothesized that early-life perturbations of 5-HT signaling affect corticolimbic circuits that do not reach maturity until the peri-adolescent period. In support of this idea, we found that abnormal behaviors resulting from postnatal fluoxetine exposure have a post-pubescent onset and persist long after reaching adult age. A better understanding of the underlying 5-HT sensitive circuits and how they are perturbed should lead to new insights into how various genetic polymorphisms confer their risk to carriers. Furthermore, these studies should help determine whether in utero exposure to 5-HTT blocking drugs poses a risk for behavioral abnormalities in later life.

A mechanical model predicts morphological abnormalities in the developing human brain

NASA Astrophysics Data System (ADS)

Budday, Silvia; Raybaud, Charles; Kuhl, Ellen

2014-07-01

The developing human brain remains one of the few unsolved mysteries of science. Advancements in developmental biology, neuroscience, and medical imaging have brought us closer than ever to understand brain development in health and disease. However, the precise role of mechanics throughout this process remains underestimated and poorly understood. Here we show that mechanical stretch plays a crucial role in brain development. Using the nonlinear field theories of mechanics supplemented by the theory of finite growth, we model the human brain as a living system with a morphogenetically growing outer surface and a stretch-driven growing inner core. This approach seamlessly integrates the two popular but competing hypotheses for cortical folding: axonal tension and differential growth. We calibrate our model using magnetic resonance images from very preterm neonates. Our model predicts that deviations in cortical growth and thickness induce morphological abnormalities. Using the gyrification index, the ratio between the total and exposed surface area, we demonstrate that these abnormalities agree with the classical pathologies of lissencephaly and polymicrogyria. Understanding the mechanisms of cortical folding in the developing human brain has direct implications in the diagnostics and treatment of neurological disorders, including epilepsy, schizophrenia, and autism.

Phenotype and management of Aicardi syndrome: new findings from a survey of 69 children

USDA-ARS?s Scientific Manuscript database

Aicardi syndrome is a rare neurodevelopmental disorder characterized by agenesis of the corpus callosum, other developmental brain abnormalities, chorioretinal lacunae, and severe seizures. Current clinical knowledge is derived from small series that focus on these major defects. The authors perform...

Neurodevelopment and executive function in autism.

PubMed

O'Hearn, Kirsten; Asato, Miya; Ordaz, Sarah; Luna, Beatriz

2008-01-01

Autism is a neurodevelopmental disorder characterized by social and communication deficits, and repetitive behavior. Studies investigating the integrity of brain systems in autism suggest a wide range of gray and white matter abnormalities that are present early in life and change with development. These abnormalities predominantly affect association areas and undermine functional integration. Executive function, which has a protracted development into adolescence and reflects the integration of complex widely distributed brain function, is also affected in autism. Evidence from studies probing response inhibition and working memory indicate impairments in these core components of executive function, as well as compensatory mechanisms that permit normative function in autism. Studies also demonstrate age-related improvements in executive function from childhood to adolescence in autism, indicating the presence of plasticity and suggesting a prolonged window for effective treatment. Despite developmental gains, mature executive functioning is limited in autism, reflecting abnormalities in wide-spread brain networks that may lead to impaired processing of complex information across all domains.

Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging

PubMed Central

Alston, Robert; Wright, Neville B; Chandler, Kate; Bonney, Denise; Wynn, Robert F; Will, Andrew M; Punekar, Maqsood; Loughran, Sean; Kilday, John-Paul; Schindler, Detlev; Patel, Leena; Meyer, Stefan

2015-01-01

Objective: Fanconi anaemia (FA) is an inherited disease associated with congenital and developmental abnormalities resulting from the disruption of a multigenic DNA damage response pathway. This study aimed to define the MRI appearances of the brain in patients with FA in correlation with their genetic and clinical features. Methods: A review of the brain MRI in 20 patients with FA was performed. Pituitary size and frequencies of the radiological findings of individuals with FA and age-matched controls were determined. Results: Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males). In five cases (25%, p = 0.02), the pituitary morphology was also abnormal. Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy–Walker variant (n = 2) and cerebellar atrophy (n = 2). Six patients (30%, p = 0.01) had morphological structural variation of the corpus callosum (CC). Conclusion: The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development. MRI brain imaging is important for endocrine assessment and pre-transplant evaluation and can make an important contribution to clinical decision-making. Advances in knowledge: The incidence of brain structural abnormalities in FA is higher than previously reported, with abnormalities of the posterior fossa, CC and pituitary being common. There is an association with gender and reduction in pituitary size which does not strongly correlate with biochemically evident endocrine abnormality. PMID:26369989

Gestational lead exposure induces developmental abnormalities and up-regulates apoptosis of fetal cerebellar cells in rats.

PubMed

Mousa, Alyaa M; Al-Fadhli, Ameera S; Rao, Muddanna S; Kilarkaje, Narayana

2015-01-01

Lead (Pb), a known environmental toxicant, adversely affects almost all organ systems. In this study, we investigated the effects of maternal lead exposure on fetal rat cerebellum. Female Sprague-Dawley rats were given lead nitrate in drinking water (0, 0.5, and 1%) for two weeks before conception, and during pregnancy. Fetuses were collected by caesarian section on gestational day 21 and observed for developmental abnormalities. The fetal cerebellar sections from control and 1% lead group were stained with cresyl violet. Immunohistochemical expressions of p53, Bax, Bcl-2, and caspase 3 were quantified by AnalySIS image analyzer (Life Science, Germany). Lead exposure induced developmental abnormalities of eyes, ear, limbs, neck and ventral abdominal wall; however, these abnormalities were commonly seen in the 1% lead-treated group. In addition, lead also caused fetal mortality and reduced body growth in both dose groups and reduced brain weight in the 1% lead-treated group. The fetal cerebella from the 1% lead-treated group showed unorganized cerebellar cortical layers, and degenerative changes in granule and Purkinje cells such as the formation of clumps of Nissl granules. An increase in Bax and caspase 3, and a decrease in Bcl-2 (p < 0.05), but not in p53, showed apoptosis of the neurons. In conclusion, gestational lead exposure in rats induces fetal toxicity and developmental abnormalities. The lead exposure also impairs development of cerebellar layers, induces structural changes, and apoptosis in the fetal cerebellar cortex. These results suggest that lead exposure during gestation is extremely toxic to developing cerebellum in rats.

How cortical neurons help us see: visual recognition in the human brain

PubMed Central

Blumberg, Julie; Kreiman, Gabriel

2010-01-01

Through a series of complex transformations, the pixel-like input to the retina is converted into rich visual perceptions that constitute an integral part of visual recognition. Multiple visual problems arise due to damage or developmental abnormalities in the cortex of the brain. Here, we provide an overview of how visual information is processed along the ventral visual cortex in the human brain. We discuss how neurophysiological recordings in macaque monkeys and in humans can help us understand the computations performed by visual cortex. PMID:20811161

Brain single-photon emission computed tomography in fetal alcohol syndrome: a case report and study implications.

PubMed

Codreanu, Ion; Yang, JiGang; Zhuang, Hongming

2012-12-01

The indications of brain single-photon emission computed tomography (SPECT) in fetal alcohol syndrome are not clearly defined, even though the condition is recognized as one of the most common causes of mental retardation. This article reports a case of a 9-year-old adopted girl with developmental delay, mildly dysmorphic facial features, and behavioral and cognitive abnormalities. Extensive investigations including genetic studies and brain magnetic resonance imaging (MRI) revealed no abnormalities, and a diagnosis of fetal alcohol syndrome was considered since official diagnostic criteria were met. A brain SPECT was requested and showed severely decreased tracer activity in the thalami, basal ganglia, and temporal lobes on both sides, the overall findings being consistent with the established diagnosis of fetal alcohol syndrome. With increasing availability of functional brain imaging, the study indications and possible ethical implications in suspected prenatal alcohol exposure or even before adoption need further consideration. In this patient, SPECT was the only test to yield positive results.

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS.

PubMed

Silva, Mauro Sb; Prescott, Melanie; Campbell, Rebecca E

2018-04-05

Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP-transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype.

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS

PubMed Central

Silva, Mauro S.B.; Prescott, Melanie; Campbell, Rebecca E.

2018-01-01

Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP–transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype. PMID:29618656

Quantitative evaluation of brain development using anatomical MRI and diffusion tensor imaging☆

PubMed Central

Oishi, Kenichi; Faria, Andreia V.; Yoshida, Shoko; Chang, Linda; Mori, Susumu

2013-01-01

The development of the brain is structure-specific, and the growth rate of each structure differs depending on the age of the subject. Magnetic resonance imaging (MRI) is often used to evaluate brain development because of the high spatial resolution and contrast that enable the observation of structure-specific developmental status. Currently, most clinical MRIs are evaluated qualitatively to assist in the clinical decision-making and diagnosis. The clinical MRI report usually does not provide quantitative values that can be used to monitor developmental status. Recently, the importance of image quantification to detect and evaluate mild-to-moderate anatomical abnormalities has been emphasized because these alterations are possibly related to several psychiatric disorders and learning disabilities. In the research arena, structural MRI and diffusion tensor imaging (DTI) have been widely applied to quantify brain development of the pediatric population. To interpret the values from these MR modalities, a “growth percentile chart,” which describes the mean and standard deviation of the normal developmental curve for each anatomical structure, is required. Although efforts have been made to create such a growth percentile chart based on MRI and DTI, one of the greatest challenges is to standardize the anatomical boundaries of the measured anatomical structures. To avoid inter- and intra-reader variability about the anatomical boundary definition, and hence, to increase the precision of quantitative measurements, an automated structure parcellation method, customized for the neonatal and pediatric population, has been developed. This method enables quantification of multiple MR modalities using a common analytic framework. In this paper, the attempt to create an MRI- and a DTI-based growth percentile chart, followed by an application to investigate developmental abnormalities related to cerebral palsy, Williams syndrome, and Rett syndrome, have been introduced. Future directions include multimodal image analysis and personalization for clinical application. PMID:23796902

The red tide toxin, brevetoxin, induces embryo toxicity and developmental abnormalities.

PubMed Central

Kimm-Brinson, K L; Ramsdell, J S

2001-01-01

Brevetoxins are lipophilic polyether toxins produced by the red tide dinoflagellate Gymnodinium breve, and their neurotoxic effects on adult animals have been documented. In this study, we characterized adverse developmental effects of brevetoxin-1 (PbTx-1) using an exposure paradigm that parallels the maternal oocyte transfer of toxin. Medaka fish (Oryzias latipes) embryos were exposed to PbTx-1 via microinjection of toxin reconstituted in a triolein oil droplet. Embryos microinjected with doses of 0.1-8.0 ng/egg (ppm) of brevetoxin-1 exhibited pronounced muscular activity (hyperkinesis) after embryonic day 4. Upon hatching, morphologic abnormalities were commonly found in embryos at the following lowest adverse effect levels: 1.0-3.0 ppm, lateral curvature of the spinal column; 3.1-3.4 ppm, herniation of brain meninges through defects in the skull; and 3.4-4.0 ppm, malpositioned eye. Hatching abnormalities were also commonly observed at brevetoxin doses of 2.0 ppm and higher with head-first, as opposed to the normal tail-first, hatching, and doses > 4.1 ng/egg produced embryos that developed but failed to hatch. Given the similarity of developmental processes found between higher and lower vertebrates, teratogenic effects of brevetoxins have the potential to occur among different phylogenetic classes. The observation of developmental abnormalities after PbTx-1 exposure identifies a new spectrum of adverse effects that may be expected to occur following exposure to G. breve red tide events. PMID:11335186

Thalamofrontal neurodevelopment in new-onset pediatric idiopathic generalized epilepsy

PubMed Central

Dabbs, K.; Tuchsherer, V.; Sheth, R.D.; Koehn, M.A.; Hermann, B.P.; Seidenberg, M.

2011-01-01

Background: Quantitative MRI techniques have demonstrated thalamocortical abnormalities in idiopathic generalized epilepsy (IGE). However, there are few studies examining IGE early in its course and the neurodevelopmental course of this region is not adequately defined. Objective: We examined the 2-year developmental course of the thalamus and frontal lobes in pediatric new-onset IGE (i.e., within 12 months of diagnosis). Methods: We performed whole-brain MRI in 22 patients with new-onset IGE and 36 age-matched healthy controls. MRI was repeated 24 months after baseline MRI. Quantitative volumetrics were used to examine thalamic and frontal lobe volumes. Results: The IGE group showed significant differences in thalamic volume within 1 year of seizure onset (baseline) and went on to show thalamic volume loss at a significantly faster rate than healthy control children over the 2-year interval. The control group also showed a significantly greater increase in frontal white matter expansion than the IGE group. In contrast, frontal lobe gray matter volume differences were moderate at baseline and persisted over time, indicating similar developmental trajectories with differences early in the disease process that are maintained. Conclusions: Brain tissue abnormalities in thalamic and frontal regions can be identified very early in the course of IGE and an abnormal trajectory of growth continues over a 2-year interval. PMID:21205692

Thalamofrontal neurodevelopment in new-onset pediatric idiopathic generalized epilepsy.

PubMed

Pulsipher, D T; Dabbs, K; Tuchsherer, V; Sheth, R D; Koehn, M A; Hermann, B P; Seidenberg, M

2011-01-04

Quantitative MRI techniques have demonstrated thalamocortical abnormalities in idiopathic generalized epilepsy (IGE). However, there are few studies examining IGE early in its course and the neurodevelopmental course of this region is not adequately defined. We examined the 2-year developmental course of the thalamus and frontal lobes in pediatric new-onset IGE (i.e., within 12 months of diagnosis). We performed whole-brain MRI in 22 patients with new-onset IGE and 36 age-matched healthy controls. MRI was repeated 24 months after baseline MRI. Quantitative volumetrics were used to examine thalamic and frontal lobe volumes. The IGE group showed significant differences in thalamic volume within 1 year of seizure onset (baseline) and went on to show thalamic volume loss at a significantly faster rate than healthy control children over the 2-year interval. The control group also showed a significantly greater increase in frontal white matter expansion than the IGE group. In contrast, frontal lobe gray matter volume differences were moderate at baseline and persisted over time, indicating similar developmental trajectories with differences early in the disease process that are maintained. Brain tissue abnormalities in thalamic and frontal regions can be identified very early in the course of IGE and an abnormal trajectory of growth continues over a 2-year interval.

Neurodevelopmental behavioral and cognitive disorders.

PubMed

Jeste, Shafali Spurling

2015-06-01

Neurodevelopmental disorders are a group of heterogeneous conditions characterized by a delay or disturbance in the acquisition of skills in a variety of developmental domains, including motor, social, language, and cognition. This article reviews the most commonly diagnosed neurodevelopmental disorders, which include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, global developmental delay, and intellectual disability and also provides updates on diagnosis, neurobiology, treatment, and issues surrounding the transition to adulthood. Although symptoms emerge at discrete points in childhood, these disorders result from abnormal brain maturation that likely precedes clinical impairment. As a result, research has focused on the identification of predictive biological and behavioral markers, with the ultimate goal of initiating treatments that may either alter developmental trajectories or lessen clinical severity. Advances in the methods used to identify genetic variants, from chromosomal microarray analysis to whole exome sequencing, have facilitated the characterization of many genetic mutations and syndromes that share common pathways to abnormal circuit formation and brain development. Not only do genetic discoveries enrich our understanding of mechanisms underlying atypical development, but they also allow us to identify more homogeneous subgroups within this spectrum of conditions. Impairments do continue into adulthood, with challenges in the transition to adulthood including the management of comorbidities and the provision of educational and vocational supports. Advances in our understanding of the neurobiology and developmental trajectories of these disorders will pave the way for tremendous advances in treatment. Mechanism-based therapies for genetic syndromes are being studied with the goal of expanding targeted treatments to nonsyndromic forms of neurodevelopmental disorders.

Contribution of fetal brain MRI in management of severe fetal anemia.

PubMed

Ghesquière, L; Houfflin-Debarge, V; Verpillat, P; Fourquet, T; Joriot, S; Coulon, C; Vaast, P; Garabedian, C

2018-06-06

Intrauterine transfusion (IUT) has changed fetal anemia prognosis. However, long-term neurodevelopmental outcome is altered in 5% of children. Our objective was to study the contribution of fetal MRI to diagnosis brain lesions in case of fetal anemia. Retrospective monocentric descriptive study from 2005 to 2016, including all patients followed for fetal anemia requiring IUT. The indications for MRI were: hydrops fetalis and / or hemoglobin <5 g / dL and / or more than 3 IUTs and / or acute severe anemia and / or ultrasound abnormality. Fetal and neonatal outcome and pediatric neurological monitoring were studied. 89 patients were followed for fetal anemia with IUT and 28 (29.1%) had fetal MRI, 12 of which were abnormal. Two out of twelve had abnormal ultrasound. Seven out of twelve had poor neurological prognosis: 2 medical terminations of pregnancy were performed; 2 children had severe developmental delay and 3 children had schooling difficulties. Five out of twelve children had favorable neurological prognosis. MRI of the fetal brain makes it possible to better detect brain lesions than ultrasound does in the management of severe fetal anemia and seems particularly appropriate in cases of acute anemia. Copyright © 2018 Elsevier B.V. All rights reserved.

EEG - A Valuable Biomarker of Brain Injury in Preterm Infants.

PubMed

Pavlidis, Elena; Lloyd, Rhodri O; Boylan, Geraldine B

2017-01-01

This review focuses on the role of electroencephalography (EEG) in monitoring abnormalities of preterm brain function. EEG features of the most common developmental brain injuries in preterm infants, including intraventricular haemorrhage, periventricular leukomalacia, and perinatal asphyxia, are described. We outline the most common EEG biomarkers associated with these injuries, namely seizures, positive rolandic sharp waves, EEG suppression/increased interburst intervals, mechanical delta brush activity, and other deformed EEG waveforms, asymmetries, and asynchronies. The increasing survival rate of preterm infants, in particular those that are very and extremely preterm, has led to a growing demand for a specific and shared characterization of the patterns related to adverse outcome in this unique population. This review includes abundant high-quality images of the EEG patterns seen in premature infants and will provide a valuable resource for everyone working in developmental neuroscience. © 2017 S. Karger AG, Basel.

Holoprosencephaly: from Homer to Hedgehog.

PubMed

Ming, J E; Muenke, M

1998-03-01

Holoprosencephaly (HPE), a common developmental defect affecting the forebrain and face, is etiologically heterogeneous and exhibits wide phenotypic variation. Graded degrees of severity of the brain malformation are also reflected in the highly variable craniofacial malformations associated with HPE. In addition, individuals with microforms of HPE, who usually have normal cognition and normal brain imaging, are at risk for having children with HPE. Some obligate carriers for HPE may not have any phenotypic abnormalities. Recurrent chromosomal rearrangements in individuals with HPE suggest loci containing genes important for brain development, and abnormalities in these genes may result in HPE. Recently, Sonic Hedgehog (SHH) was the first gene identified as causing HPE in humans. Proper function of SHH depends on cholesterol modification. Other candidate genes that may be involved in HPE include components of the SHH pathway, elements involved in cholesterol metabolism, and genes expressed in the developing forebrain.

Fetal brain disruption sequence versus fetal brain arrest: A distinct autosomal recessive developmental brain malformation phenotype.

PubMed

Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; El-Khayat, Hamed A; Eid, Ola M; Saba, Soliman; Farag, Mona K; Saleem, Sahar N; Gaber, Khaled R

2015-05-01

The term fetal brain disruption sequence (FBDS) was coined to describe a number of sporadic conditions caused by numerous external disruptive events presenting with variable imaging findings. However, rare familial occurrences have been reported. We describe five patients (two sib pairs and one sporadic) with congenital severe microcephaly, seizures, and profound intellectual disability. Brain magnetic resonance imaging (MRI) revealed unique and uniform picture of underdeveloped cerebral hemispheres with increased extraxial CSF, abnormal gyral pattern (polymicrogyria-like lesions in two sibs and lissencephaly in the others), loss of white matter, dysplastic ventricles, hypogenesis of corpus callosum, and hypoplasia of the brainstem, but hypoplastic cerebellum in one. Fetal magnetic resonance imaging (FMRI) of two patients showed the same developmental brain malformations in utero. These imaging findings are in accordance with arrested brain development rather than disruption. Molecular analysis excluded mutations in potentially related genes such as NDE1, MKL2, OCLN, and JAM3. These unique clinical and imaging findings were described before among familial reports with FBDS. However, our patients represent a recognizable phenotype of developmental brain malformations, that is, apparently distinguishable from either familial microhydranencephaly or microlissencephaly that were collectively termed FBDS. Thus, the use of the umbrella term FBDS is no longer helpful. Accordingly, we propose the term fetal brain arrest to distinguish them from other familial patients diagnosed as FBDS. The presence of five affected patients from three unrelated consanguineous families suggests an autosomal-recessive mode of inheritance. The spectrum of fetal brain disruption sequence is reviewed. © 2015 Wiley Periodicals, Inc.

Decreased cohesin in the brain leads to defective synapse development and anxiety-related behavior

PubMed Central

Fujita, Yuki; Masuda, Koji; Bando, Masashige; Nakato, Ryuichiro; Katou, Yuki; Tanaka, Takashi; Nakayama, Masahiro; Takao, Keizo; Miyakawa, Tsuyoshi; Tanaka, Tatsunori; Ago, Yukio

2017-01-01

Abnormal epigenetic regulation can cause the nervous system to develop abnormally. Here, we sought to understand the mechanism by which this occurs by investigating the protein complex cohesin, which is considered to regulate gene expression and, when defective, is associated with higher-level brain dysfunction and the developmental disorder Cornelia de Lange syndrome (CdLS). We generated conditional Smc3-knockout mice and observed greater dendritic complexity and larger numbers of immature synapses in the cerebral cortex of Smc3+/− mice. Smc3+/− mice also exhibited more anxiety-related behavior, which is a symptom of CdLS. Further, a gene ontology analysis after RNA-sequencing suggested the enrichment of immune processes, particularly the response to interferons, in the Smc3+/− mice. Indeed, fewer synapses formed in their cortical neurons, and this phenotype was rescued by STAT1 knockdown. Thus, low levels of cohesin expression in the developing brain lead to changes in gene expression that in turn lead to a specific and abnormal neuronal and behavioral phenotype. PMID:28408410

Effects of heavy ion radiation on the brain vascular system and embryonic development

NASA Technical Reports Server (NTRS)

Yang, T. C.; Tobias, C. A.

1984-01-01

The present investigation is concerned with the effects of heavy-ion radiation on the vascular system and the embryonic development, taking into account the results of experiments with neonatal rats and mouse embryos. It is found that heavy ions can be highly effective in producing brain hemorrhages and in causing body deformities. Attention is given to aspects of methodology, the induction of brain hemorrhages by X-rays and heavy ions, and the effect of iron particles on embryonic development. Reported results suggest that high linear energy transfer (LET) heavy ions can be very effective in producing developmental abnormalities.

Description of 13 Infants Born During October 2015-January 2016 With Congenital Zika Virus Infection Without Microcephaly at Birth - Brazil.

PubMed

van der Linden, Vanessa; Pessoa, André; Dobyns, William; Barkovich, A James; Júnior, Hélio van der Linden; Filho, Epitacio Leite Rolim; Ribeiro, Erlane Marques; Leal, Mariana de Carvalho; Coimbra, Pablo Picasso de Araújo; Aragão, Maria de Fátima Viana Vasco; Verçosa, Islane; Ventura, Camila; Ramos, Regina Coeli; Cruz, Danielle Di Cavalcanti Sousa; Cordeiro, Marli Tenório; Mota, Vivian Maria Ribeiro; Dott, Mary; Hillard, Christina; Moore, Cynthia A

2016-12-02

Congenital Zika virus infection can cause microcephaly and severe brain abnormalities (1). Congenital Zika syndrome comprises a spectrum of clinical features (2); however, as is the case with most newly recognized teratogens, the earliest documented clinical presentation is expected to be the most severe. Initial descriptions of the effects of in utero Zika virus infection centered prominently on the finding of congenital microcephaly (3). To assess the possibility of clinical presentations that do not include congenital microcephaly, a retrospective assessment of 13 infants from the Brazilian states of Pernambuco and Ceará with normal head size at birth and laboratory evidence of congenital Zika virus infection was conducted. All infants had brain abnormalities on neuroimaging consistent with congenital Zika syndrome, including decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. The earliest evaluation occurred on the second day of life. Among all infants, head growth was documented to have decelerated as early as 5 months of age, and 11 infants had microcephaly. These findings provide evidence that among infants with prenatal exposure to Zika virus, the absence of microcephaly at birth does not exclude congenital Zika virus infection or the presence of Zika-related brain and other abnormalities. These findings support the recommendation for comprehensive medical and developmental follow-up of infants exposed to Zika virus prenatally. Early neuroimaging might identify brain abnormalities related to congenital Zika infection even among infants with a normal head circumference (4).

The Emergence of Network Inefficiencies in Infants With Autism Spectrum Disorder.

PubMed

Lewis, John D; Evans, Alan C; Pruett, John R; Botteron, Kelly N; McKinstry, Robert C; Zwaigenbaum, Lonnie; Estes, Annette M; Collins, D Louis; Kostopoulos, Penelope; Gerig, Guido; Dager, Stephen R; Paterson, Sarah; Schultz, Robert T; Styner, Martin A; Hazlett, Heather C; Piven, Joseph

2017-08-01

Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral features that emerge during the first years of life. Research indicates that abnormalities in brain connectivity are associated with these behavioral features. However, the inclusion of individuals past the age of onset of the defining behaviors complicates interpretation of the observed abnormalities: they may be cascade effects of earlier neuropathology and behavioral abnormalities. Our recent study of network efficiency in a cohort of 24-month-olds at high and low familial risk for ASD reduced this confound; we reported reduced network efficiencies in toddlers classified with ASD. The current study maps the emergence of these inefficiencies in the first year of life. This study uses data from 260 infants at 6 and 12 months of age, including 116 infants with longitudinal data. As in our earlier study, we use diffusion data to obtain measures of the length and strength of connections between brain regions to compute network efficiency. We assess group differences in efficiency within linear mixed-effects models determined by the Akaike information criterion. Inefficiencies in high-risk infants later classified with ASD were detected from 6 months onward in regions involved in low-level sensory processing. In addition, within the high-risk infants, these inefficiencies predicted 24-month symptom severity. These results suggest that infants with ASD, even before 6 months of age, have deficits in connectivity related to low-level processing, which contribute to a developmental cascade affecting brain organization and eventually higher-level cognitive processes and social behavior. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Primary microcephaly caused by novel compound heterozygous mutations in ASPM

PubMed Central

Okamoto, Nobuhiko; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Imoto, Issei

2018-01-01

Autosomal recessive primary microcephaly (microcephaly primary hereditary, MCPH) is a genetically heterogeneous rare developmental disorder that is characterized by prenatal onset of abnormal brain growth, which leads to intellectual disability of variable severity. We report a 5-year-old male who presented with a severe form of primary microcephaly. Targeted panel sequencing revealed compound heterozygous truncating mutations of the abnormal spindle-like microcephaly-associated (ASPM) gene, which confirmed the MCPH5 diagnosis. A novel NM_018136.4: c.9742_9745del (p.Lys3248Serfs*13) deletion mutation was identified. PMID:29644084

Primary microcephaly caused by novel compound heterozygous mutations in ASPM.

PubMed

Okamoto, Nobuhiko; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Imoto, Issei

2018-01-01

Autosomal recessive primary microcephaly (microcephaly primary hereditary, MCPH) is a genetically heterogeneous rare developmental disorder that is characterized by prenatal onset of abnormal brain growth, which leads to intellectual disability of variable severity. We report a 5-year-old male who presented with a severe form of primary microcephaly. Targeted panel sequencing revealed compound heterozygous truncating mutations of the abnormal spindle-like microcephaly-associated ( ASPM ) gene, which confirmed the MCPH5 diagnosis. A novel NM_018136.4: c.9742_9745del (p.Lys3248Serfs*13) deletion mutation was identified.

Quantifying cortical development in typically developing toddlers and young children, 1-6 years of age.

PubMed

Remer, Justin; Croteau-Chonka, Elise; Dean, Douglas C; D'Arpino, Sara; Dirks, Holly; Whiley, Dannielle; Deoni, Sean C L

2017-06-01

Cortical maturation, including age-related changes in thickness, volume, surface area, and folding (gyrification), play a central role in developing brain function and plasticity. Further, abnormal cortical maturation is a suspected substrate in various behavioral, intellectual, and psychiatric disorders. However, in order to characterize the altered development associated with these disorders, appreciation of the normative patterns of cortical development in neurotypical children between 1 and 6 years of age, a period of peak brain development during which many behavioral and developmental disorders emerge, is necessary. To this end, we examined measures of cortical thickness, surface area, mean curvature, and gray matter volume across 34 bilateral regions in a cohort of 140 healthy children devoid of major risk factors for abnormal development. From these data, we observed linear, logarithmic, and quadratic patterns of change with age depending on brain region. Cortical thinning, ranging from 10% to 20%, was observed throughout most of the brain, with the exception of posterior brain structures, which showed initial cortical thinning from 1 to 5 years, followed by thickening. Cortical surface area expansion ranged from 20% to 108%, and cortical curvature varied by 1-20% across the investigated age range. Right-left hemisphere asymmetry was observed across development for each of the 4 cortical measures. Our results present new insight into the normative patterns of cortical development across an important but under studied developmental window, and provide a valuable reference to which trajectories observed in neurodevelopmental disorders may be compared. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Rapid Postnatal Expansion of Neural Networks Occurs in an Environment of Altered Neurovascular and Neurometabolic Coupling.

PubMed

Kozberg, Mariel G; Ma, Ying; Shaik, Mohammed A; Kim, Sharon H; Hillman, Elizabeth M C

2016-06-22

In the adult brain, increases in neural activity lead to increases in local blood flow. However, many prior measurements of functional hemodynamics in the neonatal brain, including functional magnetic resonance imaging (fMRI) in human infants, have noted altered and even inverted hemodynamic responses to stimuli. Here, we demonstrate that localized neural activity in early postnatal mice does not evoke blood flow increases as in the adult brain, and elucidate the neural and metabolic correlates of these altered functional hemodynamics as a function of developmental age. Using wide-field GCaMP imaging, the development of neural responses to somatosensory stimulus is visualized over the entire bilaterally exposed cortex. Neural responses are observed to progress from tightly localized, unilateral maps to bilateral responses as interhemispheric connectivity becomes established. Simultaneous hemodynamic imaging confirms that spatiotemporally coupled functional hyperemia is not present during these early stages of postnatal brain development, and develops gradually as cortical connectivity is established. Exploring the consequences of this lack of functional hyperemia, measurements of oxidative metabolism via flavoprotein fluorescence suggest that neural activity depletes local oxygen to below baseline levels at early developmental stages. Analysis of hemoglobin oxygenation dynamics at the same age confirms oxygen depletion for both stimulus-evoked and resting-state neural activity. This state of unmet metabolic demand during neural network development poses new questions about the mechanisms of neurovascular development and its role in both normal and abnormal brain development. These results also provide important insights for the interpretation of fMRI studies of the developing brain. This work demonstrates that the postnatal development of neuronal connectivity is accompanied by development of the mechanisms that regulate local blood flow in response to neural activity. Novel in vivo imaging reveals that, in the developing mouse brain, strong and localized GCaMP neural responses to stimulus fail to evoke local blood flow increases, leading to a state in which oxygen levels become locally depleted. These results demonstrate that the development of cortical connectivity occurs in an environment of altered energy availability that itself may play a role in shaping normal brain development. These findings have important implications for understanding the pathophysiology of abnormal developmental trajectories, and for the interpretation of functional magnetic resonance imaging data acquired in the developing brain. Copyright © 2016 the authors 0270-6474/16/366704-14$15.00/0.

Neonatal anesthetic neurotoxicity: Insight into the molecular mechanisms of long-term neurocognitive deficits.

PubMed

Yu, Deshui; Li, Linji; Yuan, Weiguo

2017-03-01

Mounting animal studies have demonstrated that almost all the clinically used general anesthetics could induce widespread neuroapoptosis in the immature brain. Alarmingly, some published findings have reported long-term neurocognitive deficits in response to early anesthesia exposure which deeply stresses the potential seriousness of developmental anesthetic neurotoxicity. However, the connection between anesthesia induced neuroapoptosis and subsequent neurocognitive deficits remains controversial. It should be noted that developmental anesthesia related neurotoxicity is not limited to neuroapoptosis. Early anesthesia exposure caused transient suppression of neurogenesis, ultrastructural abnormalities in synapse and alteration in the development of neuronal networks also could contribute to the long-term neurocognitive dysfunction. Understanding the mechanisms of developmental anesthetic neurotoxicity, especially by which anesthesia impairs brain function months after exposure, may lead to development of rational preventive and therapeutic strategies. The focus of present review is on some of those potential mechanisms that have been proposed for anesthesia induced cognitive decline. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Fetal Alcohol Spectrum Disorders: An Overview from the Glia Perspective.

PubMed

Wilhelm, Clare J; Guizzetti, Marina

2015-01-01

Alcohol consumption during pregnancy can produce a variety of central nervous system (CNS) abnormalities in the offspring resulting in a broad spectrum of cognitive and behavioral impairments that constitute the most severe and long-lasting effects observed in fetal alcohol spectrum disorders (FASD). Alcohol-induced abnormalities in glial cells have been suspected of contributing to the adverse effects of alcohol on the developing brain for several years, although much research still needs to be done to causally link the effects of alcohol on specific brain structures and behavior to alterations in glial cell development and function. Damage to radial glia due to prenatal alcohol exposure may underlie observations of abnormal neuronal and glial migration in humans with Fetal Alcohol Syndrome (FAS), as well as primate and rodent models of FAS. A reduction in cell number and altered development has been reported for several glial cell types in animal models of FAS. In utero alcohol exposure can cause microencephaly when alcohol exposure occurs during the brain growth spurt a period characterized by rapid astrocyte proliferation and maturation; since astrocytes are the most abundant cells in the brain, microenchephaly may be caused by reduced astrocyte proliferation or survival, as observed in in vitro and in vivo studies. Delayed oligodendrocyte development and increased oligodendrocyte precursor apoptosis has also been reported in experimental models of FASD, which may be linked to altered myelination/white matter integrity found in FASD children. Children with FAS exhibit hypoplasia of the corpus callosum and anterior commissure, two areas requiring guidance from glial cells and proper maturation of oligodendrocytes. Finally, developmental alcohol exposure disrupts microglial function and induces microglial apoptosis; given the role of microglia in synaptic pruning during brain development, the effects of alcohol on microglia may be involved in the abnormal brain plasticity reported in FASD. The consequences of prenatal alcohol exposure on glial cells, including radial glia and other transient glial structures present in the developing brain, astrocytes, oligodendrocytes and their precursors, and microglia contributes to abnormal neuronal development, reduced neuron survival and disrupted brain architecture and connectivity. This review highlights the CNS structural abnormalities caused by in utero alcohol exposure and outlines which abnormalities are likely mediated by alcohol effects on glial cell development and function.

Differential Neurodevelopmental Trajectories in Patients With Early-Onset Bipolar and Schizophrenia Disorders

PubMed Central

Arango, Celso

2014-01-01

Schizophrenia and bipolar disorders share not only clinical features but also some risk factors such as genetic markers and childhood adversity, while other risk factors such as urbanicity and obstetric complications seem to be specific to schizophrenia. An intriguing question is whether the well-established abnormal neurodevelopment present in many children and adolescents who eventually develop schizophrenia is also present in bipolar patients. The literature on adult bipolar patients is controversial. We report data on a subgroup of patients with pediatric-onset psychotic bipolar disorder who seem to share some developmental trajectories with patients with early-onset schizophrenia. These early-onset psychotic bipolar patients have low intelligence quotient, more neurological signs, reduced frontal gray matter at the time of their first psychotic episode, and greater brain changes than healthy controls in a pattern similar to early-onset schizophrenia cases. However, patients with early-onset schizophrenia seem to have more social impairment, developmental abnormalities (eg, language problems), and lower academic achievement in childhood than early-onset bipolar patients. We suggest that some of these abnormal developmental trajectories are more related to the phenotypic features (eg, early-onset psychotic symptoms) of these 2 syndromes than to categorically defined Diagnostic and Statistical Manual of Mental Disorders disorders. PMID:24371326

Neurodevelopmental alterations of large-scale structural networks in children with new-onset epilepsy

PubMed Central

Bonilha, Leonardo; Tabesh, Ali; Dabbs, Kevin; Hsu, David A.; Stafstrom, Carl E.; Hermann, Bruce P.; Lin, Jack J.

2014-01-01

Recent neuroimaging and behavioral studies have revealed that children with new onset epilepsy already exhibit brain structural abnormalities and cognitive impairment. How the organization of large-scale brain structural networks is altered near the time of seizure onset and whether network changes are related to cognitive performances remain unclear. Recent studies also suggest that regional brain volume covariance reflects synchronized brain developmental changes. Here, we test the hypothesis that epilepsy during early-life is associated with abnormalities in brain network organization and cognition. We used graph theory to study structural brain networks based on regional volume covariance in 39 children with new-onset seizures and 28 healthy controls. Children with new-onset epilepsy showed a suboptimal topological structural organization with enhanced network segregation and reduced global integration compared to controls. At the regional level, structural reorganization was evident with redistributed nodes from the posterior to more anterior head regions. The epileptic brain network was more vulnerable to targeted but not random attacks. Finally, a subgroup of children with epilepsy, namely those with lower IQ and poorer executive function, had a reduced balance between network segregation and integration. Taken together, the findings suggest that the neurodevelopmental impact of new onset childhood epilepsies alters large-scale brain networks, resulting in greater vulnerability to network failure and cognitive impairment. PMID:24453089

Amyloid Precursor Protein 96–110 and β-Amyloid 1–42 Elicit Developmental Anomalies in Sea Urchin Embryos and Larvae that are Alleviated by Neurotransmitter Analogs for Acetylcholine, Serotonin and Cannabinoids

PubMed Central

Buznikov, Gennady A.; Nikitina, Lyudmila A.; Seidler, Frederic J.; Slotkin, Theodore A.; Bezuglov, Vladimir V.; Milošević, Ivan; Lazarević, Lidija; Rogač, Ljubica; Ruzdijić, Sabera; Rakić, Ljubiša M.

2008-01-01

Amyloid precursor protein (APP) is overexpressed in the developing brain and portions of its extracellular domain, especially amino acid residues 96–110, play an important role in neurite outgrowth and neural cell differentiation. In the current study, we evaluated the developmental abnormalities caused by administration of exogenous APP96–110 in sea urchin embryos and larvae, which, like the developing mammalian brain, utilize acetylcholine and other neurotransmitters as morphogens; effects were compared to those of β-amyloid 1–42 (Aβ42), the neurotoxic APP fragment contained within neurodegenerative plaques in Alzheimer’s Disease. Although both peptides elicited dysmorphogenesis, Aβ42 was far more potent; in addition, whereas Aβ42 produced abnormalities at developmental stages ranging from early cleavage divisions to the late pluteus, APP96–110 effects were restricted to the intermediate, mid-blastula stage. For both agents, anomalies were prevented or reduced by addition of lipid-permeable analogs of acetylcholine, serotonin or cannabinoids; physostigmine, a carbamate-derived cholinesterase inhibitor, was also effective. In contrast, agents that act on NMDA receptors (memantine) or α-adrenergic receptors (nicergoline), and that are therapeutic in Alzheimer’s Disease, were themselves embryotoxic, as was tacrine, a cholinesterase inhibitor from a different chemical class than physostigmine. Protection was also provided by agents acting downstream from receptor-mediated events: increasing cyclic AMP with caffeine or isobutylmethylxanthine, or administering the antioxidant, α-tocopherol, were all partially effective. Our findings reinforce a role for APP in development and point to specific interactions with neurotransmitter systems that act as morphogens in developing sea urchins as well as in the mammalian brain. PMID:18565728

Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome.

PubMed

Aziz, Nadine M; Guedj, Faycal; Pennings, Jeroen L A; Olmos-Serrano, Jose Luis; Siegel, Ashley; Haydar, Tarik F; Bianchi, Diana W

2018-06-12

Down syndrome (DS) results from triplication of human chromosome 21. Neuropathological hallmarks of DS include atypical central nervous system development that manifests prenatally and extends throughout life. As a result, individuals with DS exhibit cognitive and motor deficits, and have delays in achieving developmental milestones. To determine whether different mouse models of DS recapitulate the human prenatal and postnatal phenotypes, here, we directly compared brain histogenesis, gene expression and behavior over the lifespan of three cytogenetically distinct mouse models of DS: Ts1Cje, Ts65Dn and Dp(16)1/Yey. Histological data indicated that Ts65Dn mice were the most consistently affected with respect to somatic growth, neurogenesis and brain morphogenesis. Embryonic and adult gene expression results showed that Ts1Cje and Ts65Dn brains had considerably more differentially expressed (DEX) genes compared with Dp(16)1/Yey mice, despite the larger number of triplicated genes in the latter model. In addition, DEX genes showed little overlap in identity and chromosomal distribution in the three models, leading to dissimilarities in affected functional pathways. Perinatal and adult behavioral testing also highlighted differences among the models in their abilities to achieve various developmental milestones and perform hippocampal- and motor-based tasks. Interestingly, Dp(16)1/Yey mice showed no abnormalities in prenatal brain phenotypes, yet they manifested behavioral deficits starting at postnatal day 15 that continued through adulthood. In contrast, Ts1Cje mice showed mildly abnormal embryonic brain phenotypes, but only select behavioral deficits as neonates and adults. Altogether, our data showed widespread and unexpected fundamental differences in behavioral, gene expression and brain development phenotypes between these three mouse models. Our findings illustrate unique limitations of each model when studying aspects of brain development and function in DS. This work helps to inform model selection in future studies investigating how observed neurodevelopmental abnormalities arise, how they contribute to cognitive impairment, and when testing therapeutic molecules to ameliorate the intellectual disability associated with DS.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

Subtle hemorrhagic brain injury is associated with neurodevelopmental impairment in infants with repaired congenital heart disease.

PubMed

Soul, Janet S; Robertson, Richard L; Wypij, David; Bellinger, David C; Visconti, Karen J; du Plessis, Adré J; Kussman, Barry D; Scoppettuolo, Lisa A; Pigula, Frank; Jonas, Richard A; Newburger, Jane W

2009-08-01

Perioperative stroke and periventricular leukomalacia have been reported to occur commonly in infants with congenital heart disease. We aimed to determine the incidence and type of brain injury in infants undergoing 2-ventricle repair in infancy and to determine risk factors associated with such injury. Forty-eight infants enrolled in a trial comparing 2 different hematocrits during surgical repair of congenital heart disease underwent brain magnetic resonance imaging scans and neurodevelopmental testing at 1 year of age. Eighteen (38%) of our subjects had tiny foci of hemosiderin by susceptibility imaging, without evidence of abnormalities in corresponding regions on conventional magnetic resonance imaging sequences. Subjects with foci of hemosiderin had a significantly lower Psychomotor Developmental Index at 1 year of age (79.6 +/- 16.5, mean +/- standard deviation) compared with subjects without these foci (89.5 +/- 15.3; P = .04). Older age at surgery and diagnostic group were significantly associated with the presence of hemosiderin foci. Only 1 subject had a small stroke (2%), and 2 subjects had periventricular leukomalacia (4%). Foci of hemosiderin without radiologic evidence of ischemic brain injury are an abnormality associated with adverse neurodevelopmental outcome not previously described in magnetic resonance imaging studies of children with surgically repaired congenital heart disease. The association of hemosiderin foci with older age at surgery and cardiac diagnosis, and not with risk factors associated with brain injury, in previous studies suggests that the cause and pathogenesis of this abnormality are different from ischemic brain lesions reported previously.

Neurobehavioral development in Joubert syndrome.

PubMed

Gitten, J; Dede, D; Fennell, E; Quisling, R; Maria, B L

1998-08-01

Research on children with Joubert syndrome has focused on brain structural abnormalities and associated clinical symptoms. The degree of developmental delay has not been objectively reported. We investigated the neurobehavioral development of children with Joubert syndrome through neurobehavioral assessment in the largest sample to date. Thirty-two parents of children with Joubert syndrome completed the Child Development Inventory and magnetic resonance imaging (MRI) data was gathered on 17 of these children. Results indicate that 94% were severely impaired according to the Child Development Inventory, with age being positively correlated with degree of neurobehavioral impairment. The average developmental age of our sample was 19 months (63% below chronological age). Severity of illness as measured by the General Development scale of the Child Development Inventory and severity of illness as measured by MRI (overall severity rating) did not yield consistent data regarding severity of the midbrain and cerebellar malformations. Similarly, markers of abnormal cerebral development such as cortical atrophy and delayed myelination were independent of severity of illness ratings on the Child Development Inventory. The degree of developmental delay in Joubert syndrome and the severity of gross central nervous system malformations appear independent.

Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors

PubMed Central

Belinson, H; Nakatani, J; Babineau, BA; Birnbaum, RY; Ellegood, J; Bershteyn, M; McEvilly, RJ; Long, JM; Willert, K; Klein, OD; Ahituv, N; Lerch, JP; Rosenfeld, GM; Wynshaw-Boris, A

2015-01-01

Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Dishevelled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a β-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the β-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism. PMID:26830142

Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.

PubMed

Belinson, H; Nakatani, J; Babineau, B A; Birnbaum, R Y; Ellegood, J; Bershteyn, M; McEvilly, R J; Long, J M; Willert, K; Klein, O D; Ahituv, N; Lerch, J P; Rosenfeld, M G; Wynshaw-Boris, A

2016-10-01

Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a β-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the β-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism.

Siblings with opposite chromosome constitutions, dup(2q)/del(7q) and del(2q)/dup(7q).

PubMed

Shim, Sung Han; Shim, Jae Sun; Min, Kyunghoon; Lee, Hee Song; Park, Ji Eun; Park, Sang Hee; Hwang, Euna; Kim, Minyoung

2014-01-15

Chromosome 7q36 microdeletion syndrome is a rare genomic disorder characterized by underdevelopment of the brain, microcephaly, anomalies of the sex organs, and language problems. Developmental delay, intellectual disability, autistic spectrum disorders, BDMR syndrome, and unusual facial morphology are the key features of the chromosome 2q37 microdeletion syndrome. A genetic screening for two brothers with global developmental delay using high-resolution chromosomal analysis and subtelomeric multiplex ligation-dependent probe amplification revealed subtelomeric rearrangements on the same sites of 2q37.2 and 7q35, with reversed deletion and duplication. Both of them showed dysmorphic facial features, severe disability of physical and intellectual development, and abnormal genitalia with differential abnormalities in their phenotypes. The family did not have abnormal genetic phenotypes. According to the genetic analysis of their parents, adjacent-1 segregation from their mother's was suggested as a mechanism of their gene mutation. By comparing the phenotypes of our patients with previous reports on similar patients, we tried to obtain the information of related genes and their chromosomal locations. © 2013.

Editorial brain malformation surveillance in the Zika era

PubMed Central

Trevathan, Edwin

2016-01-01

The current surveillance systems for congenital microcephaly are necessary to monitor the impact of Zika virus (ZIKV) on the developing human brain, as well as the ZIKV prevention efforts. However, these congenital microcephaly surveillance systems are insufficient. Abnormalities of neuronal differentiation, development and migration may occur among infants with normal head circumference who have intrauterine exposure to ZIKV. Therefore, surveillance for congenital microcephaly does not ascertain many of the infants seriously impacted by congenital ZIKV infection. Furthermore, many infants with normal head circumference and with malformations of the brain cortex do not have clinical manifestations of their congenital malformations until several months to many years after birth, when they present with clinical manifestations such as seizures/epilepsy, developmental delays with or without developmental regression, and/or motor impairment. In response to the ZIKV threat, public health surveillance systems must be enhanced to ascertain a wide variety of congenital brain malformations, as well as their clinical manifestations that lead to diagnostic brain imaging. Birth Defects Research (Part A) 106:869–874, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc. PMID:27891785

Assessment of the usefulness of magnetic resonance brain imaging in patients presenting with acute seizures.

PubMed

Olszewska, D A; Costello, D J

2014-12-01

Magnetic Resonance Imaging (MRI) is increasingly available as a tool for assessment of patients presenting to acute services with seizures. We set out to prospectively determine the usefulness of early MRI brain in a cohort of patients presenting with acute seizures. We examined the MR imaging studies performed in patients admitted solely because of acute seizures to Cork University Hospital over a 12-month period. The main aim of the study was to determine if the MRI established the proximate cause for the patient's recent seizure. We identified 91 patients who underwent MRI brain within 48 h of admission for seizures. Of the 91 studies, 51 were normal (56 %). The remaining 40 studies were abnormal as follows: microvascular disease (usually moderate/severe) (n = 19), post-traumatic gliosis (n = 7), remote symptomatic lesion (n = 6), primary brain tumour (n = 5), venous sinus thrombosis (n = 3), developmental lesion (n = 3), post-surgical gliosis (n = 3) and single cases of demyelination, unilateral hippocampal sclerosis, lobar haemorrhage and metastatic malignant melanoma. Abnormalities in diffusion-weighted sequences that were attributable to prolonged ictal activity were seen in nine patients, all of who had significant ongoing clinical deficits, most commonly delirium. Of the 40 patients with abnormal MRI studies, seven patients had unremarkable CT brain. MR brain imaging revealed the underlying cause for acute seizures in 44 % of patients. CT brain imaging failed to detect the cause of the acute seizures in 19 % of patients in whom subsequent MRI established the cause. This study emphasises the importance of obtaining optimal imaging in people admitted with acute seizures.

Dampened hippocampal oscillations and enhanced spindle activity in an asymptomatic model of developmental cortical malformations

PubMed Central

Cid, Elena; Gomez-Dominguez, Daniel; Martin-Lopez, David; Gal, Beatriz; Laurent, François; Ibarz, Jose M.; Francis, Fiona; Menendez de la Prida, Liset

2014-01-01

Developmental cortical malformations comprise a large spectrum of histopathological brain abnormalities and syndromes. Their genetic, developmental and clinical complexity suggests they should be better understood in terms of the complementary action of independently timed perturbations (i.e., the multiple-hit hypothesis). However, understanding the underlying biological processes remains puzzling. Here we induced developmental cortical malformations in offspring, after intraventricular injection of methylazoxymethanol (MAM) in utero in mice. We combined extensive histological and electrophysiological studies to characterize the model. We found that MAM injections at E14 and E15 induced a range of cortical and hippocampal malformations resembling histological alterations of specific genetic mutations and transplacental mitotoxic agent injections. However, in contrast to most of these models, intraventricularly MAM-injected mice remained asymptomatic and showed no clear epilepsy-related phenotype as tested in long-term chronic recordings and with pharmacological manipulations. Instead, they exhibited a non-specific reduction of hippocampal-related brain oscillations (mostly in CA1); including theta, gamma and HFOs; and enhanced thalamocortical spindle activity during non-REM sleep. These data suggest that developmental cortical malformations do not necessarily correlate with epileptiform activity. We propose that the intraventricular in utero MAM approach exhibiting a range of rhythmopathies is a suitable model for multiple-hit studies of associated neurological disorders. PMID:24782720

Dampened hippocampal oscillations and enhanced spindle activity in an asymptomatic model of developmental cortical malformations.

PubMed

Cid, Elena; Gomez-Dominguez, Daniel; Martin-Lopez, David; Gal, Beatriz; Laurent, François; Ibarz, Jose M; Francis, Fiona; Menendez de la Prida, Liset

2014-01-01

Developmental cortical malformations comprise a large spectrum of histopathological brain abnormalities and syndromes. Their genetic, developmental and clinical complexity suggests they should be better understood in terms of the complementary action of independently timed perturbations (i.e., the multiple-hit hypothesis). However, understanding the underlying biological processes remains puzzling. Here we induced developmental cortical malformations in offspring, after intraventricular injection of methylazoxymethanol (MAM) in utero in mice. We combined extensive histological and electrophysiological studies to characterize the model. We found that MAM injections at E14 and E15 induced a range of cortical and hippocampal malformations resembling histological alterations of specific genetic mutations and transplacental mitotoxic agent injections. However, in contrast to most of these models, intraventricularly MAM-injected mice remained asymptomatic and showed no clear epilepsy-related phenotype as tested in long-term chronic recordings and with pharmacological manipulations. Instead, they exhibited a non-specific reduction of hippocampal-related brain oscillations (mostly in CA1); including theta, gamma and HFOs; and enhanced thalamocortical spindle activity during non-REM sleep. These data suggest that developmental cortical malformations do not necessarily correlate with epileptiform activity. We propose that the intraventricular in utero MAM approach exhibiting a range of rhythmopathies is a suitable model for multiple-hit studies of associated neurological disorders.

Brain magnetic resonance imaging and motor and intellectual functioning in 86 patients born at term with spastic diplegia.

PubMed

Numata, Yurika; Onuma, Akira; Kobayashi, Yasuko; Sato-Shirai, Ikuko; Tanaka, Soichiro; Kobayashi, Satoru; Wakusawa, Keisuke; Inui, Takehiko; Kure, Shigeo; Haginoya, Kazuhiro

2013-02-01

To investigate the association between magnetic resonance imaging (MRI) patterns and motor function, epileptic episodes, and IQ or developmental quotient in patients born at term with spastic diplegia. Eighty-six patients born at term with cerebral palsy (CP) and spastic diplegia (54 males, 32 females; median age 20 y, range 7-42 y) among 829 patients with CP underwent brain MRI between 1990 and 2008. The MRI and clinical findings were analysed retrospectively. Intellectual disability was classified according to the Enjoji developmental test or the Wechsler Intelligence Scale for Children (3rd edition). The median ages at diagnosis of CP, assignment of Gross Motor Function Classification System (GMFCS) level, cognitive assessment, and MRI were 2 years (range 5 mo-8 y), 6 years (2 y 8 mo-19 y), 6 years (1 y 4 mo-19 y), and 7 years (10 mo-30 y) respectively. MRI included normal findings (41.9%), periventricular leukomalacia, hypomyelination, and porencephaly/periventricular venous infarction. The frequency of patients in GMFCS levels III to V and intellectual disability did not differ between those with normal and abnormal MRI findings. Patients with normal MRI findings had significantly fewer epileptic episodes than those with abnormal ones (p=0.001). Varied MRI findings, as well as the presence of severe motor dysfunction and intellectual disability (despite normal MRI), suggest that patients born at term with spastic diplegia had heterogeneous and unidentified pathophysiology. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

New Evidence of Cerebellar and Brainstem Hypoplasia in Autistic Infants, Children and Adolescents: The MR Imaging Study by Hashimoto and Colleagues.

ERIC Educational Resources Information Center

Courchesne, Eric

1995-01-01

In a study by Toshiaki Hashimoto and colleagues (EC 611 142), 10 infants with developmental delay, poor eye contact, and poor facial expression underwent magnetic resonance brain imaging and were later diagnosed with autism. This offered direct evidence of abnormality of the cerebellar vermis and the brainstem at the beginning stages of behavioral…

Delayed Development of Brain Connectivity in Adolescents With Schizophrenia and Their Unaffected Siblings.

PubMed

Zalesky, Andrew; Pantelis, Christos; Cropley, Vanessa; Fornito, Alex; Cocchi, Luca; McAdams, Harrison; Clasen, Liv; Greenstein, Deanna; Rapoport, Judith L; Gogtay, Nitin

2015-09-01

Abnormalities in structural brain connectivity have been observed in patients with schizophrenia. Mapping these abnormalities longitudinally and understanding their genetic risk via sibship studies will provide crucial insight into progressive developmental changes associated with schizophrenia. To identify corticocortical connections exhibiting an altered developmental trajectory in adolescents with childhood-onset schizophrenia (COS) and to determine whether similar alterations are found in patients' unaffected siblings. Using prospective structural brain magnetic resonance imaging, large-scale corticocortical connectivity was mapped from ages 12 to 24 years in 109 patients with COS (272 images), 86 of their unaffected siblings (184 images), and 102 healthy controls (262 images) over a 20-year period beginning January 1, 1991, through April 30, 2011, as part of the ongoing COS study at the National Institute of Mental Health. Structural connectivity between pairs of cortical regions was estimated using a validated technique based on across-subject covariation in magnetic resonance imaging-derived cortical thickness measurements. Compared with normally developing controls, significant left-hemisphere occipitotemporal deficits in cortical thickness correlations were found in patients with COS as well as their healthy siblings (P < .05). Deficits in siblings normalized by mid-adolescence, whereas patients with COS showed significantly longer maturational delays, with cortical thickness correlations between the left temporal lobe and left occipital cortex not showing evidence of development until early adulthood. The normalization of deficits with age in patients with COS correlated with improvement in symptoms. Compared with controls, left-hemisphere occipitotemporal thickness correlations in a subgroup of patients with high positive symptoms were significantly reduced from age 14 to 18 years (P < .05); however, other patients with low positive symptoms showed no significant deficits. Delayed maturation of occipitotemporal connectivity appears to be a trait marker in patients with COS, with a milder endophenotype in unaffected siblings associated with resilience to developing schizophrenia. These findings indicate genetically influenced and connection-specific developmental abnormalities in the schizophrenia connectome, and lead to the hypothesis that visual hallucinations in patients with COS may be because of delayed development of the inferior longitudinal fasciculus, a prominent occipitotemporal fiber.

Serotonin Receptor 6 Mediates Defective Brain Development in Monoamine Oxidase A-deficient Mouse Embryos

PubMed Central

Wang, Chi Chiu; Man, Gene Chi Wai; Chu, Ching Yan; Borchert, Astrid; Ugun-Klusek, Aslihan; Billett, E. Ellen; Kühn, Hartmut; Ufer, Christoph

2014-01-01

Monoamine oxidases A and B (MAO-A and MAO-B) are enzymes of the outer mitochondrial membrane that metabolize biogenic amines. In the adult central nervous system, MAOs have important functions for neurotransmitter homeostasis. Expression of MAO isoforms has been detected in the developing embryo. However, suppression of MAO-B does not induce developmental alterations. In contrast, targeted inhibition and knockdown of MAO-A expression (E7.5–E10.5) caused structural abnormalities in the brain. Here we explored the molecular mechanisms underlying defective brain development induced by MAO-A knockdown during in vitro embryogenesis. The developmental alterations were paralleled by diminished apoptotic activity in the affected neuronal structures. Moreover, dysfunctional MAO-A expression led to elevated levels of embryonic serotonin (5-hydroxytryptamine (5-HT)), and we found that knockdown of serotonin receptor-6 (5-Htr6) expression or pharmacologic inhibition of 5-Htr6 activity rescued the MAO-A knockdown phenotype and restored apoptotic activity in the developing brain. Our data suggest that excessive 5-Htr6 activation reduces activation of caspase-3 and -9 of the intrinsic apoptotic pathway and enhances expression of antiapoptotic proteins Bcl-2 and Bcl-XL. Moreover, we found that elevated 5-HT levels in MAO-A knockdown embryos coincided with an enhanced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and a reduction of proliferating cell numbers. In summary, our findings suggest that excessive 5-HT in MAO-A-deficient mouse embryos triggers cellular signaling cascades via 5-Htr6, which suppresses developmental apoptosis in the brain and thus induces developmental retardations. PMID:24497636

Cognition and brain development in children with benign epilepsy with centrotemporal spikes.

PubMed

Garcia-Ramos, Camille; Jackson, Daren C; Lin, Jack J; Dabbs, Kevin; Jones, Jana E; Hsu, David A; Stafstrom, Carl E; Zawadzki, Lucy; Seidenberg, Michael; Prabhakaran, Vivek; Hermann, Bruce P

2015-10-01

Benign epilepsy with centrotemporal spikes (BECTS), the most common focal childhood epilepsy, is associated with subtle abnormalities in cognition and possible developmental alterations in brain structure when compared to healthy participants, as indicated by previous cross-sectional studies. To examine the natural history of BECTS, we investigated cognition, cortical thickness, and subcortical volumes in children with new/recent onset BECTS and healthy controls (HC). Participants were 8-15 years of age, including 24 children with new-onset BECTS and 41 age- and gender-matched HC. At baseline and 2 years later, all participants completed a cognitive assessment, and a subset (13 BECTS, 24 HC) underwent T1 volumetric magnetic resonance imaging (MRI) scans focusing on cortical thickness and subcortical volumes. Baseline cognitive abnormalities associated with BECTS (object naming, verbal learning, arithmetic computation, and psychomotor speed/dexterity) persisted over 2 years, with the rate of cognitive development paralleling that of HC. Baseline neuroimaging revealed thinner cortex in BECTS compared to controls in frontal, temporal, and occipital regions. Longitudinally, HC showed widespread cortical thinning in both hemispheres, whereas BECTS participants showed sparse regions of both cortical thinning and thickening. Analyses of subcortical volumes showed larger left and right putamens persisting over 2 years in BECTS compared to HC. Cognitive and structural brain abnormalities associated with BECTS are present at onset and persist (cognition) and/or evolve (brain structure) over time. Atypical maturation of cortical thickness antecedent to BECTS onset results in early identified abnormalities that continue to develop abnormally over time. However, compared to anatomic development, cognition appears more resistant to further change over time. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Nervous system disruption and concomitant behavioral abnormality in early hatched pufferfish larvae exposed to heavy oil.

PubMed

Kawaguchi, Masahumi; Sugahara, Yuki; Watanabe, Tomoe; Irie, Kouta; Ishida, Minoru; Kurokawa, Daisuke; Kitamura, Shin-Ichi; Takata, Hiromi; Handoh, Itsuki C; Nakayama, Kei; Murakami, Yasunori

2011-08-01

Spills of heavy oil (HO) over the oceans have been proven to have an adverse effect on marine life. It has been hypothesized that exposure of early larvae of sinking eggs to HO leads largely to normal morphology, whereas abnormal organization of the developing neural scaffold is likely to be found. HO-induced disruption of the nervous system, which controls animal behavior, may in turn cause abnormalities in the swimming behavior of hatched larvae. To clarify the toxicological effects of HO, we performed exposure experiments and morphological and behavioral analyses in pufferfish (Takifugu rubripes) larvae. Fertilized eggs of pufferfish were exposed to 50 mg/L of HO for 8 days and transferred to fresh seawater before hatching. The hatched larvae were observed for their swimming behavior, morphological appearance, and construction of muscles and nervous system. In HO-exposed larvae, we did not detect any anomaly of body morphology. However, they showed an abnormal swimming pattern and disorganized midbrain, a higher center controlling movement. Our results suggest that HO-exposed fishes suffer developmental disorder of the brain that triggers an abnormal swimming behavior and that HO may be selectively toxic to the brain and cause physical disability throughout the life span of these fishes.

The neonatal brain in critical congenital heart disease: Insights and future directions.

PubMed

Peyvandi, Shabnam; Latal, Beatrice; Miller, Steven P; McQuillen, Patrick S

2018-05-19

Neurodevelopmental outcomes are impaired in survivors of critical congenital heart disease (CHD) in several developmental domains including motor, cognitive and sensory outcomes. These deficits can extend into the adolescent and early adulthood years. The cause of these neurodevelopmental impairments is multi-factorial and includes patient specific risk factors, cardiac anatomy and physiology as well as brain changes seen on MRI. Advances in imaging techniques have identified delayed brain development in the neonate with critical CHD as well as acquired brain injury. These abnormalities are seen even before corrective neonatal cardiac surgery. This review focuses on describing brain changes seen on MRI in neonates with CHD, risk factors for these changes and the association with neurodevelopmental outcome. There is an emerging focus on the impact of cardiovascular physiology on brain health and the complex heart-brain interplay that influences ultimate neurodevelopmental outcome in these patients. Copyright © 2018. Published by Elsevier Inc.

Comparison of brain MRI findings with language and motor function in the dystroglycanopathies.

PubMed

Brun, Brianna N; Mockler, Shelley R H; Laubscher, Katie M; Stephan, Carrie M; Wallace, Anne M; Collison, Julia A; Zimmerman, M Bridget; Dobyns, William B; Mathews, Katherine D

2017-02-14

To describe the spectrum of brain MRI findings in a cohort of individuals with dystroglycanopathies (DGs) and relate MRI results to function. All available brain MRIs done for clinical indications on individuals enrolled in a DG natural history study (NCT00313677) were reviewed. Reports were reviewed when MRI was not available. MRIs were categorized as follows: (1) cortical, brainstem, and cerebellar malformations; (2) cortical and cerebellar malformations; or (3) normal. Language development was assigned to 1 of 3 categories by a speech pathologist. Maximal motor function and presence of epilepsy were determined by history or examination. Twenty-five MRIs and 9 reports were reviewed. The most common MRI abnormalities were cobblestone cortex or dysgyria with an anterior-posterior gradient and cerebellar hypoplasia. Seven individuals had MRIs in group 1, 8 in group 2, and 19 in group 3. Language was impaired in 100% of those in MRI groups 1 and 2, and degree of language impairment correlated with severity of imaging. Eighty-five percent of the whole group achieved independent walking, but only 33% did in group 1. Epilepsy was present in 8% of the cohort and rose to 37% of those with an abnormal MRI. Developmental abnormalities of the brain such as cobblestone lissencephaly, cerebellar cysts, pontine hypoplasia, and brainstem bowing are hallmarks of DG and should prompt consideration of these diagnoses. Brain imaging in individuals with DG helps to predict outcomes, especially language development, aiding clinicians in prognostic counseling. © 2017 American Academy of Neurology.

Recent Insights Into Molecular Mechanisms of Propofol-Induced Developmental Neurotoxicity: Implications for the Protective Strategies.

PubMed

Bosnjak, Zeljko J; Logan, Sarah; Liu, Yanan; Bai, Xiaowen

2016-11-01

Mounting evidence has demonstrated that general anesthetics could induce developmental neurotoxicity, including acute widespread neuronal cell death, followed by long-term memory and learning abnormalities. Propofol is a commonly used intravenous anesthetic agent for the induction and maintenance of anesthesia and procedural and critical care sedation in children. Compared with other anesthetic drugs, little information is available on its potential contributions to neurotoxicity. Growing evidence from multiple experimental models showed a similar neurotoxic effect of propofol as observed in other anesthetic drugs, raising serious concerns regarding pediatric propofol anesthesia. The aim of this review is to summarize the current findings of propofol-induced developmental neurotoxicity. We first present the evidence of neurotoxicity from animal models, animal cell culture, and human stem cell-derived neuron culture studies. We then discuss the mechanism of propofol-induced developmental neurotoxicity, such as increased cell death in neurons and oligodendrocytes, dysregulation of neurogenesis, abnormal dendritic development, and decreases in neurotrophic factor expression. Recent findings of complex mechanisms of propofol action, including alterations in microRNAs and mitochondrial fission, are discussed as well. An understanding of the toxic effect of propofol and the underlying mechanisms may help to develop effective novel protective or therapeutic strategies for avoiding the neurotoxicity in the developing human brain.

Retinopathy of prematurity and brain damage in the very preterm newborn.

PubMed

Allred, Elizabeth N; Capone, Antonio; Fraioli, Anthony; Dammann, Olaf; Droste, Patrick; Duker, Jay; Gise, Robert; Kuban, Karl; Leviton, Alan; O'Shea, T Michael; Paneth, Nigel; Petersen, Robert; Trese, Michael; Stoessel, Kathleen; Vanderveen, Deborah; Wallace, David K; Weaver, Grey

2014-06-01

To explain why very preterm newborns who develop retinopathy of prematurity (ROP) appear to be at increased risk of abnormalities of both brain structure and function. A total of 1,085 children born at <28 weeks' gestation had clinically indicated retinal examinations and had a developmental assessment at 2 years corrected age. Relationships between ROP categories and brain abnormalities were explored using logistic regression models with adjustment for potential confounders. The 173 children who had severe ROP, defined as prethreshold ROP (n = 146) or worse (n = 27) were somewhat more likely than their peers without ROP to have brain ultrasound lesions or cerebral palsy. They were approximately twice as likely to have very low Bayley Scales scores. After adjusting for risk factors common to both ROP and brain disorders, infants who developed severe ROP were at increased risk of low Bayley Scales only. Among children with prethreshold ROP, exposure to anesthesia was not associated with low Bayley Scales. Some but not all of the association of ROP with brain disorders can be explained by common risk factors. Most of the increased risks of very low Bayley Scales associated with ROP are probably not a consequence of exposure to anesthetic agents. Copyright © 2014 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.

Neurodevelopmental alterations of large-scale structural networks in children with new-onset epilepsy.

PubMed

Bonilha, Leonardo; Tabesh, Ali; Dabbs, Kevin; Hsu, David A; Stafstrom, Carl E; Hermann, Bruce P; Lin, Jack J

2014-08-01

Recent neuroimaging and behavioral studies have revealed that children with new onset epilepsy already exhibit brain structural abnormalities and cognitive impairment. How the organization of large-scale brain structural networks is altered near the time of seizure onset and whether network changes are related to cognitive performances remain unclear. Recent studies also suggest that regional brain volume covariance reflects synchronized brain developmental changes. Here, we test the hypothesis that epilepsy during early-life is associated with abnormalities in brain network organization and cognition. We used graph theory to study structural brain networks based on regional volume covariance in 39 children with new-onset seizures and 28 healthy controls. Children with new-onset epilepsy showed a suboptimal topological structural organization with enhanced network segregation and reduced global integration compared with controls. At the regional level, structural reorganization was evident with redistributed nodes from the posterior to more anterior head regions. The epileptic brain network was more vulnerable to targeted but not random attacks. Finally, a subgroup of children with epilepsy, namely those with lower IQ and poorer executive function, had a reduced balance between network segregation and integration. Taken together, the findings suggest that the neurodevelopmental impact of new onset childhood epilepsies alters large-scale brain networks, resulting in greater vulnerability to network failure and cognitive impairment. Copyright © 2014 Wiley Periodicals, Inc.

Assessment and evaluation of the high risk neonate: the NICU Network Neurobehavioral Scale.

PubMed

Lester, Barry M; Andreozzi-Fontaine, Lynne; Tronick, Edward; Bigsby, Rosemarie

2014-08-25

There has been a long-standing interest in the assessment of the neurobehavioral integrity of the newborn infant. The NICU Network Neurobehavioral Scale (NNNS) was developed as an assessment for the at-risk infant. These are infants who are at increased risk for poor developmental outcome because of insults during prenatal development, such as substance exposure or prematurity or factors such as poverty, poor nutrition or lack of prenatal care that can have adverse effects on the intrauterine environment and affect the developing fetus. The NNNS assesses the full range of infant neurobehavioral performance including neurological integrity, behavioral functioning, and signs of stress/abstinence. The NNNS is a noninvasive neonatal assessment tool with demonstrated validity as a predictor, not only of medical outcomes such as cerebral palsy diagnosis, neurological abnormalities, and diseases with risks to the brain, but also of developmental outcomes such as mental and motor functioning, behavior problems, school readiness, and IQ. The NNNS can identify infants at high risk for abnormal developmental outcome and is an important clinical tool that enables medical researchers and health practitioners to identify these infants and develop intervention programs to optimize the development of these infants as early as possible. The video shows the NNNS procedures, shows examples of normal and abnormal performance and the various clinical populations in which the exam can be used.

Subtle Hemorrhagic Brain Injury is Associated with Neurodevelopmental Impairment in Infants with Repaired Congenital Heart Disease

PubMed Central

Soul, Janet S.; Robertson, Richard L.; Wypij, David; Bellinger, David C.; Visconti, Karen J.; du Plessis, Adré J.; Kussman, Barry D.; Scoppettuolo, Lisa A.; Pigula, Frank; Jonas, Richard A.; Newburger, Jane W.

2009-01-01

Objective Perioperative stroke and periventricular leukomalacia have been reported to occur commonly in infants with congenital heart disease. We aimed to determine the incidence and type of brain injury in infants undergoing two-ventricle repair in infancy and to determine risk factors associated with such injury. Methods Forty-eight infants enrolled in a trial comparing two different hematocrits during surgical repair of congenital heart disease underwent brain MRI scans and neurodevelopmental testing at one year of age. Results Eighteen (38%) of our subjects had tiny foci of hemosiderin by susceptibility imaging, without evidence of abnormalities in corresponding regions on conventional MRI sequences. Subjects who had foci of hemosiderin had a significantly lower Psychomotor Developmental Index at one year of age (79.6 ± 16.5, mean ± SD) compared with subjects who did not have these foci (89.5 ± 15.3; p=0.04). Older age at surgery and diagnostic group were significantly associated with presence of hemosiderin foci. Only one subject had a small stroke (2%) and two had periventricular leukomalacia (4%). Conclusions Foci of hemosiderin without radiologic evidence of ischemic brain injury are an abnormality associated with adverse neurodevelopmental outcome not previously described in MRI studies of children with surgically repaired congenital heart disease. The association of hemosiderin foci with older age at surgery and cardiac diagnosis and not risk factors associated with brain injury in previous studies suggests that the etiology and pathogenesis of this abnormality is different from ischemic brain lesions reported previously. PMID:19619781

Developmental Coordination Disorder in a Patient with Mental Disability and a Mild Phenotype Carrying Terminal 6q26-qter Deletion

PubMed Central

De Cinque, Marianna; Palumbo, Orazio; Mazzucco, Ermelinda; Simone, Antonella; Palumbo, Pietro; Ciavatta, Renata; Maria, Giuliana; Ferese, Rosangela; Gambardella, Stefano; Angiolillo, Antonella; Carella, Massimo; Garofalo, Silvio

2017-01-01

Terminal deletion of chromosome 6q is a rare chromosomal abnormality associated with variable phenotype spectrum. Although intellectual disability, facial dysmorphism, seizures and brain abnormalities are typical features of this syndrome, genotype–phenotype correlation needs to be better understood. We report the case of a 6-year-old Caucasian boy with a clinical diagnosis of intellectual disability, delayed language development and dyspraxia who carries an approximately 8 Mb de novo heterozygous microdeletion in the 6q26-q27 locus identified by karyotype and defined by high-resolution SNP-array analysis. This patient has no significant structural brain or other organ malformation, and he shows a very mild phenotype compared to similar 6q26-qter deletion. The patient phenotype also suggests that a dyspraxia susceptibility gene is located among the deleted genes. PMID:29270193

αB-crystallin negative astrocytic inclusions.

PubMed

Barnett, Brad P; Bressler, Joseph; Chen, Terina; Hutchins, Grover M; Crain, Barbara J; Kaufmann, Walter E

2011-04-01

We report on an unusual pathological finding of astrocytes, observed in the brain of a 16-year-old African-American male with severe intellectual disability and spastic quadriplegia. The brain showed bilateral pericentral, perisylvian polymicrogyria and pachygyria, in conjunction with a large number of hypertrophic astrocytes with eosinophilic granular cytoplasmic inclusions. The astrocytic abnormality was more severe in the dysgenetic area but present throughout the cerebral cortex. Astrocytic inclusions stained with acid fuchsin, azocarmine and Holzer's stain, and were immunoreactive for GFAP, S-100, and ubiquitin, but not for αB-crystallin, filamin, vimentin, nestin, tau or α-synuclein. Based on the case and a review of the literature, the authors postulate that these astrocytic inclusions in the cerebral cortex reflect abnormalities in radial glial developmental processes, such as migration, differentiation, or glial-neuronal interaction function during neuronal migration. Copyright © 2010 The Japanese Society of Child Neurology. All rights reserved.

Angelman syndrome: current understanding and research prospects.

PubMed

Dan, Bernard

2009-11-01

Angelman syndrome is a neurogenetic disorder characterized by developmental delay, severe intellectual disability, absent speech, exuberant behavior with happy demeanor, motor impairment, and epilepsy, due to deficient UBE3A gene expression that may be caused by various abnormalities of chromosome 15. Recent findings in animal models demonstrated altered dendritic spine formation as well as both synaptic [including gamma-aminobutyric acid (GABA)(A) and N-methyl-D-aspartate (NMDA) transmission] and nonsynaptic (including gap junction) influences in various brain regions, including hippocampus and cerebellar cortex. Reversal of selected abnormalities in rescue genetically engineered animal models is encouraging, although it should not be misinterpreted as promising "cure" for affected patients. Much research is still required to fully understand the functional links between lack of UBE3A expression and clinical manifestations of Angelman syndrome. Studies of regulation of UBE3A expression, including imprinting-related methylation, may point to possibilities of therapeutic upregulation. Understanding relevant roles of the gene product might lead to targeted intervention. Further documentation of brain network dynamics, with particular emphasis on hippocampus, thalamocortical, and cerebellar networks is needed, including in a developmental perspective. There is also a need for further clinical research for improving management of problems such as epilepsy, behavior, communication, learning, motor impairment, and sleep disturbances.

NEW FRONTIER IN UNDERSTANDING THE MECHANISMS OF DEVELOPMENTAL ABNORMALITIES

EPA Science Inventory

Recent advancements in molecular developmental biology afford an opportunity to apply newly developed tools for understanding the mechanisms of both normal and abnormal development. lthough a number of agents have been identified as causing developmental abnormalities, knowledge ...

Visual function at 11 years of age in preterm-born children with and without fetal brain sparing.

PubMed

Kok, Joke H; Prick, Liesbeth; Merckel, Elly; Everhard, Yolande; Verkerk, Gijs J Q; Scherjon, Sicco A

2007-06-01

We have demonstrated earlier an accelerated maturation of the visual evoked potential in the first year of life in preterm infants with antenatal brain sparing. We have now assessed visual functioning at 11 years of age in the same cohort and compared the groups with and without brain sparing. One hundred sixteen survivors included in a study on the outcome of preterm infants born at <33 weeks' gestation with and without fetal brain sparing and admitted to the NICU were followed extensively. Ninety-eight infants (85%) were again assessed at 11 years of age. Data were available for fetal Doppler measurements indicating brain sparing, neonatal cerebral ultrasound scanning, and developmental outcome in the first 5 years. Mean birth weight was 1303 g; mean gestational age was 29.8 weeks. The infants were divided into 2 groups with and without brain sparing. Visual functioning was estimated by measuring visual acuity, visual fields, eye position, and binocular function and by visual motor tests. Six percent of the children were found to have a visual acuity of <0.8, 12% had strabismus, and 14% to 46% showed abnormal results on the visual motor tests. No statistical differences were found between the 2 groups. However, children with severe cerebral ultrasound diagnoses in the neonatal period were found to have significantly more abnormalities on visual functioning and lower scores on visual motor tests than children without these morbidities. Children with fetal brain sparing do not demonstrate a different development of their visual functioning at late school age. However, an abnormal cerebral ultrasound in the neonatal period is associated with impaired visual function in later life.

Abnormal functional activation and maturation of ventromedial prefrontal cortex and cerebellum during temporal discounting in autism spectrum disorder.

PubMed

Murphy, Clodagh M; Christakou, Anastasia; Giampietro, Vincent; Brammer, Michael; Daly, Eileen M; Ecker, Christine; Johnston, Patrick; Spain, Debbie; Robertson, Dene M; Murphy, Declan G; Rubia, Katya

2017-11-01

People with autism spectrum disorder (ASD) have poor decision-making and temporal foresight. This may adversely impact on their everyday life, mental health, and productivity. However, the neural substrates underlying poor choice behavior in people with ASD, or its' neurofunctional development from childhood to adulthood, are unknown. Despite evidence of atypical structural brain development in ASD, investigation of functional brain maturation in people with ASD is lacking. This cross-sectional developmental fMRI study investigated the neural substrates underlying performance on a temporal discounting (TD) task in 38 healthy (11-35 years old) male adolescents and adults with ASD and 40 age, sex, and IQ-matched typically developing healthy controls. Most importantly, we assessed group differences in the neurofunctional maturation of TD across childhood and adulthood. Males with ASD had significantly poorer task performance and significantly lower brain activation in typical regions that mediate TD for delayed choices, in predominantly right hemispheric regions of ventrolateral/dorsolateral prefrontal cortices, ventromedial prefrontal cortex, striatolimbic regions, and cerebellum. Importantly, differential activation in ventromedial frontal cortex and cerebellum was associated with abnormal functional brain maturation; controls, in contrast to people with ASD, showed progressively increasing activation with increasing age in these regions; which furthermore was associated with performance measures and clinical ASD measures (stereotyped/restricted interests). Findings provide first cross-sectional evidence that reduced activation of TD mediating brain regions in people with ASD during TD is associated with abnormal functional brain development in these regions between childhood and adulthood, and this is related to poor task performance and clinical measures of ASD. Hum Brain Mapp 38:5343-5355, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Developmental Neurotoxicology: History and Outline of ...

EPA Pesticide Factsheets

The present work provides a brief review of basic concepts in developmental neurotoxicology, as well as current representative testing guidelines for evaluating developmental neurotoxicity (DNT) of xenobiotics. Historically, DNT was initially recognized as a “functional” teratogenicity: the main concern was that prenatal and/or early postnatal exposures to chemicals during critical periods of central nervous system (CNS) development would cause later functional abnormalities of the brain. Current internationally harmonized DNT study guidelines are thus intended to predict adverse effects of test compounds on the developing CNS by observing such postnatal parameters as motor activity, startle response, and learning and memory, as well as neropathological alterations. The reliability of current DNT study guidelines and sensitivity of testing methodologies recommended in these guidelines have been confirmed by retrospective evaluations of the many international and domestic collaborative validation studies in developed nations including Japan. Invited review with brief review of basic concepts in developmental neurotoxicology, as well as current representative testing guidelines for evaluating developmental neurotoxicity (DNT) of xenobiotics.

Speech and oromotor outcome in adolescents born preterm: relationship to motor tract integrity.

PubMed

Northam, Gemma B; Liégeois, Frédérique; Chong, Wui K; Baker, Kate; Tournier, Jacques-Donald; Wyatt, John S; Baldeweg, Torsten; Morgan, Angela

2012-03-01

To assess speech abilities in adolescents born preterm and investigate whether there is an association between specific speech deficits and brain abnormalities. Fifty adolescents born prematurely (<33 weeks' gestation) with a spectrum of brain injuries were recruited (mean age, 16 years). Speech examination included tests of speech-sound processing and production and speech and oromotor control. Conventional magnetic resonance imaging and diffusion-weighted imaging was acquired in all adolescents born preterm and 30 term-born control subjects. Radiological ratings of brain injury were recorded and the integrity of the primary motor projections was measured (corticospinal tract and speech-motor corticobulbar tract [CST/CBT]). There were no clinical diagnoses of developmental dysarthria, dyspraxia, or a speech-sound disorder, but difficulties in speech and oromotor control were common. A regression analysis revealed that presence of a neurologic impairment, and diffusion-weighted imaging abnormalities in the left CST/CBT were significant independent predictors of poor speech and oromotor outcome. These left-lateralized abnormalities were most evident at the level of the posterior limb of the internal capsule. Difficulties in speech and oromotor control are common in adolescents born preterm, and adolescents with injury to the CST/CBT pathways in the left-hemisphere may be most at risk. Copyright © 2012 Mosby, Inc. All rights reserved.

How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans.

PubMed

Frodl, Thomas; O'Keane, Veronica

2013-04-01

There is evidence that excessive stress exposure of the brain, mediated through the neurotoxic effects of cortisol and possibly neuroinflammation, causes damage to brain structure and function: the glucocorticoid cascade hypothesis. Functional changes of hypothalamic-pituitary-adrenal (HPA) axis as well as alterations in brain structures like the hippocampus have been consistently reported in major depression. However, there has not been a lot of emphasis on bringing findings from studies on early childhood stress, HPA axis functioning and hippocampal imaging together. This is the subject for this systematic review of the literature on how developmental stress, specifically childhood maltreatment, may impact on HPA axis function and hippocampal structure. We will also review the literature on the relationship between HPA axis function and hippocampal volume in healthy, depressed and other disease states. There is evidence that prenatal stress and childhood maltreatment is associated with an abnormally developing HPA system, as well as hippocampal volume reduction. Smaller hippocampal volumes are associated with increased cortisol secretion during the day. We conclude that a model integrating childhood maltreatment, cortisol abnormalities and hippocampal volume may need to take other factors into account, such as temperament, genetics or the presence of depression; to provide a cohesive explanation of all the findings. Finally, we have to conclude that the cascade hypothesis, mainly based on preclinical studies, has not been translated enough into humans. While there is evidence that early life maltreatment results in structural hippocampal changes and these are in turn more prominent in subjects with higher continuous cortisol secretion it is less clear which role early life maltreatment plays in HPA axis alteration. Copyright © 2012 Elsevier Inc. All rights reserved.

Which visual functions depend on intermediate visual regions? Insights from a case of developmental visual form agnosia.

PubMed

Gilaie-Dotan, Sharon

2016-03-01

A key question in visual neuroscience is the causal link between specific brain areas and perceptual functions; which regions are necessary for which visual functions? While the contribution of primary visual cortex and high-level visual regions to visual perception has been extensively investigated, the contribution of intermediate visual areas (e.g. V2/V3) to visual processes remains unclear. Here I review more than 20 visual functions (early, mid, and high-level) of LG, a developmental visual agnosic and prosopagnosic young adult, whose intermediate visual regions function in a significantly abnormal fashion as revealed through extensive fMRI and ERP investigations. While expectedly, some of LG's visual functions are significantly impaired, some of his visual functions are surprisingly normal (e.g. stereopsis, color, reading, biological motion). During the period of eight-year testing described here, LG trained on a perceptual learning paradigm that was successful in improving some but not all of his visual functions. Following LG's visual performance and taking into account additional findings in the field, I propose a framework for how different visual areas contribute to different visual functions, with an emphasis on intermediate visual regions. Thus, although rewiring and plasticity in the brain can occur during development to overcome and compensate for hindering developmental factors, LG's case seems to indicate that some visual functions are much less dependent on strict hierarchical flow than others, and can develop normally in spite of abnormal mid-level visual areas, thereby probably less dependent on intermediate visual regions. Copyright © 2015 Elsevier Ltd. All rights reserved.

PM2.5-bound metal metabolic distribution and coupled lipid abnormality at different developmental windows.

PubMed

Ku, Tingting; Zhang, Yingying; Ji, Xiaotong; Li, Guangke; Sang, Nan

2017-09-01

Atmospheric fine particulate matter (PM 2.5 ) is a serious threat to human health. As a toxicant constituent, metal leads to significant health risks in a population, but exposure to PM 2.5 -bound metals and their biological impacts are not fully understood. In this study, we determined the metal contents of PM 2.5 samples collected from a typical coal-burning city and then investigated the metabolic distributions of six metals (Zn, Pb, Mn, As, Cu, and Cd) following PM 2.5 inhalation in mice in different developmental windows. The results indicate that fine particles were mainly deposited in the lung, but PM 2.5 -bound metals could reach and gather in secondary off-target tissues (the lung, liver, heart and brain) with a developmental window-dependent property. Furthermore, elevations in triglycerides and cholesterol levels in sensitive developmental windows (the young and elderly stages) occurred, and significant associations between metals (Pb, Mn, As and Cd) and cholesterol in the heart, brain, liver and lung were observed. These findings suggest that PM 2.5 inhalation caused selective metal metabolic distribution in tissues with a developmental window-dependent property and that the effects were associated with lipid alterations. This provides a foundation for the underlying systemic toxicity following PM 2.5 exposure based on metal components. Copyright © 2017 Elsevier Ltd. All rights reserved.

CDC Kerala 5: Developmental therapy clinic experience--use of Child Development Centre grading for motor milestones.

PubMed

Nair, M K C; Resmi, V R; Krishnan, Rajee; Harikumaran Nair, G S; Leena, M L; Bhaskaran, Deepa; George, Babu; Russell, Paul Swamidhas Sudhakar

2014-12-01

To document the experiences of the intervention given to children who attended the developmental therapy clinic of Child Development Centre (CDC) Kerala, a specialized clinic for providing developmental intervention/therapy for babies less than two years with developmental delay/disability. All the babies referred to this speciality clinic from developmental screening/evaluation clinics of CDC were registered in the clinic and re-evaluation was done using CDC grading for head holding, sitting, standing, Amiel Tison passive angles, and Trivandrum Developmental Screening Chart (TDSC) 0-2 y. Out of a total of 600 consecutive babies below 2 y with developmental delay/disability referred to developmental therapy clinic, on comparing the test results at enrollment and after 6 mo of intervention, a statistically significant reduction was observed (i) in the 2-4 mo age group with regard to abnormal TDSC (25.5%), (ii) in the 4-8 mo age group with regard to abnormal head holding grade (87.1%) and abnormal TDSC (19.4%), (iii) in the 8-12 mo age group, with regard to abnormal sitting grade (71.7%) and (iv) in the above 12 mo age group with regard to abnormal sitting grade (35.3%) and abnormal standing grade (78.8%). The experience of organizing the developmental intervention/therapy clinic at CDC Kerala has shown that therapy services by developmental therapists in a centre and supportive therapy by mother at home is useful in improving the developmental status of children with developmental delay.

Neurodevelopmental origins of abnormal cortical morphology in dissociative identity disorder.

PubMed

Reinders, A A T S; Chalavi, S; Schlumpf, Y R; Vissia, E M; Nijenhuis, E R S; Jäncke, L; Veltman, D J; Ecker, C

2018-02-01

To examine the two constitutes of cortical volume (CV), that is, cortical thickness (CT) and surface area (SA), in individuals with dissociative identity disorder (DID) with the view of gaining important novel insights into the underlying neurobiological mechanisms mediating DID. This study included 32 female patients with DID and 43 matched healthy controls. Between-group differences in CV, thickness, and SA, the degree of spatial overlap between differences in CT and SA, and their relative contribution to differences in regional CV were assessed using a novel spatially unbiased vertex-wise approach. Whole-brain correlation analyses were performed between measures of cortical anatomy and dissociative symptoms and traumatization. Individuals with DID differed from controls in CV, CT, and SA, with significantly decreased CT in the insula, anterior cingulate, and parietal regions and reduced cortical SA in temporal and orbitofrontal cortices. Abnormalities in CT and SA shared only about 3% of all significantly different cerebral surface locations and involved distinct contributions to the abnormality of CV in DID. Significant negative associations between abnormal brain morphology (SA and CV) and dissociative symptoms and early childhood traumatization (0 and 3 years of age) were found. In DID, neuroanatomical areas with decreased CT and SA are in different locations in the brain. As CT and SA have distinct genetic and developmental origins, our findings may indicate that different neurobiological mechanisms and environmental factors impact on cortical morphology in DID, such as early childhood traumatization. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Imaging Characteristics of Children with Auditory Neuropathy Spectrum Disorder

PubMed Central

Roche, Joseph P.; Huang, Benjamin Y.; Castillo, Mauricio; Bassim, Marc K.; Adunka, Oliver F.; Buchman, Craig A.

2013-01-01

Objective To identify and define the imaging characteristics of children with auditory neuropathy spectrum disorder (ANSD). Design Retrospective medical records review and analysis of both temporal bone computed tomography (CT) and magnetic resonance images (MRI) in from children with the diagnosis of ANSD. Setting Tertiary referral center. Patients 118 children with the electrophysiological characteristics of ANSD with available imaging studies for review. Interventions Two neuroradiologists and a neurotologist reviewed each study and consensus descriptions were established. Main outcome measures The type and number of imaging findings were tabulated. Results Sixty-eight (64%) MRIs revealed at least one imaging abnormality while selective use of CT identified 23 (55%) with anomalies. The most prevalent MRI findings included cochlear nerve deficiency (n=51; 28% of 183 nerves), brain abnormalities (n=42; 40% of 106 brains) and prominent temporal horns (n=33, 16% of 212 temporal lobes). The most prevalent CT finding from selective use of CT was cochlear dysplasia (n=13; 31%). Conclusions MRI will identify many abnormalities in children with ANSD that are not readily discernable on CT. Specifically, both developmental and acquired abnormalities of the brain, posterior cranial fossa, and cochlear nerves are not uncommonly seen in this patient population. Inner ear anomalies are well delineated using either imaging modality. Since many of the central nervous system findings identified in this study using MRI can alter the treatment and prognosis for these children, we believe that MRI should be the initial imaging study of choice for children with ANSD. PMID:20593543

Fetal alcohol spectrum disorders: an overview.

PubMed

Riley, Edward P; Infante, M Alejandra; Warren, Kenneth R

2011-06-01

When fetal alcohol syndrome (FAS) was initially described, diagnosis was based upon physical parameters including facial anomalies and growth retardation, with evidence of developmental delay or mental deficiency. Forty years of research has shown that FAS lies towards the extreme end of what are now termed fetal alcohol spectrum disorders (FASD). The most profound effects of prenatal alcohol exposure are on the developing brain and the cognitive and behavioral effects that ensue. Alcohol exposure affects brain development via numerous pathways at all stages from neurogenesis to myelination. For example, the same processes that give rise to the facial characteristics of FAS also cause abnormal brain development. Behaviors as diverse as executive functioning to motor control are affected. This special issue of Neuropsychology Review addresses these changes in brain and behavior highlighting the relationship between the two. A diagnostic goal is to recognize FAS as a disorder of brain rather than one of physical characteristics.

Atypical MR lenticular signal change in infantile isovaleric acidemia.

PubMed

Wani, Nisar A; Qureshi, Umer Amin; Jehangir, Majid; Ahmad, Kaiser; Hussain, Zahid

2016-01-01

Isovaleric acidemia (IVA) is an inborn error of branched chain amino acid metabolism that may manifest as acute neonatal metabolic acidosis or as chronic intermittent form with developmental delay or recurrent episodes of acute metabolic acidosis. Early diagnosis is the key to prevent morbidity and mortality. Brain imaging abnormalities are rarely described in IVA. We report a case of chronic intermittent IVA with acute presentation in a 4-month-old infant who presented with acute metabolic acidosis. Brain magnetic resonance imaging (MRI) revealed symmetric signal intensity changes in bilateral lentiform nuclei with an unreported T1-weighted (T1W) symmetric hyperintense ring-like appearance in bilateral putamen.

CNS development: an overview

NASA Technical Reports Server (NTRS)

Nowakowski, R. S.; Hayes, N. L.

1999-01-01

The basic principles of the development of the central nervous system (CNS) are reviewed, and their implications for both normal and abnormal development of the brain are discussed. The goals of this review are (a) to provide a set of concepts to aid in understanding the variety of complex processes that occur during CNS development, (b) to illustrate how these concepts contribute to our knowledge of the normal anatomy of the adult brain, and (c) to provide a basis for understanding how modifications of normal developmental processes by traumatic injury, by environmental or experiential influences, or by genetic variations may lead to modifications in the resultant structure and function of the adult CNS.

A common brain network links development, aging, and vulnerability to disease.

PubMed

Douaud, Gwenaëlle; Groves, Adrian R; Tamnes, Christian K; Westlye, Lars Tjelta; Duff, Eugene P; Engvig, Andreas; Walhovd, Kristine B; James, Anthony; Gass, Achim; Monsch, Andreas U; Matthews, Paul M; Fjell, Anders M; Smith, Stephen M; Johansen-Berg, Heidi

2014-12-09

Several theories link processes of development and aging in humans. In neuroscience, one model posits for instance that healthy age-related brain degeneration mirrors development, with the areas of the brain thought to develop later also degenerating earlier. However, intrinsic evidence for such a link between healthy aging and development in brain structure remains elusive. Here, we show that a data-driven analysis of brain structural variation across 484 healthy participants (8-85 y) reveals a largely--but not only--transmodal network whose lifespan pattern of age-related change intrinsically supports this model of mirroring development and aging. We further demonstrate that this network of brain regions, which develops relatively late during adolescence and shows accelerated degeneration in old age compared with the rest of the brain, characterizes areas of heightened vulnerability to unhealthy developmental and aging processes, as exemplified by schizophrenia and Alzheimer's disease, respectively. Specifically, this network, while derived solely from healthy subjects, spatially recapitulates the pattern of brain abnormalities observed in both schizophrenia and Alzheimer's disease. This network is further associated in our large-scale healthy population with intellectual ability and episodic memory, whose impairment contributes to key symptoms of schizophrenia and Alzheimer's disease. Taken together, our results suggest that the common spatial pattern of abnormalities observed in these two disorders, which emerge at opposite ends of the life spectrum, might be influenced by the timing of their separate and distinct pathological processes in disrupting healthy cerebral development and aging, respectively.

Genetics of human hydrocephalus

PubMed Central

Williams, Michael A.; Rigamonti, Daniele

2006-01-01

Human hydrocephalus is a common medical condition that is characterized by abnormalities in the flow or resorption of cerebrospinal fluid (CSF), resulting in ventricular dilatation. Human hydrocephalus can be classified into two clinical forms, congenital and acquired. Hydrocephalus is one of the complex and multifactorial neurological disorders. A growing body of evidence indicates that genetic factors play a major role in the pathogenesis of hydrocephalus. An understanding of the genetic components and mechanism of this complex disorder may offer us significant insights into the molecular etiology of impaired brain development and an accumulation of the cerebrospinal fluid in cerebral compartments during the pathogenesis of hydrocephalus. Genetic studies in animal models have started to open the way for understanding the underlying pathology of hydrocephalus. At least 43 mutants/loci linked to hereditary hydrocephalus have been identified in animal models and humans. Up to date, 9 genes associated with hydrocephalus have been identified in animal models. In contrast, only one such gene has been identified in humans. Most of known hydrocephalus gene products are the important cytokines, growth factors or related molecules in the cellular signal pathways during early brain development. The current molecular genetic evidence from animal models indicate that in the early development stage, impaired and abnormal brain development caused by abnormal cellular signaling and functioning, all these cellular and developmental events would eventually lead to the congenital hydrocephalus. Owing to our very primitive knowledge of the genetics and molecular pathogenesis of human hydrocephalus, it is difficult to evaluate whether data gained from animal models can be extrapolated to humans. Initiation of a large population genetics study in humans will certainly provide invaluable information about the molecular and cellular etiology and the developmental mechanisms of human hydrocephalus. This review summarizes the recent findings on this issue among human and animal models, especially with reference to the molecular genetics, pathological, physiological and cellular studies, and identifies future research directions. PMID:16773266

Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain.

PubMed

Ebbink, Berendine J; Poelman, Esther; Aarsen, Femke K; Plug, Iris; Régal, Luc; Muentjes, Carsten; van der Beek, Nadine A M E; Lequin, Maarten H; van der Ploeg, Ans T; van den Hout, Johanna M P

2018-06-01

To examine the long-term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy. Using neuropsychological tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years. From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white-matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white-matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities. As treatment enables patients with classic infantile Pompe disease to reach adulthood, white-matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow-up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next-generation therapeutic strategies for classic infantile Pompe disease. In our long-term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white-matter abnormalities. Cognitive development varied from stable and normal to declines towards intellectual disabilities. © 2018 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.

Dyslexic brain activation abnormalities in deep and shallow orthographies: A meta‐analysis of 28 functional neuroimaging studies

PubMed Central

Martin, Anna; Kronbichler, Martin

2016-01-01

Abstract We used coordinate‐based meta‐analysis to objectively quantify commonalities and differences of dyslexic functional brain abnormalities between alphabetic languages differing in orthographic depth. Specifically, we compared foci of under‐ and overactivation in dyslexic readers relative to nonimpaired readers reported in 14 studies in deep orthographies (DO: English) and in 14 studies in shallow orthographies (SO: Dutch, German, Italian, Swedish). The separate meta‐analyses of the two sets of studies showed universal reading‐related dyslexic underactivation in the left occipitotemporal cortex (including the visual word form area (VWFA)). The direct statistical comparison revealed higher convergence of underactivation for DO compared with SO in bilateral inferior parietal regions, but this abnormality disappeared when foci resulting from stronger dyslexic task‐negative activation (i.e., deactivation relative to baseline) were excluded. Higher convergence of underactivation for DO compared with SO was further identified in the left inferior frontal gyrus (IFG) pars triangularis, left precuneus, and right superior temporal gyrus, together with higher convergence of overactivation in the left anterior insula. Higher convergence of underactivation for SO compared with DO was found in the left fusiform gyrus, left temporoparietal cortex, left IFG pars orbitalis, and left frontal operculum, together with higher convergence of overactivation in the left precentral gyrus. Taken together, the findings support the notion of a biological unity of dyslexia, with additional orthography‐specific abnormalities and presumably different compensatory mechanisms. The results are discussed in relation to current functional neuroanatomical models of developmental dyslexia. Hum Brain Mapp 37:2676–2699, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:27061464

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia.

PubMed

Nakagawa, Yutaka; Chiba, Kenji

2016-09-01

Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits, although age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features, including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence, whereas hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

[Examining the developing brain in Dutch child and adolescent psychiatry].

PubMed

Popma, A

2015-01-01

Research on the developing brain in children and adolescents is delivering new insights into the underlying mechanisms of childhood psychiatric disorders. To provide important information about the role that departments of Dutch child and adolescent psychiatry are playing in this international field that is expanding rapidly. This article provides an overview of recent, mainly Dutch neuro-imaging studies on the developing brain. A large number of studies from Dutch research centers have greatly increased our knowledge about normal and abnormal brain development in relation to the development of psychiatric disorders. Neuro-developmental research can help us to understand the underlying mechanisms of developing psychiatric disorders. This is likely to lead to new preventive measures and to more effective treatment in the future. Policy-makers should therefore commit a larger proportion of their neuroscience research budgets to neurodevelopmental studies in children.

A two-year longitudinal pilot MRI study of the brainstem in autism.

PubMed

Jou, Roger J; Frazier, Thomas W; Keshavan, Matcheri S; Minshew, Nancy J; Hardan, Antonio Y

2013-08-15

Research has demonstrated the potential role of the brainstem in the pathobiology of autism. Previous studies have suggested reductions in brainstem volume and a relationship between this structure and sensory abnormalities. However, little is known regarding the developmental aspects of the brainstem across childhood and adolescence. The goal of this pilot study was to examine brainstem development via MRI volumetry using a longitudinal research design. Participants included 23 boys with autism and 23 matched controls (age range=8-17 years), all without intellectual disability. Participants underwent structural MRI scans once at baseline and again at two-year follow-up. Brainstem volumetric measurements were performed using the BRAINS2 software package. There were no significant group differences in age, gender, handedness, and total brain volume; however, full-scale IQ was higher in controls. Autism and control groups showed different patterns of growth in brainstem volume. While whole brainstem volume remained stable in controls over the two-year period, the autism group showed increases with age reaching volumes comparable to controls by age 15 years. This increase of whole brainstem volume was primarily driven by bilateral increases in gray matter volume. Findings from this preliminary study are suggestive of developmental brainstem abnormalities in autism primarily involving gray matter structures. These findings are consistent with autism being conceptualized as a neurodevelopmental disorder with alterations in brain-growth trajectories. More longitudinal MRI studies are needed integrating longitudinal cognitive/behavioral data to confirm and elucidate the clinical significance of these atypical growth patterns. Copyright © 2013 Elsevier B.V. All rights reserved.

DEVELOPMENT OF THE “RICH CLUB” IN BRAIN CONNECTIVITY NETWORKS FROM 438 ADOLESCENTS & ADULTS AGED 12 TO 30

PubMed Central

Dennis, Emily L.; Jahanshad, Neda; Toga, Arthur W.; McMahon, Katie L.; de Zubicaray, Greig I.; Hickie, Ian; Wright, Margaret J.; Thompson, Paul M.

2014-01-01

The ‘rich club’ coefficient describes a phenomenon where a network's hubs (high-degree nodes) are on average more intensely interconnected than lower-degree nodes. Networks with rich clubs often have an efficient, higher-order organization, but we do not yet know how the rich club emerges in the living brain, or how it changes as our brain networks develop. Here we chart the developmental trajectory of the rich club in anatomical brain networks from 438 subjects aged 12-30. Cortical networks were constructed from 68×68 connectivity matrices of fiber density, using whole-brain tractography in 4-Tesla 105-gradient high angular resolution diffusion images (HARDI). The adult and younger cohorts had rich clubs that included different nodes; the rich club effect intensified with age. Rich-club organization is a sign of a network's efficiency and robustness. These concepts and findings may be advantageous for studying brain maturation and abnormal brain development. PMID:24827471

Developmental vitamin D deficiency causes abnormal brain development.

PubMed

Eyles, D W; Feron, F; Cui, X; Kesby, J P; Harms, L H; Ko, P; McGrath, J J; Burne, T H J

2009-12-01

There is now clear evidence that vitamin D is involved in brain development. Our group is interested in environmental factors that shape brain development and how this may be relevant to neuropsychiatric diseases including schizophrenia. The origins of schizophrenia are considered developmental. We hypothesised that developmental vitamin D (DVD) deficiency may be the plausible neurobiological explanation for several important epidemiological correlates of schizophrenia namely: (1) the excess winter/spring birth rate, (2) increased incidence of the disease in 2nd generation Afro-Caribbean migrants and (3) increased urban birth rate. Moreover we have published two pieces of direct epidemiological support for this hypothesis in patients. In order to establish the "Biological Plausibility" of this hypothesis we have developed an animal model to study the effect of DVD deficiency on brain development. We do this by removing vitamin D from the diet of female rats prior to breeding. At birth we return all dams to a vitamin D containing diet. Using this procedure we impose a transient, gestational vitamin D deficiency, while maintaining normal calcium levels throughout. The brains of offspring from DVD-deficient dams are characterised by (1) a mild distortion in brain shape, (2) increased lateral ventricle volumes, (3) reduced differentiation and (4) diminished expression of neurotrophic factors. As adults, the alterations in ventricular volume persist and alterations in brain gene and protein expression emerge. Adult DVD-deficient rats also display behavioural sensitivity to agents that induce psychosis (the NMDA antagonist MK-801) and have impairments in attentional processing. In this review we summarise the literature addressing the function of vitamin D on neuronal and non-neuronal cells as well as in vivo results from DVD-deficient animals. Our conclusions from these data are that vitamin D is a plausible biological risk factor for neuropsychiatric disorders and that vitamin D acts as a neurosteroid with direct effects on brain development.

Enriched expression of the ciliopathy gene Ick in cell proliferating regions of adult mice.

PubMed

Tsutsumi, Ryotaro; Chaya, Taro; Furukawa, Takahisa

2018-04-07

Cilia are essential for sensory and motile functions across species. In humans, ciliary dysfunction causes "ciliopathies", which show severe developmental abnormalities in various tissues. Several missense mutations in intestinal cell kinase (ICK) gene lead to endocrine-cerebro-osteodysplasia syndrome or short rib-polydactyly syndrome, lethal recessive developmental ciliopathies. We and others previously reported that Ick-deficient mice exhibit neonatal lethality with developmental defects. Mechanistically, Ick regulates intraflagellar transport and cilia length at ciliary tips. Although Ick plays important roles during mammalian development, roles of Ick at the adult stage are poorly understood. In the current study, we investigated the Ick gene expression in adult mouse tissues. RT-PCR analysis showed that Ick is ubiquitously expressed, with enrichment in the retina, brain, lung, intestine, and reproductive system. In the adult brain, we found that Ick expression is enriched in the walls of the lateral ventricle, in the rostral migratory stream of the olfactory bulb, and in the subgranular zone of the hippocampal dentate gyrus by in situ hybridization analysis. We also observed that Ick staining pattern is similar to pachytene spermatocyte to spermatid markers in the mature testis and to an intestinal stem cell marker in the adult small intestine. These results suggest that Ick is expressed in proliferating regions in the adult mouse brain, testis, and intestine. Copyright © 2018 Elsevier B.V. All rights reserved.

Atypical sulcal anatomy in young children with autism spectrum disorder

PubMed Central

Auzias, G.; Viellard, M.; Takerkart, S.; Villeneuve, N.; Poinso, F.; Fonséca, D. Da; Girard, N.; Deruelle, C.

2014-01-01

Autism spectrum disorder is associated with an altered early brain development. However, the specific cortical structure abnormalities underlying this disorder remain largely unknown. Nonetheless, atypical cortical folding provides lingering evidence of early disruptions in neurodevelopmental processes and identifying changes in the geometry of cortical sulci is of primary interest for characterizing these structural abnormalities in autism and their evolution over the first stages of brain development. Here, we applied state-of-the-art sulcus-based morphometry methods to a large highly-selective cohort of 73 young male children of age spanning from 18 to 108 months. Moreover, such large cohort was selected through extensive behavioral assessments and stringent inclusion criteria for the group of 59 children with autism. After manual labeling of 59 different sulci in each hemisphere, we computed multiple shape descriptors for each single sulcus element, hereby separating the folding measurement into distinct factors such as the length and depth of the sulcus. We demonstrated that the central, intraparietal and frontal medial sulci showed a significant and consistent pattern of abnormalities across our different geometrical indices. We also found that autistic and control children exhibited strikingly different relationships between age and structural changes in brain morphology. Lastly, the different measures of sulcus shapes were correlated with the CARS and ADOS scores that are specific to the autistic pathology and indices of symptom severity. Inherently, these structural abnormalities are confined to regions that are functionally relevant with respect to cognitive disorders in ASD. In contrast to those previously reported in adults, it is very unlikely that these abnormalities originate from general compensatory mechanisms unrelated to the primary pathology. Rather, they most probably reflect an early disruption on developmental trajectory that could be part of the primary pathology. PMID:24936410

Impacts of stress and sex hormones on dopamine neurotransmission in the adolescent brain.

PubMed

Sinclair, Duncan; Purves-Tyson, Tertia D; Allen, Katherine M; Weickert, Cynthia Shannon

2014-04-01

Adolescence is a developmental period of complex neurobiological change and heightened vulnerability to psychiatric illness. As a result, understanding factors such as sex and stress hormones which drive brain changes in adolescence, and how these factors may influence key neurotransmitter systems implicated in psychiatric illness, is paramount. In this review, we outline the impact of sex and stress hormones at adolescence on dopamine neurotransmission, a signaling pathway which is critical to healthy brain function and has been implicated in psychiatric illness. We review normative developmental changes in dopamine, sex hormone, and stress hormone signaling during adolescence and throughout postnatal life, then highlight the interaction of sex and stress hormones and review their impacts on dopamine neurotransmission in the adolescent brain. Adolescence is a time of increased responsiveness to sex and stress hormones, during which the maturing dopaminergic neural circuitry is profoundly influenced by these factors. Testosterone, estrogen, and glucocorticoids interact with each other and have distinct, brain region-specific impacts on dopamine neurotransmission in the adolescent brain, shaping brain maturation and cognitive function in adolescence and adulthood. Some effects of stress/sex hormones on cortical and subcortical dopamine parameters bear similarities with dopaminergic abnormalities seen in schizophrenia, suggesting a possible role for sex/stress hormones at adolescence in influencing risk for psychiatric illness via modulation of dopamine neurotransmission. Stress and sex hormones may prove useful targets in future strategies for modifying risk for psychiatric illness.

MRI anatomy of schizophrenia.

PubMed

McCarley, R W; Wible, C G; Frumin, M; Hirayasu, Y; Levitt, J J; Fischer, I A; Shenton, M E

1999-05-01

Structural magnetic resonance imaging (MRI) data have provided much evidence in support of our current view that schizophrenia is a brain disorder with altered brain structure, and consequently involving more than a simple disturbance in neurotransmission. This review surveys 118 peer-reviewed studies with control group from 1987 to May 1998. Most studies (81%) do not find abnormalities of whole brain/intracranial contents, while lateral ventricle enlargement is reported in 77%, and third ventricle enlargement in 67%. The temporal lobe was the brain parenchymal region with the most consistently documented abnormalities. Volume decreases were found in 62% of 37 studies of whole temporal lobe, and in 81% of 16 studies of the superior temporal gyrus (and in 100% with gray matter separately evaluated). Fully 77% of the 30 studies of the medial temporal lobe reported volume reduction in one or more of its constituent structures (hippocampus, amygdala, parahippocampal gyrus). Despite evidence for frontal lobe functional abnormalities, structural MRI investigations less consistently found abnormalities, with 55% describing volume reduction. It may be that frontal lobe volume changes are small, and near the threshold for MRI detection. The parietal and occipital lobes were much less studied; about half of the studies showed positive findings. Most studies of cortical gray matter (86%) found volume reductions were not diffuse, but more pronounced in certain areas. About two thirds of the studies of subcortical structures of thalamus, corpus callosum and basal ganglia (which tend to increase volume with typical neuroleptics), show positive findings, as do almost all (91%) studies of cavum septi pellucidi (CSP). Most data were consistent with a developmental model, but growing evidence was compatible also with progressive, neurodegenerative features, suggesting a "two-hit" model of schizophrenia, for which a cellular hypothesis is discussed. The relationship of clinical symptoms to MRI findings is reviewed, as is the growing evidence suggesting structural abnormalities differ in affective (bipolar) psychosis and schizophrenia.

Grey Matter Alterations Co-Localize with Functional Abnormalities in Developmental Dyslexia: An ALE Meta-Analysis

PubMed Central

Linkersdörfer, Janosch; Lonnemann, Jan; Lindberg, Sven; Hasselhorn, Marcus; Fiebach, Christian J.

2012-01-01

The neural correlates of developmental dyslexia have been investigated intensively over the last two decades and reliable evidence for a dysfunction of left-hemispheric reading systems in dyslexic readers has been found in functional neuroimaging studies. In addition, structural imaging studies using voxel-based morphometry (VBM) demonstrated grey matter reductions in dyslexics in several brain regions. To objectively assess the consistency of these findings, we performed activation likelihood estimation (ALE) meta-analysis on nine published VBM studies reporting 62 foci of grey matter reduction in dyslexic readers. We found six significant clusters of convergence in bilateral temporo-parietal and left occipito-temporal cortical regions and in the cerebellum bilaterally. To identify possible overlaps between structural and functional deviations in dyslexic readers, we conducted additional ALE meta-analyses of imaging studies reporting functional underactivations (125 foci from 24 studies) or overactivations (95 foci from 11 studies ) in dyslexics. Subsequent conjunction analyses revealed overlaps between the results of the VBM meta-analysis and the meta-analysis of functional underactivations in the fusiform and supramarginal gyri of the left hemisphere. An overlap between VBM results and the meta-analysis of functional overactivations was found in the left cerebellum. The results of our study provide evidence for consistent grey matter variations bilaterally in the dyslexic brain and substantial overlap of these structural variations with functional abnormalities in left hemispheric regions. PMID:22916214

Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease.

PubMed

Li, Rui; Sun, Le; Fang, Ai; Li, Peng; Wu, Qian; Wang, Xiaoqun

2017-11-01

The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.

Postnatal Vitamin D Intake Modulates Hippocampal Learning and Memory in Adult Mice

PubMed Central

Liang, Qiujuan; Cai, Chunhui; Duan, Dongxia; Hu, Xinyu; Hua, Wanhao; Jiang, Peicheng; Zhang, Liu; Xu, Jun; Gao, Zhengliang

2018-01-01

Vitamin D (VD) is a neuroactive steroid crucial for brain development, function and homeostasis. Its deficiency is associated with numerous brain conditions. As such, VD and its variants are routinely taken by a broad of groups with/without known VD deficiency. In contrast, the harmful effects of VD overdose have been poorly studied. Similarly, the developmental stage-specific VD deficiency and overdose have been rarely explored. In the present work, we showed that postnatal VD supplementation enhanced the motor function transiently in the young adult, but not in the older one. Postnatal VD intake abnormality did not impact the anxiety and depressive behavior but was detrimental to spatial learning and hippocampus-dependent memory. At the molecular level we failed to observe an obvious and constant change with the neural development and activity-related genes examined. However, disrupted developmental expression dynamics were observed for most of the genes, suggesting that the altered neural development dynamics and therefore aberrant adult plasticity might underlie the functional deficits. Our work highlights the essence of VD homeostasis in neural development and adult brain function. Further studies are needed to determine the short- and long-term effects VD intake status may have on brain development, homeostasis, and diseases. PMID:29666565

Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greenberg, F.; Lewis, R.A.; Potocki, L.

1996-03-29

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation (MCA/MR) syndrome associated with deletion of chromosome 17 band p11.2. As part of a multi-disciplinary clinical, cytogenetic, and molecular approach to SMS, detailed clinical studies including radiographic neurologic, developmental, ophthalmologic, otolaryngologic, and audiologic evaluations were performed on 27 SMS patients. Significant findings include otolaryngologic abnormalities in 94%, eye abnormalities in 85%, sleep abnormalities (especially reduced REM sleep) in 75%, hearing impairment in 68% (approximately 65% conductive and 35% sensorineural), scoliosis in 65% brain abnormalities (predominantly ventriculomegaly) in 52%, cardiac abnormalities in at least 37%, renal anomalies (especially duplication of themore » collecting system) in 35%, low thyroxine levels in 29%, low immunoglobulin levels in 23%, and forearm abnormalities in 16%. The measured IQ ranged between 20-78, most patients falling in the moderate range of mental retardation at 40-54, although several patients scored in the mild or borderline range. The frequency of these many abnormalities in SMS suggests that patients should be evaluated thoroughly for associated complications both at the time of diagnosis and at least annually thereafter. 42 refs., 2 figs., 3 tabs.« less

Developmental heterochrony and the evolution of autistic perception, cognition and behavior

PubMed Central

2013-01-01

Background Autism is usually conceptualized as a disorder or disease that involves fundamentally abnormal neurodevelopment. In the present work, the hypothesis that a suite of core autism-related traits may commonly represent simple delays or non-completion of typical childhood developmental trajectories is evaluated. Discussion A comprehensive review of the literature indicates that, with regard to the four phenotypes of (1) restricted interests and repetitive behavior, (2) short-range and long-range structural and functional brain connectivity, (3) global and local visual perception and processing, and (4) the presence of absolute pitch, the differences between autistic individuals and typically developing individuals closely parallel the differences between younger and older children. Summary The results of this study are concordant with a model of ‘developmental heterochrony’, and suggest that evolutionary extension of child development along the human lineage has potentiated and structured genetic risk for autism and the expression of autistic perception, cognition and behavior. PMID:23639054

Developmental heterochrony and the evolution of autistic perception, cognition and behavior.

PubMed

Crespi, Bernard

2013-05-02

Autism is usually conceptualized as a disorder or disease that involves fundamentally abnormal neurodevelopment. In the present work, the hypothesis that a suite of core autism-related traits may commonly represent simple delays or non-completion of typical childhood developmental trajectories is evaluated. A comprehensive review of the literature indicates that, with regard to the four phenotypes of (1) restricted interests and repetitive behavior, (2) short-range and long-range structural and functional brain connectivity, (3) global and local visual perception and processing, and (4) the presence of absolute pitch, the differences between autistic individuals and typically developing individuals closely parallel the differences between younger and older children. The results of this study are concordant with a model of 'developmental heterochrony', and suggest that evolutionary extension of child development along the human lineage has potentiated and structured genetic risk for autism and the expression of autistic perception, cognition and behavior.

Gestational Age is Dimensionally Associated with Structural Brain Network Abnormalities Across Development.

PubMed

Nassar, Rula; Kaczkurkin, Antonia N; Xia, Cedric Huchuan; Sotiras, Aristeidis; Pehlivanova, Marieta; Moore, Tyler M; Garcia de La Garza, Angel; Roalf, David R; Rosen, Adon F G; Lorch, Scott A; Ruparel, Kosha; Shinohara, Russell T; Davatzikos, Christos; Gur, Ruben C; Gur, Raquel E; Satterthwaite, Theodore D

2018-04-21

Prematurity is associated with diverse developmental abnormalities, yet few studies relate cognitive and neurostructural deficits to a dimensional measure of prematurity. Leveraging a large sample of children, adolescents, and young adults (age 8-22 years) studied as part of the Philadelphia Neurodevelopmental Cohort, we examined how variation in gestational age impacted cognition and brain structure later in development. Participants included 72 preterm youth born before 37 weeks' gestation and 206 youth who were born at term (37 weeks or later). Using a previously-validated factor analysis, cognitive performance was assessed in three domains: (1) executive function and complex reasoning, (2) social cognition, and (3) episodic memory. All participants completed T1-weighted neuroimaging at 3 T to measure brain volume. Structural covariance networks were delineated using non-negative matrix factorization, an advanced multivariate analysis technique. Lower gestational age was associated with both deficits in executive function and reduced volume within 11 of 26 structural covariance networks, which included orbitofrontal, temporal, and parietal cortices as well as subcortical regions including the hippocampus. Notably, the relationship between lower gestational age and executive dysfunction was accounted for in part by structural network deficits. Together, these findings emphasize the durable impact of prematurity on cognition and brain structure, which persists across development.

Magnetic resonance microscopy-based analyses of the neuroanatomical effects of gestational day 9 ethanol exposure in mice

PubMed Central

Parnell, Scott E.; Holloway, Hunter T.; O’Leary-Moore, Shonagh K.; Dehart, Deborah B.; Paniaqua, Beatriz; Oguz, Ipek; Budin, Francois; Styner, Martin A.; Johnson, G. Allan; Sulik, Kathleen K.

2013-01-01

Animal model-based studies have shown that ethanol exposure during early gestation induces developmental stage-specific abnormalities of the face and brain. The exposure time-dependent variability in ethanol’s teratogenic outcomes is expected to contribute significantly to the wide spectrum of effects observed in humans with fetal alcohol spectrum disorder (FASD). The work presented here employs a mouse FASD model and magnetic resonance microscopy (MRM; high resolution magnetic resonance imaging) in studies designed to further our understanding of the developmental stage-specific defects of the brain that are induced by ethanol. At neurulation stages, i.e. at the beginning of gestational day (GD) 9 and again 4 hours later, time-mated C57Bl/6J dams were intraperitoneally administered 2.9 g/kg ethanol or vehicle. Ethanol-exposed fetuses were collected on GD 17, processed for MRM analysis, and results compared to comparably staged controls. Linear and volume measurements as well as shape changes for numerous individual brain regions were determined. GD 9 ethanol exposure resulted in significantly increased septal region width, reduction of cerebellar volume, and enlargement of all of the ventricles. Additionally, the results of shape analyses showed that many areas of the ethanol-exposed brains including the cerebral cortex, hippocampus and right striatum were significantly misshapen. These data demonstrate that ethanol can induce dysmorphology that may not be obvious based on volumetric analyses alone, highlight the asymmetric aspects of ethanol-induced defects, and add to our understanding of ethanol’s developmental stage-dependent neuroteratogenesis. PMID:23911654

Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features

PubMed Central

Ouyang, Qing; Nakayama, Tojo; Baytas, Ozan; Davidson, Shawn M.; Yang, Chendong; Schmidt, Michael; Lizarraga, Sofia B.; Mishra, Sasmita; EI-Quessny, Malak; Niaz, Saima; Gul Butt, Mirrat; Imran Murtaza, Syed; Javed, Afzal; Chaudhry, Haroon Rashid; Vaughan, Dylan J.; Hill, R. Sean; Partlow, Jennifer N.; Yoo, Seung-Yun; Lam, Anh-Thu N.; Nasir, Ramzi; Al-Saffar, Muna; Barkovich, A. James; Schwede, Matthew; Nagpal, Shailender; Rajab, Anna; DeBerardinis, Ralph J.; Housman, David E.; Mochida, Ganeshwaran H.; Morrow, Eric M.

2016-01-01

Mutations that cause neurological phenotypes are highly informative with regard to mechanisms governing human brain function and disease. We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD). GPT2 [also known as alanine transaminase 2 (ALT2)] is one of two related transaminases that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and ∼80% of those followed over time show progressive motor symptoms, a spastic paraplegia. Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function. The GPT2 gene demonstrates increasing expression in brain in the early postnatal period, and GPT2 protein localizes to mitochondria. Akin to the human phenotype, Gpt2-null mice exhibit reduced brain growth. Through metabolomics and direct isotope tracing experiments, we find a number of metabolic abnormalities associated with loss of Gpt2. These include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids. Also, we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates. Finally, mutant brains demonstrate misregulated metabolites in pathways implicated in neuroprotective mechanisms previously associated with neurodegenerative disorders. Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism with relevance to developmental as well as potentially to neurodegenerative mechanisms. PMID:27601654

Promoting social plasticity in developmental disorders with non-invasive brain stimulation techniques

PubMed Central

Boggio, Paulo S.; Asthana, Manish K.; Costa, Thiago L.; Valasek, Cláudia A.; Osório, Ana A. C.

2015-01-01

Being socially connected directly impacts our basic needs and survival. People with deficits in social cognition might exhibit abnormal behaviors and face many challenges in our highly social-dependent world. These challenges and limitations are associated with a substantial economical and subjective impact. As many conditions where social cognition is affected are highly prevalent, more treatments have to be developed. Based on recent research, we review studies where non-invasive neuromodulatory techniques have been used to promote Social Plasticity in developmental disorders. We focused on three populations where non-invasive brain stimulation seems to be a promising approach in inducing social plasticity: Schizophrenia, Autism Spectrum Disorder (ASD) and Williams Syndrome (WS). There are still very few studies directly evaluating the effects of transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) in the social cognition of these populations. However, when considering the promising preliminary evidences presented in this review and the limited amount of clinical interventions available for treating social cognition deficits in these populations today, it is clear that the social neuroscientist arsenal may profit from non-invasive brain stimulation techniques for rehabilitation and promotion of social plasticity. PMID:26388712

Neurodevelopmental model of schizophrenia: update 2012

PubMed Central

Rapoport, JL; Giedd, JN; Gogtay, N

2012-01-01

The neurodevelopmental model of schizophrenia, which posits that the illness is the end state of abnormal neurodevelopmental processes that started years before the illness onset, is widely accepted, and has long been dominant for childhood-onset neuropsychiatric disorders. This selective review updates our 2005 review of recent studies that have impacted, or have the greatest potential to modify or extend, the neurodevelopmental model of schizophrenia. Longitudinal whole-population studies support a dimensional, rather than categorical, concept of psychosis. New studies suggest that placental pathology could be a key measure in future prenatal high-risk studies. Both common and rare genetic variants have proved surprisingly diagnostically nonspecific, and copy number variants (CNVs) associated with schizophrenia are often also associated with autism, epilepsy and intellectual deficiency. Large post-mortem gene expression studies and prospective developmental multi-modal brain imaging studies are providing critical data for future clinical and high-risk developmental brain studies. Whether there can be greater molecular specificity for phenotypic characterization is a subject of current intense study and debate, as is the possibility of neuronal phenotyping using human pluripotent-inducible stem cells. Biological nonspecificity, such as in timing or nature of early brain development, carries the possibility of new targets for broad preventive treatments. PMID:22488257

Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex

PubMed Central

Kenet, T.; Froemke, R. C.; Schreiner, C. E.; Pessah, I. N.; Merzenich, M. M.

2007-01-01

Noncoplanar polychlorinated biphenyls (PCBs) are widely dispersed in human environment and tissues. Here, an exemplar noncoplanar PCB was fed to rat dams during gestation and throughout three subsequent nursing weeks. Although the hearing sensitivity and brainstem auditory responses of pups were normal, exposure resulted in the abnormal development of the primary auditory cortex (A1). A1 was irregularly shaped and marked by internal nonresponsive zones, its topographic organization was grossly abnormal or reversed in about half of the exposed pups, the balance of neuronal inhibition to excitation for A1 neurons was disturbed, and the critical period plasticity that underlies normal postnatal auditory system development was significantly altered. These findings demonstrate that developmental exposure to this class of environmental contaminant alters cortical development. It is proposed that exposure to noncoplanar PCBs may contribute to common developmental disorders, especially in populations with heritable imbalances in neurotransmitter systems that regulate the ratio of inhibition and excitation in the brain. We conclude that the health implications associated with exposure to noncoplanar PCBs in human populations merit a more careful examination. PMID:17460041

Imaging evidence for disturbances in multiple learning and memory systems in persons with autism spectrum disorders.

PubMed

Goh, Suzanne; Peterson, Bradley S

2012-03-01

The aim of this article is to review neuroimaging studies of autism spectrum disorders (ASD) that examine declarative, socio-emotional, and procedural learning and memory systems. We conducted a search of PubMed from 1996 to 2010 using the terms 'autism,''learning,''memory,' and 'neuroimaging.' We limited our review to studies correlating learning and memory function with neuroimaging features of the brain. The early literature supports the following preliminary hypotheses: (1) abnormalities of hippocampal subregions may contribute to autistic deficits in episodic and relational memory; (2) disturbances to an amygdala-based network (which may include the fusiform gyrus, superior temporal cortex, and mirror neuron system) may contribute to autistic deficits in socio-emotional learning and memory; and (3) abnormalities of the striatum may contribute to developmental dyspraxia in individuals with ASD. Characterizing the disturbances to learning and memory systems in ASD can inform our understanding of the neural bases of autistic behaviors and the phenotypic heterogeneity of ASD. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

Small rare recurrent deletions and reciprocal duplications in 2q21.1, including brain-specific ARHGEF4 and GPR148

PubMed Central

Dharmadhikari, Avinash V.; Kang, Sung-Hae L.; Szafranski, Przemyslaw; Person, Richard E.; Sampath, Srirangan; Prakash, Siddharth K.; Bader, Patricia I.; Phillips, John A.; Hannig, Vickie; Williams, Misti; Vinson, Sherry S.; Wilfong, Angus A.; Reimschisel, Tyler E.; Craigen, William J.; Patel, Ankita; Bi, Weimin; Lupski, James R.; Belmont, John; Cheung, Sau Wai; Stankiewicz, Pawel

2012-01-01

We have identified a rare small (∼450 kb unique sequence) recurrent deletion in a previously linked attention-deficit hyperactivity disorder (ADHD) locus at 2q21.1 in five unrelated families with developmental delay (DD)/intellectual disability (ID), ADHD, epilepsy and other neurobehavioral abnormalities from 17 035 samples referred for clinical chromosomal microarray analysis. Additionally, a DECIPHER (http://decipher.sanger.ac.uk) patient 2311 was found to have the same deletion and presented with aggressive behavior. The deletion was not found in either six control groups consisting of 13 999 healthy individuals or in the DGV database. We have also identified reciprocal duplications in five unrelated families with autism, developmental delay (DD), seizures and ADHD. This genomic region is flanked by large, complex low-copy repeats (LCRs) with directly oriented subunits of ∼109 kb in size that have 97.7% DNA sequence identity. We sequenced the deletion breakpoints within the directly oriented paralogous subunits of the flanking LCR clusters, demonstrating non-allelic homologous recombination as a mechanism of formation. The rearranged segment harbors five genes: GPR148, FAM123C, ARHGEF4, FAM168B and PLEKHB2. Expression of ARHGEF4 (Rho guanine nucleotide exchange factor 4) is restricted to the brain and may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function. GPR148 encodes a G-protein-coupled receptor protein expressed in the brain and testes. We suggest that small rare recurrent deletion of 2q21.1 is pathogenic for DD/ID, ADHD, epilepsy and other neurobehavioral abnormalities and, because of its small size, low frequency and more severe phenotype might have been missed in other previous genome-wide screening studies using single-nucleotide polymorphism analyses. PMID:22543972

Developmental abnormalities of the occipital bone in human chondrodystrophies (achondroplasia and thanatophoric dwarfism).

PubMed

Marin-Padilla, M; Marin-Padilla, T M

1977-01-01

Specific developmental malformations have been demonstrated in the occipital bone of two chondrodysplastic disorders (achondroplasia and thanatophoric dwarfism). Analysis of these malformations indicates that the occipital bone is primary affected in these disorders. In both cases, the endochondral-derived components of the occipital bone (the basioccipital, the two lateral parts, and the planum nuchale of the squama occipitalis) have failed to grow properly and are smaller and shorter than normal. On the other hand, the planum occipitalis of the squama, which derives from intramembranous ossification, is unaffected. In addition, the nature of these abnormalities indicates that the occipital synchondroses, together with the epiphyseal plates of other bones, are primarily affected in these two chondrodysplasias. The components of the occipital bone formed between the affected synchondroses failed to grow normally. The resulting malformation of the occipital bone is undoubtedly the cause of the shortening of the posterior cerebral fossa and of the considerable narrowing of the foramen magnum often described in these chondrodysplasias. It is postulated that growth disturbances between the affected occipital bone and the unaffected central nervous system results in the inadequacy of the posterior cerebral fossa and the foramen magnum to accommodate the growing brain. Consequently, compression of the brain at the posterior cerebral fossa or the foramen magnum levels could occur and thus lead to neurologic complications such as hydrocephalus and compression of the brain stem. It is suggested that the surgical removal of the fused posterior border of the lateral parts of the occipital bone (partial nuchalectomy) for the purpose of enlarging the narrow foramen magnum may be indicated in those chondrodysplastic children who develop these types of neurologic complications.

Gestational Age and Neonatal Brain Microstructure in Term Born Infants: A Birth Cohort Study

PubMed Central

Broekman, Birit F. P.; Wang, Changqing; Li, Yue; Rifkin-Graboi, Anne; Saw, Seang Mei; Chong, Yap-Seng; Kwek, Kenneth; Gluckman, Peter D.; Fortier, Marielle V.; Meaney, Michael J.; Qiu, Anqi

2014-01-01

Objective Understanding healthy brain development in utero is crucial in order to detect abnormal developmental trajectories due to developmental disorders. However, in most studies neuroimaging was done after a significant postnatal period, and in those studies that performed neuroimaging on fetuses, the quality of data has been affected due to complications of scanning during pregnancy. To understand healthy brain development between 37–41 weeks of gestational age, our study assessed the in utero growth of the brain in healthy term born babies with DTI scanning soon after birth. Methods A cohort of 93 infants recruited from maternity hospitals in Singapore underwent diffusion tensor imaging between 5 to 17 days after birth. We did a cross-sectional examination of white matter microstructure of the brain among healthy term infants as a function of gestational age via voxel-based analysis on fractional anisotropy. Results Greater gestational age at birth in term infants was associated with larger fractional anisotropy values in early developing brain regions, when corrected for age at scan. Specifically, it was associated with a cluster located at the corpus callosum (corrected p<0.001), as well as another cluster spanning areas of the anterior corona radiata, anterior limb of internal capsule, and external capsule (corrected p<0.001). Conclusions Our findings show variation in brain maturation associated with gestational age amongst ‘term’ infants, with increased brain maturation when born with a relatively higher gestational age in comparison to those infants born with a relatively younger gestational age. Future studies should explore if these differences in brain maturation between 37 and 41 weeks of gestational age will persist over time due to development outside the womb. PMID:25535959

Frontal networks in adults with autism spectrum disorder.

PubMed

Catani, Marco; Dell'Acqua, Flavio; Budisavljevic, Sanja; Howells, Henrietta; Thiebaut de Schotten, Michel; Froudist-Walsh, Seán; D'Anna, Lucio; Thompson, Abigail; Sandrone, Stefano; Bullmore, Edward T; Suckling, John; Baron-Cohen, Simon; Lombardo, Michael V; Wheelwright, Sally J; Chakrabarti, Bhismadev; Lai, Meng-Chuan; Ruigrok, Amber N V; Leemans, Alexander; Ecker, Christine; Consortium, Mrc Aims; Craig, Michael C; Murphy, Declan G M

2016-02-01

It has been postulated that autism spectrum disorder is underpinned by an 'atypical connectivity' involving higher-order association brain regions. To test this hypothesis in a large cohort of adults with autism spectrum disorder we compared the white matter networks of 61 adult males with autism spectrum disorder and 61 neurotypical controls, using two complementary approaches to diffusion tensor magnetic resonance imaging. First, we applied tract-based spatial statistics, a 'whole brain' non-hypothesis driven method, to identify differences in white matter networks in adults with autism spectrum disorder. Following this we used a tract-specific analysis, based on tractography, to carry out a more detailed analysis of individual tracts identified by tract-based spatial statistics. Finally, within the autism spectrum disorder group, we studied the relationship between diffusion measures and autistic symptom severity. Tract-based spatial statistics revealed that autism spectrum disorder was associated with significantly reduced fractional anisotropy in regions that included frontal lobe pathways. Tractography analysis of these specific pathways showed increased mean and perpendicular diffusivity, and reduced number of streamlines in the anterior and long segments of the arcuate fasciculus, cingulum and uncinate--predominantly in the left hemisphere. Abnormalities were also evident in the anterior portions of the corpus callosum connecting left and right frontal lobes. The degree of microstructural alteration of the arcuate and uncinate fasciculi was associated with severity of symptoms in language and social reciprocity in childhood. Our results indicated that autism spectrum disorder is a developmental condition associated with abnormal connectivity of the frontal lobes. Furthermore our findings showed that male adults with autism spectrum disorder have regional differences in brain anatomy, which correlate with specific aspects of autistic symptoms. Overall these results suggest that autism spectrum disorder is a condition linked to aberrant developmental trajectories of the frontal networks that persist in adult life. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Brain calcifications and PCDH12 variants

PubMed Central

Nicolas, Gaël; Sanchez-Contreras, Monica; Ramos, Eliana Marisa; Lemos, Roberta R.; Ferreira, Joana; Moura, Denis; Sobrido, Maria J.; Richard, Anne-Claire; Lopez, Alma Rosa; Legati, Andrea; Deleuze, Jean-François; Boland, Anne; Quenez, Olivier; Krystkowiak, Pierre; Favrole, Pascal; Geschwind, Daniel H.; Aran, Adi; Segel, Reeval; Levy-Lahad, Ephrat; Dickson, Dennis W.; Coppola, Giovanni; Rademakers, Rosa

2017-01-01

Objective: To assess the potential connection between PCDH12 and brain calcifications in a patient carrying a homozygous nonsense variant in PCDH12 and in adult patients with brain calcifications. Methods: We performed a CT scan in 1 child with a homozygous PCDH12 nonsense variant. We screened DNA samples from 53 patients with primary familial brain calcification (PFBC) and 26 patients with brain calcification of unknown cause (BCUC). Results: We identified brain calcifications in subcortical and perithalamic regions in the patient with a homozygous PCDH12 nonsense variant. The calcification pattern was different from what has been observed in PFBC and more similar to what is described in in utero infections. In patients with PFBC or BCUC, we found no protein-truncating variant and 3 rare (minor allele frequency <0.001) PCDH12 predicted damaging missense heterozygous variants in 3 unrelated patients, albeit with no segregation data available. Conclusions: Brain calcifications should be added to the phenotypic spectrum associated with PCDH12 biallelic loss of function, in the context of severe cerebral developmental abnormalities. A putative role for PCDH12 variants remains to be determined in PFBC. PMID:28804758

[Neurological and psychomotor development of foetuses and children with congenital heart disease--causes and prevalence of disorders and long-term prognosis].

PubMed

Herberg, U; Hövels-Gürich, H

2012-06-01

Children with severe congenital heart defects (CHD) requiring open heart surgery in the first year of life are at high risk for developing neurological and psychomotor abnormalities. Depending on the type and severity of the CHD, between 15 and over 50% of these children have deficits, which are usually confined to distinct domains of development, although formal intelligence tends to be normal. Children with mild CHD, who comprise the majority of congenital heart defects, have a far better developmental prognosis than those with complex CHD. This review concentrates on the impact of severe CHD on the developing brain of the foetus and infant. It also provides a summary of recent clinical and neuroimaging studies, and an overview of the long-term neurological prognosis. Advanced neuroimaging modalities indicate that, related to altered cerebral blood flow and oxygenation, foetuses with severe CHD show delayed third trimester brain maturation and increased vulnerability for hypoxic injury. Morphological and neurological abnormalities are present before surgery, commonly affecting the white matter. In the long-term, impaired neurological and developmental outcomes are related to the combination of prenatal, perinatal and additional perioperative risk factors. Therefore, new therapeutic approaches aim to optimise the intra- and perinatal management of foetuses and newborns with congenital heart defects. Identification and avoidance of risk factors, early neurodevelopmental assessment and therapy may optimise the long-term outcome in this high-risk population. © Georg Thieme Verlag KG Stuttgart · New York.

Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study

PubMed Central

Xavier-Neto, Jose; Carvalho, Murilo; Pascoalino, Bruno dos Santos; Cardoso, Alisson Campos; Costa, Ângela Maria Sousa; Pereira, Ana Helena Macedo; Santos, Luana Nunes; Saito, Ângela; Marques, Rafael Elias; Smetana, Juliana Helena Costa; Consonni, Silvio Roberto; Bandeira, Carla; Costa, Vivian Vasconcelos; Bajgelman, Marcio Chaim; de Oliveira, Paulo Sérgio Lopes; Cordeiro, Marli Tenorio; Gonzales Gil, Laura Helena Vega; Pauletti, Bianca Alves; Granato, Daniela Campos; Paes Leme, Adriana Franco; Freitas-Junior, Lucio; Holanda de Freitas, Carolina Borsoi Moraes; Teixeira, Mauro Martins; Bevilacqua, Estela; Franchini, Kleber

2017-01-01

The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5–9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes. PMID:28231241

Irradiation exacerbates cortical cytopathology in the Eker rat model of Tuberous Sclerosis Complex, but does not induce hyperexcitability

PubMed Central

Tschuluun, Naranzogt; Wenzel, H. Jürgen

2007-01-01

Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder characterized by multi-organ pathologies. Most TSC patients exhibit seizures, usually starting in early childhood. The neuropathological hallmarks of the disease - cortical tubers, containing cytopathological neuronal and glial cell types – appear to be the source of seizure initiation. However, the contribution of these aberrant cell populations to TSC-associated epilepsies is not fully understood. To gain further insight, investigators have attempted to generate animal models with TSC-like brain abnormalities. In the current study, we focused on the Eker rat, in which there is a spontaneous mutation of the TSC2 gene (TSC2+/−). We attempted to exacerbate TSC-like brain pathologies with a “second-hit” strategy - exposing young pups to ionizing irradiation of different intensities, and at different developmental timepoints (between E18 and P6). We found that the frequency of occurrence of dysmorphic neurons and giant astrocytes was strongly dependent on irradiation dose, and weakly dependent on timing of irradiation – in Eker rats, but not in irradiated normal controls. The frequency of TSC-like pathology was progressive; there were many more abnormal cells at 3 months compared to 1 month post-irradiation. Measures of seizure propensity (flurothyl seizure latency) and brain excitability (paired-pulse and post-tetanic stimulation studies in vitro), however, showed no functional changes associated with the appearance of TSC-like cellular abnormalities in irradiated Eker rats. PMID:17011168

Evaluation of the developmental toxicity of lead in the Danio rerio body.

PubMed

Roy, Nicole M; DeWolf, Sarah; Carneiro, Bruno

2015-01-01

Lead has been utilized throughout history and is widely distributed and mobilized globally. Although lead in the environment has been somewhat mitigated, the nature of lead and its extensive uses in the past prohibit it from being completely absent from our environment and exposure to lead is still a public health concern. Most studies regarding lead toxicity have focused on the brain. However, little is found in the literature on the effects of lead in other tissues. Here, we utilize the zebrafish model system to investigate effects of lead exposure during early developmental time windows at 24, 48 and 72 h post fertilization in the body. We analyze whole body, notochord and somatic muscle changes, vascular changes of the body, as well as motor neuron alterations. We find lead exposure induces a curved body phenotype with concomitant changes in somite length, decreased notochord staining and abnormal muscle staining using live and in situ approaches. Furthermore, altered vasculature within the somatic regions, loss and/or alternations of motor neuron extension both dorsally and ventrally from the spinal cord, loss of Rohon-Beard sensory neurons, and increased areas of apoptosis were found. We conclude that lead is developmentally toxic to other areas of the developing embryo, not just the brain. Copyright © 2014 Elsevier B.V. All rights reserved.

Validation of In utero Tractography of Human Fetal Commissural and Internal Capsule Fibers with Histological Structure Tensor Analysis

PubMed Central

Mitter, Christian; Jakab, András; Brugger, Peter C.; Ricken, Gerda; Gruber, Gerlinde M.; Bettelheim, Dieter; Scharrer, Anke; Langs, Georg; Hainfellner, Johannes A.; Prayer, Daniela; Kasprian, Gregor

2015-01-01

Diffusion tensor imaging (DTI) and tractography offer the unique possibility to visualize the developing white matter macroanatomy of the human fetal brain in vivo and in utero and are currently under investigation for their potential use in the diagnosis of developmental pathologies of the human central nervous system. However, in order to establish in utero DTI as a clinical imaging tool, an independent comparison between macroscopic imaging and microscopic histology data in the same subject is needed. The present study aimed to cross-validate normal as well as abnormal in utero tractography results of commissural and internal capsule fibers in human fetal brains using postmortem histological structure tensor (ST) analysis. In utero tractography findings from two structurally unremarkable and five abnormal fetal brains were compared to the results of postmortem ST analysis applied to digitalized whole hemisphere sections of the same subjects. An approach to perform ST-based deterministic tractography in histological sections was implemented to overcome limitations in correlating in utero tractography to postmortem histology data. ST analysis and histology-based tractography of fetal brain sections enabled the direct assessment of the anisotropic organization and main fiber orientation of fetal telencephalic layers on a micro- and macroscopic scale, and validated in utero tractography results of corpus callosum and internal capsule fiber tracts. Cross-validation of abnormal in utero tractography results could be achieved in four subjects with agenesis of the corpus callosum (ACC) and in two cases with malformations of internal capsule fibers. In addition, potential limitations of current DTI-based in utero tractography could be demonstrated in several brain regions. Combining the three-dimensional nature of DTI-based in utero tractography with the microscopic resolution provided by histological ST analysis may ultimately facilitate a more complete morphologic characterization of axon guidance disorders at prenatal stages of human brain development. PMID:26732460

A systematic literature review of neuroimaging research on developmental stuttering between 1995 and 2016.

PubMed

Etchell, Andrew C; Civier, Oren; Ballard, Kirrie J; Sowman, Paul F

2018-03-01

Stuttering is a disorder that affects millions of people all over the world. Over the past two decades, there has been a great deal of interest in investigating the neural basis of the disorder. This systematic literature review is intended to provide a comprehensive summary of the neuroimaging literature on developmental stuttering. It is a resource for researchers to quickly and easily identify relevant studies for their areas of interest and enable them to determine the most appropriate methodology to utilize in their work. The review also highlights gaps in the literature in terms of methodology and areas of research. We conducted a systematic literature review on neuroimaging studies on developmental stuttering according to the PRISMA guidelines. We searched for articles in the pubmed database containing "stuttering" OR "stammering" AND either "MRI", "PET", "EEG", "MEG", "TMS"or "brain" that were published between 1995/​01/​01 and 2016/​01/​01. The search returned a total of 359 items with an additional 26 identified from a manual search. Of these, there were a total of 111 full text articles that met criteria for inclusion in the systematic literature review. We also discuss neuroimaging studies on developmental stuttering published throughout 2016. The discussion of the results is organized first by methodology and second by population (i.e., adults or children) and includes tables that contain all items returned by the search. There are widespread abnormalities in the structural architecture and functional organization of the brains of adults and children who stutter. These are evident not only in speech tasks, but also non-speech tasks. Future research should make greater use of functional neuroimaging and noninvasive brain stimulation, and employ structural methodologies that have greater sensitivity. Newly planned studies should also investigate sex differences, focus on augmenting treatment, examine moments of dysfluency and longitudinally or cross-sectionally investigate developmental trajectories in stuttering. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Thyroid abnormalities among first-degree relatives of children with congenital hypothyroidism: an ultrasound survey.

PubMed

Adibi, Atoosa; Haghighi, Mahshid; Hosseini, Seyed Reza; Hashemipour, Mahin; Amini, Massoud; Hovsepian, Silva

2008-01-01

Congenital hypothyroidism (CH) is caused by thyroid dysgenesis and dyshormonogenesis. Evidence suggests the presence of genetic factors in both types of pathogenesis. We investigated whether an increased incidence of thyroid abnormalities could be shown by ultrasonography among first-degree relatives of children with CH. In this case-control study the presence of both developmental and non-developmental thyroid abnormalities was studied among first-degree relatives of CH patients and healthy children. Assessments included neck ultrasonography and thyroid function tests. The data obtained from parents, siblings and children were compared in the case and control groups. In the case group, 92 patients, 172 parents and 57 siblings, and in the control group, 82 healthy children, 160 parents and 39 siblings were studied. Thyroid developmental abnormalities were more prevalent among parents (3.5 vs. 0%, p = 0.03) and siblings (10.5 vs. 0, p = 0.01) of CH patients than the control group. Non-developmental abnormalities were not significantly different between the case and control groups (17 vs. 13%, p = 0.3). Thyroid developmental abnormalities were more prevalent among parents and siblings of CH patients than the control group, confirming the familial component of this entity. Copyright 2008 S. Karger AG, Basel.

Brief report: life history and neuropathology of a gifted man with Asperger syndrome.

PubMed

Weidenheim, Karen M; Escobar, Alfonso; Rapin, Isabelle

2012-03-01

Despite recent interest in the pathogenesis of the autism spectrum disorders (pervasive developmental disorders), neuropathological descriptions of brains of individuals with well documented clinical information and without potentially confounding symptomatology are exceptionally rare. Asperger syndrome differs from classic autism by lack of cognitive impairment or delay in expressive language acquisition. We examined the 1,570 g brain of a 63 year old otherwise healthy mathematician with an Autistic Spectrum Disorder of Asperger subtype. Except for an atypical gyral pattern and megalencephaly, we detected no specific neuropathologic abnormality. Taken together, the behavioral data and pathological findings in this case are compatible with an early neurodevelopmental process affecting multiple neuroanatomic networks, but without a convincing morphologic signature detectable with routine neuropathologic technology.

Basic abnormalities in visual processing affect face processing at an early age in autism spectrum disorder.

PubMed

Vlamings, Petra Hendrika Johanna Maria; Jonkman, Lisa Marthe; van Daalen, Emma; van der Gaag, Rutger Jan; Kemner, Chantal

2010-12-15

A detailed visual processing style has been noted in autism spectrum disorder (ASD); this contributes to problems in face processing and has been directly related to abnormal processing of spatial frequencies (SFs). Little is known about the early development of face processing in ASD and the relation with abnormal SF processing. We investigated whether young ASD children show abnormalities in low spatial frequency (LSF, global) and high spatial frequency (HSF, detailed) processing and explored whether these are crucially involved in the early development of face processing. Three- to 4-year-old children with ASD (n = 22) were compared with developmentally delayed children without ASD (n = 17). Spatial frequency processing was studied by recording visual evoked potentials from visual brain areas while children passively viewed gratings (HSF/LSF). In addition, children watched face stimuli with different expressions, filtered to include only HSF or LSF. Enhanced activity in visual brain areas was found in response to HSF versus LSF information in children with ASD, in contrast to control subjects. Furthermore, facial-expression processing was also primarily driven by detail in ASD. Enhanced visual processing of detailed (HSF) information is present early in ASD and occurs for neutral (gratings), as well as for socially relevant stimuli (facial expressions). These data indicate that there is a general abnormality in visual SF processing in early ASD and are in agreement with suggestions that a fast LSF subcortical face processing route might be affected in ASD. This could suggest that abnormal visual processing is causative in the development of social problems in ASD. Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

A humanoid mouse model of autism.

PubMed

Takumi, Toru

2010-10-01

Even now fruit of the human genome project is available, we have difficulties to approach neuropsychiatric disorders at the molecular level. Autism is a complex psychiatric illness but has received considerable attention as a developmental brain disorder not only from basic researchers but also from society. Substantial evidence suggests that chromosomal abnormalities contribute to autism risk. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We succeeded to generate mice with a 6.3-Mb-wide interstitial duplication in mouse chromosome 7c that is highly syntenic to human 15q11-13 by using a Cre-loxP-based chromosome-engineering technique. The only paternally duplicated mice display autistic behavioral features such as poor social interaction and stereotypical behavior, and exhibit a developmental abnormality in ultrasonic vocalizations as well as anxiety. The detailed analysis focusing on a non-coding small nucleolar RNA, MBII52, within the duplicated region, revealed that the paternally duplicated mice alter the editing ratio of serotonin (5-HT) 2c receptor pre-mRNA and intracellular calcium responses by a 5-HT2c receptor specific agonist are changed in neurons. This result may explain one of molecular mechanisms of abnormal behaviors in the paternal duplicated mice. The first chromosome-engineered mouse model for human chromosome 15q11-13 duplication fulfills not only face validity of human autistic phenotypes but also construct validity based on human chromosome abnormality. This model will be a founder mouse for forward genetics of autistic disease and an invaluable tool for its therapeutic development. Copyright © 2010 Elsevier B.V. All rights reserved.

Nestin is essential for zebrafish brain and eye development through control of progenitor cell apoptosis.

PubMed

Chen, Hua-Ling; Yuh, Chiou-Hwa; Wu, Kenneth K

2010-02-19

Nestin is expressed in neural progenitor cells (NPC) of developing brain. Despite its wide use as an NPC marker, the function of nestin in embryo development is unclear. As nestin is conserved in zebrafish and its predicted sequence is clustered with the mammalian nestin orthologue, we used zebrafish as a model to investigate its role in embryogenesis. Injection of nestin morpholino (MO) into fertilized eggs induced time- and dose-dependent brain and eye developmental defects. Nestin morphants exhibited characteristic morphological changes including small head, small eyes and hydrocephalus. Histological examinations show reduced hind- and mid-brain size, dilated ventricle, poorly organized retina and underdeveloped lens. Injection of control nestin MO did not induce brain or eye changes. Nestin MO injection reduced expression of ascl1b (achaete-scute complex-like 1b), a marker of NPCs, without affecting its distribution. Nestin MO did not influence Elavl3/4 (Embryonic lethal, abnormal vision, Drosophila-like 3/4) (a neuronal marker), or otx2 (a midbrain neuronal marker), but severely perturbed cranial motor nerve development and axon distribution. To determine whether the developmental defects are due to excessive NPC apoptosis and/or reduced NPC proliferation, we analyzed apoptosis by TUNEL assay and acridine orange staining and proliferation by BrdU incorporation, pcna and mcm5 expressions. Excessive apoptosis was noted in hindbrain and midbrain cells. Apoptotic signals were colocalized with ascl1b. Proliferation markers were not significantly altered by nestin MO. These results suggest that nestin is essential for zebrafish brain and eye development probably through control of progenitor cell apoptosis.

Resting state EEG abnormalities in autism spectrum disorders

PubMed Central

2013-01-01

Autism spectrum disorders (ASD) are a group of complex and heterogeneous developmental disorders involving multiple neural system dysfunctions. In an effort to understand neurophysiological substrates, identify etiopathophysiologically distinct subgroups of patients, and track outcomes of novel treatments with translational biomarkers, EEG (electroencephalography) studies offer a promising research strategy in ASD. Resting-state EEG studies of ASD suggest a U-shaped profile of electrophysiological power alterations, with excessive power in low-frequency and high-frequency bands, abnormal functional connectivity, and enhanced power in the left hemisphere of the brain. In this review, we provide a summary of recent findings, discuss limitations in available research that may contribute to inconsistencies in the literature, and offer suggestions for future research in this area for advancing the understanding of ASD. PMID:24040879

Addiction, adolescence, and the integration of control and motivation.

PubMed

Gladwin, Thomas E; Figner, Bernd; Crone, Eveline A; Wiers, Reinout W

2011-10-01

The likelihood of initiating addictive behaviors is higher during adolescence than during any other developmental period. The differential developmental trajectories of brain regions involved in motivation and control processes may lead to adolescents' increased risk taking in general, which may be exacerbated by the neural consequences of drug use. Neuroimaging studies suggest that increased risk-taking behavior in adolescence is related to an imbalance between prefrontal cortical regions, associated with executive functions, and subcortical brain regions related to affect and motivation. Dual-process models of addictive behaviors are similarly concerned with difficulties in controlling abnormally strong motivational processes. We acknowledge concerns raised about dual-process models, but argue that they can be addressed by carefully considering levels of description: motivational processes and top-down biasing can be understood as intertwined, co-developing components of more versus less reflective states of processing. We illustrate this with a model that further emphasizes temporal dynamics. Finally, behavioral interventions for addiction are discussed. Insights in the development of control and motivation may help to better understand - and more efficiently intervene in - vulnerabilities involving control and motivation. Copyright © 2011 Elsevier Ltd. All rights reserved.

Cochlear Implant Outcomes and Genetic Mutations in Children with Ear and Brain Anomalies

PubMed Central

Busi, Micol; Rosignoli, Monica; Minazzi, Federica; Trevisi, Patrizia; Aimoni, Claudia; Calzolari, Ferdinando; Martini, Alessandro

2015-01-01

Background. Specific clinical conditions could compromise cochlear implantation outcomes and drastically reduce the chance of an acceptable development of perceptual and linguistic capabilities. These conditions should certainly include the presence of inner ear malformations or brain abnormalities. The aims of this work were to study the diagnostic value of high resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) in children with sensorineural hearing loss who were candidates for cochlear implants and to analyse the anatomic abnormalities of the ear and brain in patients who underwent cochlear implantation. We also analysed the effects of ear malformations and brain anomalies on the CI outcomes, speculating on their potential role in the management of language developmental disorders. Methods. The present study is a retrospective observational review of cochlear implant outcomes among hearing-impaired children who presented ear and/or brain anomalies at neuroimaging investigations with MRI and HRCT. Furthermore, genetic results from molecular genetic investigations (GJB2/GJB6 and, additionally, in selected cases, SLC26A4 or mitochondrial-DNA mutations) on this study group were herein described. Longitudinal and cross-sectional analysis was conducted using statistical tests. Results. Between January 1, 1996 and April 1, 2012, at the ENT-Audiology Department of the University Hospital of Ferrara, 620 cochlear implantations were performed. There were 426 implanted children at the time of the present study (who were <18 years). Among these, 143 patients (64 females and 79 males) presented ear and/or brain anomalies/lesions/malformations at neuroimaging investigations with MRI and HRCT. The age of the main study group (143 implanted children) ranged from 9 months and 16 years (average = 4.4; median = 3.0). Conclusions. Good outcomes with cochlear implants are possible in patients who present with inner ear or brain abnormalities, even if central nervous system anomalies represent a negative prognostic factor that is made worse by the concomitant presence of cochlear malformations. Common cavity and stenosis of the internal auditory canal (less than 2 mm) are negative prognostic factors even if brain lesions are absent. PMID:26236732

Cochlear Implant Outcomes and Genetic Mutations in Children with Ear and Brain Anomalies.

PubMed

Busi, Micol; Rosignoli, Monica; Castiglione, Alessandro; Minazzi, Federica; Trevisi, Patrizia; Aimoni, Claudia; Calzolari, Ferdinando; Granieri, Enrico; Martini, Alessandro

2015-01-01

Specific clinical conditions could compromise cochlear implantation outcomes and drastically reduce the chance of an acceptable development of perceptual and linguistic capabilities. These conditions should certainly include the presence of inner ear malformations or brain abnormalities. The aims of this work were to study the diagnostic value of high resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) in children with sensorineural hearing loss who were candidates for cochlear implants and to analyse the anatomic abnormalities of the ear and brain in patients who underwent cochlear implantation. We also analysed the effects of ear malformations and brain anomalies on the CI outcomes, speculating on their potential role in the management of language developmental disorders. The present study is a retrospective observational review of cochlear implant outcomes among hearing-impaired children who presented ear and/or brain anomalies at neuroimaging investigations with MRI and HRCT. Furthermore, genetic results from molecular genetic investigations (GJB2/GJB6 and, additionally, in selected cases, SLC26A4 or mitochondrial-DNA mutations) on this study group were herein described. Longitudinal and cross-sectional analysis was conducted using statistical tests. Between January 1, 1996 and April 1, 2012, at the ENT-Audiology Department of the University Hospital of Ferrara, 620 cochlear implantations were performed. There were 426 implanted children at the time of the present study (who were <18 years). Among these, 143 patients (64 females and 79 males) presented ear and/or brain anomalies/lesions/malformations at neuroimaging investigations with MRI and HRCT. The age of the main study group (143 implanted children) ranged from 9 months and 16 years (average = 4.4; median = 3.0). Good outcomes with cochlear implants are possible in patients who present with inner ear or brain abnormalities, even if central nervous system anomalies represent a negative prognostic factor that is made worse by the concomitant presence of cochlear malformations. Common cavity and stenosis of the internal auditory canal (less than 2 mm) are negative prognostic factors even if brain lesions are absent.

Self-regulation of brain oscillations as a treatment for aberrant brain connections in children with autism.

PubMed

Pineda, J A; Juavinett, A; Datko, M

2012-12-01

Autism is a highly varied developmental disorder typically characterized by deficits in reciprocal social interaction, difficulties with verbal and nonverbal communication, and restricted interests and repetitive behaviors. Although a wide range of behavioral, pharmacological, and alternative medicine strategies have been reported to ameliorate specific symptoms for some individuals, there is at present no cure for the condition. Nonetheless, among the many incompatible observations about aspects of the development, anatomy, and functionality of the autistic brain, it is widely agreed that it is characterized by widespread aberrant connectivity. Such disordered connectivity, be it increased, decreased, or otherwise compromised, may complicate healthy synchronization and communication among and within different neural circuits, thereby producing abnormal processing of sensory inputs necessary for normal social life. It is widely accepted that the innate properties of brain electrical activity produce pacemaker elements and linked networks that oscillate synchronously or asynchronously, likely reflecting a type of functional connectivity. Using phase coherence in multiple frequency EEG bands as a measure of functional connectivity, studies have shown evidence for both global hypoconnectivity and local hyperconnectivity in individuals with ASD. However, the nature of the brain's experience-dependent structural plasticity suggests that these abnormal patterns may be reversed with the proper type of treatment. Indeed, neurofeedback (NF) training, an intervention based on operant conditioning that results in self-regulation of brain electrical oscillations, has shown promise in addressing marked abnormalities in functional and structural connectivity. It is hypothesized that neurofeedback produces positive behavioral changes in ASD children by normalizing the aberrant connections within and between neural circuits. NF exploits the brain's plasticity to normalize aberrant connectivity patterns apparent in the autistic brain. By grounding this training in known anatomical (e.g., mirror neuron system) and functional markers (e.g., mu rhythms) of autism, NF training holds promise to support current treatments for this complex disorder. The proposed hypothesis specifically states that neurofeedback-induced alpha mu (8-12Hz) rhythm suppression or desynchronization, a marker of cortical activation, should induce neuroplastic changes and lead to normalization in relevant mirroring networks that have been associated with higher-order social cognition. Copyright © 2012 Elsevier Ltd. All rights reserved.

Maternal exposure to silver nanoparticles are associated with behavioral abnormalities in adulthood: Role of mitochondria and innate immunity in developmental toxicity.

PubMed

Amiri, Shayan; Yousefi-Ahmadipour, Aliakbar; Hosseini, Mir-Jamal; Haj-Mirzaian, Arya; Momeny, Majid; Hosseini-Chegeni, Heshmat; Mokhtari, Tahmineh; Kharrazi, Sharmin; Hassanzadeh, Gholamreza; Amini, Seyed Mohammad; Jafarinejad, Somayeh; Ghazi-Khansari, Mahmoud

2018-05-01

Silver nanoparticles (Ag-NPs) are currently used in a wide range of consumer products. Considering the small size of Ag-NPs, they are able to pass through variety of biological barriers and exert their effects. In this regard, the unique physicochemical properties of Ag-NPs along with its high application in the industry have raised concerns about their negative effects on human health. Therefore, it investigated whether prenatal exposure to low doses of Ag-NPs is able to induce any abnormality in the cognitive and behavioral performance of adult offspring. We gavaged pregnant NMRI mice with, 1) Deionized water as vehicle, 2) Ag-NPs 10 nm (0.26 mg/kg/day), 3) Ag-NPs 30 nm (0.26 mg/kg/day), and 4) AgNO 3 (0.26 mg/kg/day) from gestational day (GD) 0 until delivery day. At the postnatal day (PD) 1, our results showed that high concentration of silver is present in the brain of pups. Further, we observed mitochondrial dysfunction and upregulation of the genes relevant to innate immune system in the brain. At PD 60, results revealed that prenatal exposure to Ag-NPs provoked severe cognitive and behavioral abnormalities in male offspring. In addition, we found that prenatal exposure to Ag-NPs was associated with abnormal mitochondrial function and significant up-regulation of the genes relevant to innate immunity in the brain. Although the Ag-NPs have been considered as safe compounds at low doses, our results indicate that prenatal exposure to low doses of Ag-NPs is able to induce behavioral and cognitive abnormalities in adulthood. Also, we found that these effects are at least partly associated with hippocampal mitochondrial dysfunction and the activation of sterile inflammation during early stages of life. Copyright © 2018 Elsevier B.V. All rights reserved.

Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use.

PubMed

Ashtari, Manzar; Cervellione, Kelly; Cottone, John; Ardekani, Babak A; Sevy, Serge; Kumra, Sanjiv

2009-01-01

There is growing evidence that adolescence is a key period for neuronal maturation. Despite the high prevalence of marijuana use among adolescents and young adults in the United States and internationally, very little is known about its impact on the developing brain. Based on neuroimaging literature on normal brain developmental during adolescence, we hypothesized that individuals with heavy cannabis use (HCU) would have brain structure abnormalities in similar brain regions that undergo development during late adolescence, particularly the fronto-temporal connection. Fourteen young adult males in residential treatment for cannabis dependence and 14 age-matched healthy male control subjects were recruited. Patients had a history of HCU throughout adolescence; 5 had concurrent alcohol abuse. Subjects underwent structural and diffusion tensor magnetic resonance imaging. White matter integrity was compared between subject groups using voxelwise and fiber tractography analysis. Voxelwise and tractography analyses revealed that adolescents with HCU had reduced fractional anisotropy, increased radial diffusivity, and increased trace in the homologous areas known to be involved in ongoing development during late adolescence, particularly in the fronto-temporal connection via arcuate fasciculus. Our results support the hypothesis that heavy cannabis use during adolescence may affect the trajectory of normal brain maturation. Due to concurrent alcohol consumption in five HCU subjects, conclusions from this study should be considered preliminary, as the DTI findings reported here may be reflective of the combination of alcohol and marijuana use. Further research in larger samples, longitudinal in nature, and controlling for alcohol consumption is needed to better understand the pathophysiology of the effect of cannabis on the developing brain.

[Neuropsychological approach to elucidating delusion and psychotic symptoms].

PubMed

Kato, Motoichiro

2012-01-01

Neuropsychological symptom-oriented approach is a critical method to elucidate delusion and psychotic symptoms in patients with focal brain damages and schizophrenia. In Capgras delusion (CD), the delusional misidentification of familiar people disguised as others, the patients with right amygdala damage and bilateral ventromedial prefrontal lesions have a deficient or reduced emotional valence of the person with intact configurational processes of the face. Reduplicative paramnesia (RP) is a specific phenomenon characterized by subjective certainty that a familiar place or person has been duplicated. Clinical evidences indicated that the patient with RP following right prefrontal damages showed the lack of emotional valence for the present hospital. This abnormal sense of familiarity triggered the deficits of the orientation of self to the outside world, that is, double orientation, resulting in the development of geographical reduplicative paramnesia. In line with the pathogenesis of CD and RP after brain damages, the delusion in schizophrenia may have a germ as developmental origins, which include the aberrant or salient perceptual experiences and abnormal sense of agency, and might be further aggravated by the impairment of causal reasoning process such as the jumping-to-conclusions bias.

Molecular hierarchy in neurons differentiated from mouse ES cells containing a single human chromosome 21.

PubMed

Wang, Chi Chiu; Kadota, Mitsutaka; Nishigaki, Ryuichi; Kazuki, Yasuhiro; Shirayoshi, Yasuaki; Rogers, Michael Scott; Gojobori, Takashi; Ikeo, Kazuho; Oshimura, Mitsuo

2004-02-06

Defects in neurogenesis and neuronal differentiation in the fetal brain of Down syndrome (DS) patients lead to the apparent neuropathological abnormalities and contribute to the phenotypic characters of mental retardation, and premature development of Alzheimer's disease, those being the most common phenotype in DS. In order to understand the molecular mechanism underlying the cause of phenotypic abnormalities in the DS brain, we have utilized an in vitro model of TT2F mouse embryonic stem cells containing a single human chromosome 21 (hChr21) to study neuron development and neuronal differentiation by microarray containing 15K developmentally expressed cDNAs. Defective neuronal differentiation in the presence of extra hChr21 manifested primarily the post-transcriptional and translational modification, such as Mrpl10, SNAPC3, Srprb, SF3a60 in the early neuronal stem cell stage, and Mrps18a, Eef1g, and Ubce8 in the late differentiated stage. Hierarchical clustering patterned specific expression of hChr21 gene dosage effects on neuron outgrowth, migration, and differentiation, such as Syngr2, Dncic2, Eif3sf, and Peg3.

Malformations of cortical development: 3T magnetic resonance imaging features

PubMed Central

Battal, Bilal; Ince, Selami; Akgun, Veysel; Kocaoglu, Murat; Ozcan, Emrah; Tasar, Mustafa

2015-01-01

Malformation of cortical development (MCD) is a term representing an inhomogeneous group of central nervous system abnormalities, referring particularly to embriyological aspect as a consequence of any of the three developmental stages, i.e., cell proliferation, cell migration and cortical organization. These include cotical dysgenesis, microcephaly, polymicrogyria, schizencephaly, lissencephaly, hemimegalencephaly, heterotopia and focal cortical dysplasia. Since magnetic resonance imaging is the modality of choice that best identifies the structural anomalies of the brain cortex, we aimed to provide a mini review of MCD by using 3T magnetic resonance scanner images. PMID:26516429

Cell death in neural precursor cells and neurons before neurite formation prevents the emergence of abnormal neural structures in the Drosophila optic lobe.

PubMed

Hara, Yusuke; Sudo, Tatsuya; Togane, Yu; Akagawa, Hiromi; Tsujimura, Hidenobu

2018-04-01

Programmed cell death is a conserved strategy for neural development both in vertebrates and invertebrates and is recognized at various developmental stages in the brain from neurogenesis to adulthood. To understand the development of the central nervous system, it is essential to reveal not only molecular mechanisms but also the role of neural cell death (Pinto-Teixeira et al., 2016). To understand the role of cell death in neural development, we investigated the effect of inhibition of cell death on optic lobe development. Our data demonstrate that, in the optic lobe of Drosophila, cell death occurs in neural precursor cells and neurons before neurite formation and functions to prevent various developmental abnormalities. When neuronal cell death was inhibited by an effector caspase inhibitor, p35, multiple abnormal neuropil structures arose during optic lobe development-e.g., enlarged or fused neuropils, misrouted neurons and abnormal neurite lumps. Inhibition of cell death also induced morphogenetic defects in the lamina and medulla development-e.g., failures in the separation of the lamina and medulla cortices and the medulla rotation. These defects were reproduced in the mutant of an initiator caspase, dronc. If cell death was a mechanism for removing the abnormal neuropil structures, we would also expect to observe them in mutants defective for corpse clearance. However, they were not observed in these mutants. When dead cell-membranes were visualized with Apoliner, they were observed only in cortices and not in neuropils. These results suggest that the cell death occurs before mature neurite formation. Moreover, we found that inhibition of cell death induced ectopic neuroepithelial cells, neuroblasts and ganglion mother cells in late pupal stages, at sites where the outer and inner proliferation centers were located at earlier developmental stages. Caspase-3 activation was observed in the neuroepithelial cells and neuroblasts in the proliferation centers. These results indicate that cell death is required for elimination of the precursor cells composing the proliferation centers. This study substantiates an essential role of early neural cell death for ensuring normal development of the central nervous system. Copyright © 2018 Elsevier Inc. All rights reserved.

Advances in magnetic resonance neuroimaging techniques in the evaluation of neonatal encephalopathy.

PubMed

Panigrahy, Ashok; Blüml, Stefan

2007-02-01

Magnetic resonance (MR) imaging has become an essential tool in the evaluation of neonatal encephalopathy. Magnetic resonance-compatible neonatal incubators allow sick neonates to be transported to the MR scanner, and neonatal head coils can improve signal-to-noise ratio, critical for advanced MR imaging techniques. Refinement of conventional imaging techniques include the use of PROPELLER techniques for motion correction. Magnetic resonance spectroscopic imaging and diffusion tensor imaging provide quantitative assessment of both brain development and brain injury in the newborn with respect to metabolite abnormalities and hypoxic-ischemic injury. Knowledge of normal developmental changes in MR spectroscopy metabolite concentration and diffusion tensor metrics is essential to interpret pathological cases. Perfusion MR and functional MR can provide additional physiological information. Both MR spectroscopy and diffusion tensor imaging can provide additional information in the differential of neonatal encephalopathy, including perinatal white matter injury, hypoxic-ischemic brain injury, metabolic disease, infection, and birth injury.

Early life stress-induced alterations in rat brain structures measured with high resolution MRI.

PubMed

Sarabdjitsingh, R Angela; Loi, Manila; Joëls, Marian; Dijkhuizen, Rick M; van der Toorn, Annette

2017-01-01

Adverse experiences early in life impair cognitive function both in rodents and humans. In humans this increases the vulnerability to develop mental illnesses while in the rodent brain early life stress (ELS) abnormalities are associated with changes in synaptic plasticity, excitability and microstructure. Detailed information on the effects of ELS on rodent brain structural integrity at large and connectivity within the brain is currently lacking; this information is highly relevant for understanding the mechanism by which early life stress predisposes to mental illnesses. Here, we exposed rats to 24 hours of maternal deprivation (MD) at postnatal day 3, a paradigm known to increase corticosterone levels and thereby activate glucocorticoid receptors in the brain. Using structural magnetic resonance imaging we examined: i) volumetric changes and white/grey matter properties of the whole cerebrum and of specific brain areas; and ii) whether potential alterations could be normalized by blocking glucocorticoid receptors with mifepristone during the critical developmental window of early adolescence, i.e. between postnatal days 26 and 28. The results show that MD caused a volumetric reduction of the prefrontal cortex, particularly the ventromedial part, and the orbitofrontal cortex. Within the whole cerebrum, white (relative to grey) matter volume was decreased and region-specifically in prefrontal cortex and dorsomedial striatum following MD. A trend was found for the hippocampus. Grey matter fractions were not affected. Treatment with mifepristone did not normalize these changes. This study indicates that early life stress in rodents has long lasting consequences for the volume and structural integrity of the brain. However, changes were relatively modest and-unlike behavior- not mitigated by blockade of glucocorticoid receptors during a critical developmental period.

Neuropathology of leukoencephalopathy with brainstem and spinal cord involvement and high lactate caused by a homozygous mutation of DARS2.

PubMed

Yamashita, Sumimasa; Miyake, Noriko; Matsumoto, Naomichi; Osaka, Hitoshi; Iai, Mizue; Aida, Noriko; Tanaka, Yukichi

2013-04-01

We diagnosed three siblings from consanguineous east Asian parents with leukoencephalopathy with brainstem and spinal cord involvement and high lactate (LBSL) from characteristic MRI, MRS findings and a homozygous mutation in the DARS2 gene. The neurological symptoms of the three patients consisted of psychomotor developmental delay, cerebellar ataxia since infancy, spasticity in the initial phase and peripheral neuropathy in later stages. Their mental development was delayed, but did not deteriorate. MRI signal abnormalities included the same abnormalities reported previously but tended to be more extensive. Signal abnormalities in the cerebral and cerebellar white matter were homogeneous and confluent from early stages. In addition, other tract such as the central tegmental tract was involved. Furthermore, an atrophic change in the cerebral white matter was observed on follow-up in one case. Two of the patients were autopsied and neuropathological findings revealed characteristic vacuolar changes in the white matter of the cerebrum, cerebellum and the nerve tracts of the brain stem and spinal cord. The central myelin sheath showed intralamellar splitting by electron microscopy. These findings were consistent to a spongy degeneration in the diffuse white matter of the brain, or spongiform leukoencephalopathy. In addition, peripheral nerves showed both axonal degeneration and abnormal myelin structures. We discussed the relationship between deficits in mitochondrial aspartyl-tRNA synthetase activity and the neuropathology observed. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Residual number processing in dyscalculia☆

PubMed Central

Cappelletti, Marinella; Price, Cathy J.

2013-01-01

Developmental dyscalculia – a congenital learning disability in understanding numerical concepts – is typically associated with parietal lobe abnormality. However, people with dyscalculia often retain some residual numerical abilities, reported in studies that otherwise focused on abnormalities in the dyscalculic brain. Here we took a different perspective by focusing on brain regions that support residual number processing in dyscalculia. All participants accurately performed semantic and categorical colour-decision tasks with numerical and non-numerical stimuli, with adults with dyscalculia performing slower than controls in the number semantic tasks only. Structural imaging showed less grey-matter volume in the right parietal cortex in people with dyscalculia relative to controls. Functional MRI showed that accurate number semantic judgements were maintained by parietal and inferior frontal activations that were common to adults with dyscalculia and controls, with higher activation for participants with dyscalculia than controls in the right superior frontal cortex and the left inferior frontal sulcus. Enhanced activation in these frontal areas was driven by people with dyscalculia who made faster rather than slower numerical decisions; however, activation could not be accounted for by response times per se, because it was greater for fast relative to slow dyscalculics but not greater for fast controls relative to slow dyscalculics. In conclusion, our results reveal two frontal brain regions that support efficient number processing in dyscalculia. PMID:24266008

Residual number processing in dyscalculia.

PubMed

Cappelletti, Marinella; Price, Cathy J

2014-01-01

Developmental dyscalculia - a congenital learning disability in understanding numerical concepts - is typically associated with parietal lobe abnormality. However, people with dyscalculia often retain some residual numerical abilities, reported in studies that otherwise focused on abnormalities in the dyscalculic brain. Here we took a different perspective by focusing on brain regions that support residual number processing in dyscalculia. All participants accurately performed semantic and categorical colour-decision tasks with numerical and non-numerical stimuli, with adults with dyscalculia performing slower than controls in the number semantic tasks only. Structural imaging showed less grey-matter volume in the right parietal cortex in people with dyscalculia relative to controls. Functional MRI showed that accurate number semantic judgements were maintained by parietal and inferior frontal activations that were common to adults with dyscalculia and controls, with higher activation for participants with dyscalculia than controls in the right superior frontal cortex and the left inferior frontal sulcus. Enhanced activation in these frontal areas was driven by people with dyscalculia who made faster rather than slower numerical decisions; however, activation could not be accounted for by response times per se, because it was greater for fast relative to slow dyscalculics but not greater for fast controls relative to slow dyscalculics. In conclusion, our results reveal two frontal brain regions that support efficient number processing in dyscalculia.

Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease.

PubMed

Eyles, Darryl W; Burne, Thomas H J; McGrath, John J

2013-01-01

Increasingly vitamin D deficiency is being associated with a number of psychiatric conditions. In particular for disorders with a developmental basis, such as autistic spectrum disorder and schizophrenia the neurobiological plausibility of this association is strengthened by the preclinical data indicating vitamin D deficiency in early life affects neuronal differentiation, axonal connectivity, dopamine ontogeny and brain structure and function. More recently epidemiological associations have been made between low vitamin D and psychiatric disorders not typically associated with abnormalities in brain development such as depression and Alzheimer's disease. Once again the preclinical findings revealing that vitamin D can regulate catecholamine levels and protect against specific Alzheimer-like pathology increase the plausibility of this link. In this review we have attempted to integrate this clinical epidemiology with potential vitamin D-mediated basic mechanisms. Throughout the review we have highlighted areas where we think future research should focus. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Maturation of metabolic connectivity of the adolescent rat brain

PubMed Central

Choi, Hongyoon; Choi, Yoori; Kim, Kyu Wan; Kang, Hyejin; Hwang, Do Won; Kim, E Edmund; Chung, June-Key; Lee, Dong Soo

2015-01-01

Neuroimaging has been used to examine developmental changes of the brain. While PET studies revealed maturation-related changes, maturation of metabolic connectivity of the brain is not yet understood. Here, we show that rat brain metabolism is reconfigured to achieve long-distance connections with higher energy efficiency during maturation. Metabolism increased in anterior cerebrum and decreased in thalamus and cerebellum during maturation. When functional covariance patterns of PET images were examined, metabolic networks including default mode network (DMN) were extracted. Connectivity increased between the anterior and posterior parts of DMN and sensory-motor cortices during maturation. Energy efficiency, a ratio of connectivity strength to metabolism of a region, increased in medial prefrontal and retrosplenial cortices. Our data revealed that metabolic networks mature to increase metabolic connections and establish its efficiency between large-scale spatial components from childhood to early adulthood. Neurodevelopmental diseases might be understood by abnormal reconfiguration of metabolic connectivity and efficiency. DOI: http://dx.doi.org/10.7554/eLife.11571.001 PMID:26613413

Developmental neurotoxic effects of two pesticides: Behavior and biomolecular studies on chlorpyrifos and carbaryl

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Iwa; Eriksson, Per; Fredriksson, Anders

In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. We studied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brainmore » growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlorpyrifos (0.1, 1.0 or 5 mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0 mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8–12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development. - Highlights: • A single neonatal exposure to chlorpyrifos or carbaryl induced developmental neurotoxic effects. • The neurotoxic effects were not caused by acute AChE inhibition. • The neurotoxic effects manifested as altered levels of neuroproteins in the developing brain. • The neurotoxic effects manifested as adult persistent aberrant behavior and cognitive function. • The neurotoxic effects are suggested to be caused by disrupted brain development.« less

Children with Specific Language Impairment are not impaired in the acquisition and retention of Pavlovian delay and trace conditioning of the eyeblink response☆

PubMed Central

Hardiman, Mervyn J.; Hsu, Hsin-jen; Bishop, Dorothy V.M.

2013-01-01

Three converging lines of evidence have suggested that cerebellar abnormality is implicated in developmental language and literacy problems. First, some brain imaging studies have linked abnormalities in cerebellar grey matter to dyslexia and specific language impairment (SLI). Second, theoretical accounts of both dyslexia and SLI have postulated impairments of procedural learning and automatisation of skills, functions that are known to be mediated by the cerebellum. Third, motor learning has been shown to be abnormal in some studies of both disorders. We assessed the integrity of face related regions of the cerebellum using Pavlovian eyeblink conditioning in 7–11 year-old children with SLI. We found no relationship between oral language skills or literacy skills with either delay or trace conditioning in the children. We conclude that this elementary form of associative learning is intact in children with impaired language or literacy development. PMID:24139661

Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse.

PubMed

Kimura, Eiki; Kubo, Ken-Ichiro; Endo, Toshihiro; Nakajima, Kazunori; Kakeyama, Masaki; Tohyama, Chiharu

2017-01-01

The aryl hydrocarbon receptor (AhR) avidly binds dioxin, a ubiquitous environmental contaminant. Disruption of downstream AhR signaling has been reported to alter neuronal development, and rodent offspring exposed to dioxin during gestation and lactation showed abnormalities in learning and memory, emotion, and social behavior. However, the mechanism behind the disrupted AhR signaling and developmental neurotoxicity induced by xenobiotic ligands remains elusive. Therefore, we studied how excessive AhR activation affects neuronal migration in the hippocampal CA1 region of the developing mouse brain. We transfected constitutively active (CA)-AhR, AhR, or control vector plasmids into neurons via in utero electroporation on gestational day 14 and analyzed neuronal positioning in the hippocampal CA1 region of offspring on postnatal day 14. CA-AhR transfection affected neuronal positioning, whereas no change was observed in AhR-transfected or control hippocampus. These results suggest that constitutively activated AhR signaling disrupts neuronal migration during hippocampal development. Further studies are needed to investigate whether such developmental disruption in the hippocampus leads to the abnormal cognition and behavior of rodent offspring upon maternal exposure to AhR xenobiotic ligands.

Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study.

PubMed

Aly, H; Elmahdy, H; El-Dib, M; Rowisha, M; Awny, M; El-Gohary, T; Elbatch, M; Hamisa, M; El-Mashad, A-R

2015-03-01

Melatonin has been shown to be neuroprotective in animal models. The objective of this study is to examine the effect of melatonin on clinical, biochemical, neurophysiological and radiological outcomes of neonates with hypoxic-ischemic encephalopathy (HIE). We conducted a prospective trial on 45 newborns, 30 with HIE and 15 healthy controls. HIE infants were randomized into: hypothermia group (N=15; received 72-h whole-body cooling) and melatonin/hypothermia group (N=15; received hypothermia and five daily enteral doses of melatonin 10 mg kg(-1)). Serum melatonin, plasma superoxide dismutase (SOD) and serum nitric oxide (NO) were measured at enrollment for all infants (N=45) and at 5 days for the HIE groups (N=30). In addition to electroencephalography (EEG) at enrollment, all surviving HIE infants were studied with brain magnetic resonance imaging (MRI) and repeated EEG at 2 weeks of life. Neurologic evaluations and Denver Developmental Screening Test II were performed at 6 months. Compared with healthy neonates, the two HIE groups had increased melatonin, SOD and NO. At enrollment, the two HIE groups did not differ in clinical, laboratory or EEG findings. At 5 days, the melatonin/hypothermia group had greater increase in melatonin (P<0.001) and decline in NO (P<0.001), but less decline in SOD (P=0.004). The melatonin/hypothermia group had fewer seizures on follow-up EEG and less white matter abnormalities on MRI. At 6 months, the melatonin/hypothermia group had improved survival without neurological or developmental abnormalities (P<0.001). Early administration of melatonin to asphyxiated term neonates is feasible and may ameliorate brain injury.

Neurodevelopmental Hypothesis about the Etiology of Autism Spectrum Disorders

PubMed Central

Inui, Toshio; Kumagaya, Shinichiro; Myowa-Yamakoshi, Masako

2017-01-01

Previous models or hypotheses of autism spectral disorder (ASD) failed to take into full consideration the chronological and causal developmental trajectory, leading to the emergence of diverse phenotypes through a complex interaction between individual etiologies and environmental factors. Those phenotypes include persistent deficits in social communication and social interaction (criteria A in DSM-5), and restricted, repetitive patterns of behavior, interests, or activities (criteria B in DSM-5). In this article, we proposed a domain-general model that can explain criteria in DSM-5 based on the assumption that the same etiological mechanism would trigger the various phenotypes observed in different individuals with ASD. In the model, we assumed the following joint causes as the etiology of autism: (1) Hypoplasia of the pons in the brainstem, occurring immediately following neural tube closure; and (2) Deficiency in the GABA (γ-aminobutyric acid) developmental switch during the perinatal period. Microstructural abnormalities of the pons directly affect both the structural and functional development of the brain areas strongly connected to it, especially amygdala. The impairment of GABA switch could not only lead to the deterioration of inhibitory processing in the neural network, but could also cause abnormal cytoarchitecture. We introduced a perspective that atypical development in both brain structure and function can give full explanation of diverse phenotypes and pathogenetic mechanism of ASD. Finally, we discussed about neural mechanisms underlying the phenotypic characteristics of ASD that are not described in DSM-5 but should be considered as important foundation: sleep, global precedence, categorical perception, intelligence, interoception and motor control. PMID:28744208

Detection and mapping of delays in early cortical folding derived from in utero MRI

NASA Astrophysics Data System (ADS)

Habas, Piotr A.; Rajagopalan, Vidya; Scott, Julia A.; Kim, Kio; Roosta, Ahmad; Rousseau, Francois; Barkovich, A. James; Glenn, Orit A.; Studholme, Colin

2011-03-01

Understanding human brain development in utero and detecting cortical abnormalities related to specific clinical conditions is an important area of research. In this paper, we describe and evaluate methodology for detection and mapping of delays in early cortical folding from population-based studies of fetal brain anatomies imaged in utero. We use a general linear modeling framework to describe spatiotemporal changes in curvature of the developing brain and explore the ability to detect and localize delays in cortical folding in the presence of uncertainty in estimation of the fetal age. We apply permutation testing to examine which regions of the brain surface provide the most statistical power to detect a given folding delay at a given developmental stage. The presented methodology is evaluated using MR scans of fetuses with normal brain development and gestational ages ranging from 20.57 to 27.86 weeks. This period is critical in early cortical folding and the formation of the primary and secondary sulci. Finally, we demonstrate a clinical application of the framework for detection and localization of folding delays in fetuses with isolated mild ventriculomegaly.

Comprehensive Analyses of Molecules with Altered Expression in the Brain of a Mouse Model of Down Syndrome for Identification of Pharmacotherapeutic Targets.

PubMed

Ishihara, Keiichi

2017-01-01

Down syndrome, caused by the triplication of human chromosome 21, is the most frequent genetic cause of mental retardation. Mice with a segmental trisomy for mouse chromosome 16, which is orthologous to human chromosome 21, exhibit abnormalities similar to those in individuals with Down syndrome and therefore offer the opportunity for a genotype-phenotype correlation. In the current review, I present several mouse lines with trisomic regions of various lengths and discuss their usefulness for elucidating the mechanisms underlying Down syndrome-associated developmental cognitive disabilities. In addition, our recent comprehensive study attempting to identify molecules with disturbed expression in the brain of a mouse model of Down syndrome in order to develop a pharmacologic therapy for Down syndrome is described.

Mechanistic Insights into Neurotoxicity Induced by Anesthetics in the Developing Brain

PubMed Central

Lei, Xi; Guo, Qihao; Zhang, Jun

2012-01-01

Compelling evidence has shown that exposure to anesthetics used in the clinic can cause neurodegeneration in the mammalian developing brain, but the basis of this is not clear. Neurotoxicity induced by exposure to anesthestics in early life involves neuroapoptosis and impairment of neurodevelopmental processes such as neurogenesis, synaptogenesis and immature glial development. These effects may subsequently contribute to behavior abnormalities in later life. In this paper, we reviewed the possible mechanisms of anesthetic-induced neurotoxicity based on new in vitro and in vivo findings. Also, we discussed ways to protect against anesthetic-induced neurotoxicity and their implications for exploring cellular and molecular mechanisms of neuroprotection. These findings help in improving our understanding of developmental neurotoxicology and in avoiding adverse neurological outcomes in anesthesia practice. PMID:22837663

Expression and imprinting of MAGEL2 suggest a role in Prader-willi syndrome and the homologous murine imprinting phenotype.

PubMed

Lee, S; Kozlov, S; Hernandez, L; Chamberlain, S J; Brannan, C I; Stewart, C L; Wevrick, R

2000-07-22

Prader-Willi syndrome (PWS) is caused by the loss of expression of imprinted genes in chromosome 15q11-q13. Affected individuals exhibit neonatal hypotonia, developmental delay and childhood-onset obesity. Necdin, a protein implicated in the terminal differentiation of neurons, is the only PWS candidate gene to reduce viability when disrupted in a mouse model. In this study, we have characterized MAGEL2 (also known as NDNL1), a gene with 51% amino acid sequence similarity to necdin and located 41 kb distal to NDN in the PWS deletion region. MAGEL2 is expressed predominantly in brain, the primary tissue affected in PWS and in several fetal tissues as shown by northern blot analysis. MAGEL2 is imprinted with monoallelic expression in control brain, and paternal-only expression in the central nervous system as demonstrated by its lack of expression in brain from a PWS-affected individual. The orthologous mouse gene (Magel2) is located within 150 kb of NDN:, is imprinted with paternal-only expression and is expressed predominantly in late developmental stages and adult brain as shown by northern blotting, RT-PCR and whole-mount RNA in situ hybridization. Magel2 distribution partially overlaps that of NDN:, with strong expression being detected in the central nervous system in mid-gestation mouse embryos by in situ hybridization. We hypothesize that, although loss of necdin expression may be important in the neonatal presentation of PWS, loss of MAGEL2 may be critical to abnormalities in brain development and dysmorphic features in individuals with PWS.

Loss of Cation-Chloride Cotransporter Expression in Preterm Infants With White Matter Lesions: Implications for the Pathogenesis of Epilepsy

PubMed Central

Robinson, Shenandoah; Mikolaenko, Irina; Thompson, Ian; Cohen, Mark L.; Goyal, Monisha

2011-01-01

Epilepsy associated with preterm birth is often refractory to anticonvulsants. Children who are born preterm are also prone to cognitive delay and behavioral problems. Brains from these children often show diffuse abnormalities in cerebral circuitry that is likely caused by disrupted development during critical stages of cortical formation. To test the hypothesis that prenatal injury impairs the developmental switch of γ-amino butyric acid (GABA)ergic synapses from excitatory to inhibitory, thereby disrupting cortical circuit formation and predisposing to epilepsy, we used immunohistochemistry to compare the expression of cation-chloride transporters that developmentally regulate postsynaptic GABAergic discharges in postmortem cerebral samples from infants born preterm with known white matter injury (n = 11) with that of controls with minimal white matter gliosis (n = 7). Controls showed the expected developmental expression of cation-chloride transporters NKCC1 and KCC2 and of calretinin, a marker of a GABAergic neuronal subpopulation. Samples from infants with white matter damage showed a significant loss of expression of both NKCC1 and KCC2 in subplate and white matter. By contrast, there were no significant differences in total cell number or glutamate transporter VGLUT1 expression. Together, these novel findings suggest a molecular mechanism involved in the disruption of a critical stage of cerebral circuit development after brain injury from preterm birth that may predispose to epilepsy. PMID:20467335

Developmental neurotoxicity of monocrotophos and lead is linked to thyroid disruption

PubMed Central

Kumar, B. Kala; Reddy, A. Gopala; Krishna, A. Vamsi; Quadri, S. S. Y. H.; Kumar, P. Shiva

2016-01-01

Aim: A role of thyroid disruption in developmental neurotoxicity of monocrotophos (MCP) and lead is studied. Materials and Methods: A total of 24 female rats after conception were randomized into four groups of six each and treated as follows: Group I - Sham was administered distilled water orally. Group II - A positive control was administered methyl methimazole at 0.02% orally in drinking water. Group III - MCP orally at 0.3 mg/kg and Group IV - Lead acetate at 0.2% orally in drinking water. The drug was administered from gestation day 3 through post-natal day 21 in all the groups. Acetylcholinesterase (AChE) inhibition, thyroid profile (thyroid stimulating hormone, T3 and T4), neurodevelopment (brain wet weights, DNA, RNA and protein), and neurobehavioral (elevated plus maze, photoactometry, and Morris water maze) parameters were assessed in pups. A histopathology of thyroid of dams and brain of progeny was conducted. Results: Inhibition of AChE was <20%. Thyroid profile decreased in the treatment groups. Neurodevelopmental and neurobehavioral parameters did not reveal any significant changes. Thyroid architecture was affected significantly with MCP and lead. Cortical layers too were affected. The three layers of cerebellum either had abnormal arrangement or decreased cellularity in all treated groups relating to thyroid disruption. Conclusion: MCP and lead might have affected the development of cerebrum and cerebellum via thyroid disruption leading to developmental neurotoxicity. PMID:27051198

What Gene Mutations Affect Serotonin in Mice?

PubMed

Tenpenny, Richard C; Commons, Kathryn G

2017-05-17

Although serotonin neurotransmission has been implicated in several neurodevelopmental and psychological disorders, the factors that drive dysfunction of the serotonin system are poorly understood. Current research regarding the serotonin system revolves around its dysfunction in neuropsychiatric disorders, but there is no database collating genetic mutations that result in serotonin abnormalities. To bridge this gap, we developed a list of genes in mice that, when perturbed, result in altered levels of serotonin either in brain or blood. Due to the intrinsic limitations of search, the current list should be considered a preliminary subset of all relevant cases. Nevertheless, it offered an opportunity to gain insight into what types of genes have the potential to impact serotonin by using gene ontology (GO). This analysis found that genes associated with monoamine metabolism were more often associated with increases in brain serotonin than decreases. Speculatively, this could be because several pathways (and therefore many genes) are responsible for the clearance and metabolism of serotonin whereas only one pathway (and therefore fewer genes) is directly involved in the synthesis of serotonin. Another contributor could be cross talk between monoamine systems such as dopamine. In contrast, genes that were associated with decreases in brain serotonin were more likely linked to a developmental process. Sensitivity of serotonin neurons to developmental perturbations could be due to their complicated neuroanatomy or possibly they may be negatively regulated by dysfunction of their innervation targets. Thus, these observations suggest hypotheses regarding the mechanisms underlying the vulnerability of brain serotonin neurotransmission.

Neural Biomarkers for Dyslexia, ADHD, and ADD in the Auditory Cortex of Children.

PubMed

Serrallach, Bettina; Groß, Christine; Bernhofs, Valdis; Engelmann, Dorte; Benner, Jan; Gündert, Nadine; Blatow, Maria; Wengenroth, Martina; Seitz, Angelika; Brunner, Monika; Seither, Stefan; Parncutt, Richard; Schneider, Peter; Seither-Preisler, Annemarie

2016-01-01

Dyslexia, attention deficit hyperactivity disorder (ADHD), and attention deficit disorder (ADD) show distinct clinical profiles that may include auditory and language-related impairments. Currently, an objective brain-based diagnosis of these developmental disorders is still unavailable. We investigated the neuro-auditory systems of dyslexic, ADHD, ADD, and age-matched control children (N = 147) using neuroimaging, magnetencephalography and psychoacoustics. All disorder subgroups exhibited an oversized left planum temporale and an abnormal interhemispheric asynchrony (10-40 ms) of the primary auditory evoked P1-response. Considering right auditory cortex morphology, bilateral P1 source waveform shapes, and auditory performance, the three disorder subgroups could be reliably differentiated with outstanding accuracies of 89-98%. We therefore for the first time provide differential biomarkers for a brain-based diagnosis of dyslexia, ADHD, and ADD. The method allowed not only allowed for clear discrimination between two subtypes of attentional disorders (ADHD and ADD), a topic controversially discussed for decades in the scientific community, but also revealed the potential for objectively identifying comorbid cases. Noteworthy, in children playing a musical instrument, after three and a half years of training the observed interhemispheric asynchronies were reduced by about 2/3, thus suggesting a strong beneficial influence of music experience on brain development. These findings might have far-reaching implications for both research and practice and enable a profound understanding of the brain-related etiology, diagnosis, and musically based therapy of common auditory-related developmental disorders and learning disabilities.

Neural Biomarkers for Dyslexia, ADHD, and ADD in the Auditory Cortex of Children

PubMed Central

Serrallach, Bettina; Groß, Christine; Bernhofs, Valdis; Engelmann, Dorte; Benner, Jan; Gündert, Nadine; Blatow, Maria; Wengenroth, Martina; Seitz, Angelika; Brunner, Monika; Seither, Stefan; Parncutt, Richard; Schneider, Peter; Seither-Preisler, Annemarie

2016-01-01

Dyslexia, attention deficit hyperactivity disorder (ADHD), and attention deficit disorder (ADD) show distinct clinical profiles that may include auditory and language-related impairments. Currently, an objective brain-based diagnosis of these developmental disorders is still unavailable. We investigated the neuro-auditory systems of dyslexic, ADHD, ADD, and age-matched control children (N = 147) using neuroimaging, magnetencephalography and psychoacoustics. All disorder subgroups exhibited an oversized left planum temporale and an abnormal interhemispheric asynchrony (10–40 ms) of the primary auditory evoked P1-response. Considering right auditory cortex morphology, bilateral P1 source waveform shapes, and auditory performance, the three disorder subgroups could be reliably differentiated with outstanding accuracies of 89–98%. We therefore for the first time provide differential biomarkers for a brain-based diagnosis of dyslexia, ADHD, and ADD. The method allowed not only allowed for clear discrimination between two subtypes of attentional disorders (ADHD and ADD), a topic controversially discussed for decades in the scientific community, but also revealed the potential for objectively identifying comorbid cases. Noteworthy, in children playing a musical instrument, after three and a half years of training the observed interhemispheric asynchronies were reduced by about 2/3, thus suggesting a strong beneficial influence of music experience on brain development. These findings might have far-reaching implications for both research and practice and enable a profound understanding of the brain-related etiology, diagnosis, and musically based therapy of common auditory-related developmental disorders and learning disabilities. PMID:27471442

T2 Relaxometry MRI Predicts Cerebral Palsy in Preterm Infants.

PubMed

Chen, L-W; Wang, S-T; Huang, C-C; Tu, Y-F; Tsai, Y-S

2018-01-18

T2-relaxometry brain MR imaging enables objective measurement of brain maturation based on the water-macromolecule ratio in white matter, but the outcome correlation is not established in preterm infants. Our study aimed to predict neurodevelopment with T2-relaxation values of brain MR imaging among preterm infants. From January 1, 2012, to May 31, 2015, preterm infants who underwent both T2-relaxometry brain MR imaging and neurodevelopmental follow-up were retrospectively reviewed. T2-relaxation values were measured over the periventricular white matter, including sections through the frontal horns, midbody of the lateral ventricles, and centrum semiovale. Periventricular T2 relaxometry in relation to corrected age was analyzed with restricted cubic spline regression. Prediction of cerebral palsy was examined with the receiver operating characteristic curve. Thirty-eight preterm infants were enrolled for analysis. Twenty patients (52.6%) had neurodevelopmental abnormalities, including 8 (21%) with developmental delay without cerebral palsy and 12 (31.6%) with cerebral palsy. The periventricular T2-relaxation values in relation to age were curvilinear in preterm infants with normal development, linear in those with developmental delay without cerebral palsy, and flat in those with cerebral palsy. When MR imaging was performed at >1 month corrected age, cerebral palsy could be predicted with T2 relaxometry of the periventricular white matter on sections through the midbody of the lateral ventricles (area under the receiver operating characteristic curve = 0.738; cutoff value of >217.4 with 63.6% sensitivity and 100.0% specificity). T2-relaxometry brain MR imaging could provide prognostic prediction of neurodevelopmental outcomes in premature infants. Age-dependent and area-selective interpretation in preterm brains should be emphasized. © 2018 by American Journal of Neuroradiology.

Developmental antecedents of abnormal eating attitudes and behaviors in adolescence.

PubMed

Le Grange, Daniel; O'Connor, Meredith; Hughes, Elizabeth K; Macdonald, Jacqui; Little, Keriann; Olsson, Craig A

2014-11-01

This study capitalizes on developmental data from an Australian population-based birth cohort to identify developmental markers of abnormal eating attitudes and behaviors in adolescence. The aims were twofold: (1) to develop a comprehensive path model identifying infant and childhood developmental correlates of Abnormal Eating Attitudes and Behaviors in adolescence, and (2) to explore potential gender differences. Data were drawn from a 30-year longitudinal study that has followed the health and development of a population based cohort across 15 waves of data collection from infancy since 1983: The Australian Temperament Project. Participants in this analysis were the 1,300 youth who completed the 11th survey at 15-16 years (1998) and who completed the eating disorder inventory at this time point. Developmental correlates of Abnormal Eating Attitudes and Behaviors in mid-adolescence were temperamental persistence, early gestational age, persistent high weight, teen depression, stronger peer relationships, maternal dieting behavior, and pubertal timing. Overall, these factors accounted for 28% of the variance in Abnormal Eating Attitudes and Behaviors at 15-16 years of age. Depressive symptoms, maternal dieting behavior, and early puberty were more important factors for girls. Late puberty was a more important factor for boys. Findings address an important gap in our understanding of the etiology of Abnormal Eating Attitudes and Behaviors in adolescence and suggest multiple targets for preventive intervention. © 2014 Wiley Periodicals, Inc.

Aberrant Spontaneous and Task-Dependent Functional Connections in the Anxious Brain

PubMed Central

MacNamara, Annmarie; DiGangi, Julia; Phan, K. Luan

2016-01-01

A number of brain regions have been implicated in the anxiety disorders, yet none of these regions in isolation has been distinguished as the sole or discrete site responsible for anxiety disorder pathology. Therefore, the identification of dysfunctional neural networks as represented by alterations in the temporal correlation of blood-oxygen level dependent (BOLD) signal across several brain regions in anxiety disorders has been increasingly pursued in the past decade. Here, we review task-independent (e.g., resting state) and task-induced functional connectivity magnetic resonance imaging (fcMRI) studies in the adult anxiety disorders (including trauma- and stressor-related and obsessive compulsive disorders). The results of this review suggest that anxiety disorder pathophysiology involves aberrant connectivity between amygdala-frontal and frontal-striatal regions, as well as within and between canonical “intrinsic” brain networks - the default mode and salience networks, and that evidence of these aberrations may help inform findings of regional activation abnormalities observed in the anxiety disorders. Nonetheless, significant challenges remain, including the need to better understand mixed findings observed using different methods (e.g., resting state and task-based approaches); the need for more developmental work; the need to delineate disorder-specific and transdiagnostic fcMRI aberrations in the anxiety disorders; and the need to better understand the clinical significance of fcMRI abnormalities. In meeting these challenges, future work has the potential to elucidate aberrant neural networks as intermediate, brain-based phenotypes to predict disease onset and progression, refine diagnostic nosology, and ascertain treatment mechanisms and predictors of treatment response across anxiety, trauma-related and obsessive compulsive disorders. PMID:27141532

Brain structure in sagittal craniosynostosis

NASA Astrophysics Data System (ADS)

Paniagua, Beatriz; Kim, Sunghyung; Moustapha, Mahmoud; Styner, Martin; Cody-Hazlett, Heather; Gimple-Smith, Rachel; Rumple, Ashley; Piven, Joseph; Gilmore, John; Skolnick, Gary; Patel, Kamlesh

2017-03-01

Craniosynostosis, the premature fusion of one or more cranial sutures, leads to grossly abnormal head shapes and pressure elevations within the brain caused by these deformities. To date, accepted treatments for craniosynostosis involve improving surgical skull shape aesthetics. However, the relationship between improved head shape and brain structure after surgery has not been yet established. Typically, clinical standard care involves the collection of diagnostic medical computed tomography (CT) imaging to evaluate the fused sutures and plan the surgical treatment. CT is known to provide very good reconstructions of the hard tissues in the skull but it fails to acquire good soft brain tissue contrast. This study intends to use magnetic resonance imaging to evaluate brain structure in a small dataset of sagittal craniosynostosis patients and thus quantify the effects of surgical intervention in overall brain structure. Very importantly, these effects are to be contrasted with normative shape, volume and brain structure databases. The work presented here wants to address gaps in clinical knowledge in craniosynostosis focusing on understanding the changes in brain volume and shape secondary to surgery, and compare those with normally developing children. This initial pilot study has the potential to add significant quality to the surgical care of a vulnerable patient population in whom we currently have limited understanding of brain developmental outcomes.

Partial duplication of chromosome 19 associated with syndromic duane retraction syndrome.

PubMed

Abu-Amero, Khaled K; Kondkar, Altaf A; Al Otaibi, Abdullah; Alorainy, Ibrahim A; Khan, Arif O; Hellani, Ali M; Oystreck, Darren T; Bosley, Thomas M

2015-03-01

To evaluate possible monogenic and chromosomal anomalies in a patient with unilateral Duane retraction syndrome, modest dysmorphism, cerebral white matter abnormalities, and normal cognitive function. Performing high-resolution array comparative genomic hybridization (array CGH) and sequencing of HOXA1, KIF21A, SALL4, and CHN1 genes. The proband had unilateral Duane retraction syndrome (DRS) type III on the right with low-set ears, prominent forehead, clinodactyly, and a history of frequent infections during early childhood. Motor development and cognitive function were normal. Parents were not related, and no other family member was similarly affected. MRI revealed multiple small areas of high signal on T2 weighted images in cerebral white matter oriented along white matter tracts. Sequencing of HOXA1, KIF21A, SALL4, and CHN1 did not reveal any mutation(s). Array CGH showed a 95 Kb de novo duplication on chromosome 19q13.4 encompassing four killer cell immunoglobulin-like receptor (KIR) genes. Conclusions. KIR genes have not previously been linked to a developmental syndrome, although they are known to be expressed in the human brain and brainstem and to be associated with certain infections and autoimmune diseases, including some affecting the nervous system. DRS and brain neuroimaging abnormalities may imply a central and peripheral oligodendrocyte abnormality related in some fashion to an immunomodulatory disturbance.

Cerebral Developmental Abnormalities in a Mouse with Systemic Pyruvate Dehydrogenase Deficiency

PubMed Central

Pliss, Lioudmila; Hausknecht, Kathryn A.; Stachowiak, Michal K.; Dlugos, Cynthia A.; Richards, Jerry B.; Patel, Mulchand S.

2013-01-01

Pyruvate dehydrogenase (PDH) complex (PDC) deficiency is an inborn error of pyruvate metabolism causing a variety of neurologic manifestations. Systematic analyses of development of affected brain structures and the cellular processes responsible for their impairment have not been performed due to the lack of an animal model for PDC deficiency. METHODS: In the present study we investigated a murine model of systemic PDC deficiency by interrupting the X-linked Pdha1 gene encoding the α subunit of PDH to study its role on brain development and behavioral studies. RESULTS: Male embryos died prenatally but heterozygous females were born. PDC activity was reduced in the brain and other tissues in female progeny compared to age-matched control females. Immunohistochemical analysis of several brain regions showed that approximately 40% of cells were PDH−. The oxidation of glucose to CO2 and incorporation of glucose-carbon into fatty acids were reduced in brain slices from 15 day-old PDC-deficient females. Histological analyses showed alterations in several structures in white and gray matters in 35 day-old PDC-deficient females. Reduction in total cell number and reduced dendritic arbors in Purkinje neurons were observed in PDC-deficient females. Furthermore, cell proliferation, migration and differentiation into neurons by newly generated cells were reduced in the affected females during pre- and postnatal periods. PDC-deficient mice had normal locomotor activity in a novel environment but displayed decreased startle responses to loud noises and there was evidence of abnormal pre-pulse inhibition of the startle reflex. CONCLUSIONS: The results show that a reduction in glucose metabolism resulting in deficit in energy production and fatty acid biosynthesis impairs cellular differentiation and brain development in PDC-deficient mice. PMID:23840713

Converging on a core cognitive deficit: the impact of various neurodevelopmental insults on cognitive control

PubMed Central

O'Reilly, Kally C.; Kao, Hsin-Yi; Lee, Heekyung; Fenton, André A.

2014-01-01

Despite substantial effort and immense need, the treatment options for major neuropsychiatric illnesses like schizophrenia are limited and largely ineffective at improving the most debilitating cognitive symptoms that are central to mental illness. These symptoms include cognitive control deficits, the inability to selectively use information that is currently relevant and ignore what is currently irrelevant. Contemporary attempts to accelerate progress are in part founded on an effort to reconceptualize neuropsychiatric illness as a disorder of neural development. This neuro-developmental framework emphasizes abnormal neural circuits on the one hand, and on the other, it suggests there are therapeutic opportunities to exploit the developmental processes of excitatory neuron pruning, inhibitory neuron proliferation, elaboration of myelination, and other circuit refinements that extend through adolescence and into early adulthood. We have crafted a preclinical research program aimed at cognition failures that may be relevant to mental illness. By working with a variety of neurodevelopmental rodent models, we strive to identify a common pathophysiology that underlies cognitive control failure as well as a common strategy for improving cognition in the face of neural circuit abnormalities. Here we review our work to characterize cognitive control deficits in rats with a neonatal ventral hippocampus lesion and rats that were exposed to Methylazoxymethanol acetate (MAM) in utero. We review our findings as they pertain to early developmental processes, including neurogenesis, as well as the power of cognitive experience to refine neural circuit function within the mature and maturing brain's cognitive circuitry. PMID:24966811

Drugs of abuse in pregnancy, poor neonatal development, and future neurodegeneration. Is oxidative stress the culprit?

PubMed

Neri, Margherita; Bello, Stefania; Turillazzi, Emanuela; Riezzo, Irene

2015-01-01

The abuse of licit and illicit drugs is a worldwide issue that is a cause for concern in pregnant women. It may lead to complications in pregnancy that may affect the mother, fetus, and /or neonate. The effects of any substance on the developing embryo and fetus are dependent upon dosing, timing, duration of drug exposure, and the extent of drug distribution. Teratogenic effects have been described when exposure takes place during the embryonic stage; however drugs have subtle effects, including abnormal growth and/or maturation, alterations in neurotransmitters and their receptors, and brain organization. The mechanisms by which intrauterine exposure to many substances may result in neuronal injury have not been completely elucidated. Oxidative stress and epigenetic changes have been recently implicated in the pathogenesis of long - term adverse health sequelae, and neuro-developmental impairment in the offspring of addicted mothers. Transgenerational epigenetics may also explain the alarming datum that developmental abnormalities, impairment in learning and memory, and attention deficit can occur even in the absence of direct fetal exposure, when drugs are consumed prior to conception. There is a growing body of evidence demonstrating a link between redox state unbalance, epigenetic markers, developmental anomalies, and neurodegeneration. The reviewed literature data uphold redox homeostasis disruption as an important factor in the pathogenesis of drug of abuse- induced neurodegeneration, and highlight the potential for new therapies that could prevent neurodegeneration through antioxidant and epigenetic modulatory mechanisms. This therefore reveals important targets for novel neuroprotective strategies.

The Domain of Developmental Psychopathology.

ERIC Educational Resources Information Center

Sroufe, L. Alan; Rutter, Michael

1984-01-01

Describes how developmental psychopathology differs from related disciplines, including abnormal psychology, psychiatry, clinical child psychology, and developmental psychology. Points out propositions underlying a developmental perspective and discusses implications for research in developmental psychopathology. (Author/RH)

Developmental kinesiology: three levels of motor control in the assessment and treatment of the motor system.

PubMed

Kobesova, Alena; Kolar, Pavel

2014-01-01

Three levels of sensorimotor control within the central nervous system (CNS) can be distinguished. During the neonatal stage, general movements and primitive reflexes are controlled at the spinal and brain stem levels. Analysis of the newborn's spontaneous general movements and the assessment of primitive reflexes is crucial in the screening and early recognition of a risk for abnormal development. Following the newborn period, the subcortical level of the CNS motor control emerges and matures mainly during the first year of life. This allows for basic trunk stabilization, a prerequisite for any phasic movement and for the locomotor function of the extremities. At the subcortical level, orofacial muscles and afferent information are automatically integrated within postural-locomotor patterns. Finally, the cortical (the highest) level of motor control increasingly becomes activated. Cortical control is important for the individual qualities and characteristics of movement. It also allows for isolated segmental movement and relaxation. A child with impaired cortical motor control may be diagnosed with developmental dyspraxia or developmental coordination disorder. Human ontogenetic models, i.e., developmental motor patterns, can be used in both the diagnosis and treatment of locomotor system dysfunction. Copyright © 2013 Elsevier Ltd. All rights reserved.

Theories of autism.

PubMed

Levy, Florence

2007-11-01

The purpose of the present paper was to review psychological theories of autism, and to integrate these theories with neurobiological findings. Cognitive, theory of mind, language and coherence theories were identified, and briefly reviewed. Psychological theories were found not to account for the rigid/repetitive behaviours universally described in autistic subjects, and underlying neurobiological systems were identified. When the developing brain encounters constrained connectivity, it evolves an abnormal organization, the features of which may be best explained by a developmental failure of neural connectivity, where high local connectivity develops in tandem with low long-range connectivity, resulting in constricted repetitive behaviours.

The neurobiology of psychopathy: a neurodevelopmental perspective.

PubMed

Gao, Yu; Glenn, Andrea L; Schug, Robert A; Yang, Yaling; Raine, Adrian

2009-12-01

We provide an overview of the neurobiological underpinnings of psychopathy. Cognitive and affective-emotional processing deficits are associated with abnormal brain structure and function, particularly the amygdala and orbitofrontal cortex. There is limited evidence of lower cortisol levels being associated with psychopathic personality. Initial developmental research is beginning to suggest that these neurobiological processes may have their origins early in life. Findings suggest that psychopathic personality may, in part, have a neurodevelopmental basis. Future longitudinal studies delineating neurobiological correlates of the analogues of interpersonal-affective and antisocial features of psychopathy in children are needed to further substantiate a neurodevelopmental hypothesis of psychopathy.

Chromosomal Aneuploidies and Early Embryonic Developmental Arrest.

PubMed

Maurer, Maria; Ebner, Thomas; Puchner, Manuela; Mayer, Richard Bernhard; Shebl, Omar; Oppelt, Peter; Duba, Hans-Christoph

2015-01-01

Selecting the best embryo for transfer, with the highest chance of achieving a vital pregnancy, is a major goal in current in vitro fertilization (IVF) technology. The high rate of embryonic developmental arrest during IVF treatment is one of the limitations in achieving this goal. Chromosomal abnormalities are possibly linked with chromosomal arrest and selection against abnormal fertilization products. The objective of this study was to evaluate the frequency and type of chromosomal abnormalities in preimplantation embryos with developmental arrest. This cohort study included blastomeres of embryos with early developmental arrest that were biopsied and analyzed by fluorescence in-situ hybridization (FISH) with probes for chromosomes 13, 16, 18, 21 and 22. Forty-five couples undergoing IVF treatment were included, and 119 arrested embryos were biopsied. All probes were obtained from the Kinderwunsch Zentrum, Linz, Austria, between August 2009 and August 2011. Of these embryos, 31.6% were normal for all chromosomes tested, and 68.4% were abnormal. Eleven embryos were uniformly aneuploid, 20 were polyploid, 3 were haploid, 11 displayed mosaicism and 22 embryos exhibited chaotic chromosomal complement. Nearly 70% of arrested embryos exhibit chromosomal errors, making chromosomal abnormalities a major cause of embryonic arrest and may be a further explanation for the high developmental failure rates during culture of the embryos in the IVF setting.

Sociability and synapse subtype-specific defects in mice lacking SRPX2, a language-associated gene

PubMed Central

Cong, Qifei; Palmer, Christian R.

2018-01-01

The FoxP2 transcription factor and its target genes have been implicated in developmental brain diseases with a prominent language component, such as developmental verbal dyspraxia and specific language impairment. How FoxP2 affects neural circuitry development remains poorly understood. The sushi domain protein SRPX2 is a target of FoxP2, and mutations in SRPX2 are associated with language defects in humans. We have previously shown that SRPX2 is a synaptogenic protein that increases excitatory synapse density. Here we provide the first characterization of mice lacking the SRPX2 gene, and show that these mice exhibit defects in both neural circuitry and communication and social behaviors. Specifically, we show that mice lacking SRPX2 show a specific reduction in excitatory VGlut2 synapses in the cerebral cortex, while VGlut1 and inhibitory synapses were largely unaffected. SRPX2 KO mice also exhibit an abnormal ultrasonic vocalization ontogenetic profile in neonatal pups, and reduced preference for social novelty. These data demonstrate a functional role for SRPX2 during brain development, and further implicate FoxP2 and its targets in regulating the development of vocalization and social circuits. PMID:29920554

Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder.

PubMed

Fuchs, Claudia; Rimondini, Roberto; Viggiano, Rocchina; Trazzi, Stefania; De Franceschi, Marianna; Bartesaghi, Renata; Ciani, Elisabetta

2015-10-01

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a rare neurodevelopmental disorder characterized by early-onset seizures, severe developmental delay, intellectual disability and Rett syndrome-like features. CDKL5 is highly expressed in the brain during early postnatal stages, suggesting its importance for brain maturation. Using a newly-generated Cdkl5 knockout (Cdkl5 -/Y) mouse, we recently found that loss of Cdkl5 impairs postnatal hippocampal development with a reduction in neuronal precursor survival and maturation. These defects were accompanied by increased activity of the glycogen synthase kinase 3β (GSK3β) a crucial inhibitory regulator of many neurodevelopmental processes. The goal of the current study was to establish whether inhibition of GSK3β corrects hippocampal developmental defects due to Cdkl5 loss. We found that treatment with the GSK3β inhibitor SB216763 restored neuronal precursor survival, dendritic maturation, connectivity and hippocampus-dependent learning and memory in the Cdkl5 -/Y mouse. Importantly, these effects were retained one month after treatment cessation. At present, there are no therapeutic strategies to improve the neurological defects of subjects with CDKL5 disorder. Current results point at GSK3β inhibitors as potential therapeutic tools for the improvement of abnormal brain development in CDKL5 disorder. Copyright © 2015. Published by Elsevier Inc.

Developmental Ethanol Exposure Leads to Dysregulation of Lipid Metabolism and Oxidative Stress in Drosophila

PubMed Central

Logan-Garbisch, Theresa; Bortolazzo, Anthony; Luu, Peter; Ford, Audrey; Do, David; Khodabakhshi, Payam; French, Rachael L.

2014-01-01

Ethanol exposure during development causes an array of developmental abnormalities, both physiological and behavioral. In mammals, these abnormalities are collectively known as fetal alcohol effects (FAE) or fetal alcohol spectrum disorder (FASD). We have established a Drosophila melanogaster model of FASD and have previously shown that developmental ethanol exposure in flies leads to reduced expression of insulin-like peptides (dILPs) and their receptor. In this work, we link that observation to dysregulation of fatty acid metabolism and lipid accumulation. Further, we show that developmental ethanol exposure in Drosophila causes oxidative stress, that this stress is a primary cause of the developmental lethality and delay associated with ethanol exposure, and, finally, that one of the mechanisms by which ethanol increases oxidative stress is through abnormal fatty acid metabolism. These data suggest a previously uncharacterized mechanism by which ethanol causes the symptoms associated with FASD. PMID:25387828

[Gray matter abnormalities in developmental stuttering determined with voxel-based morphometry].

PubMed

Song, Lu-ping; Peng, Dan-ling; Jin, Zhen; Yao, Li; Ning, Ning; Guo, Xiao-juan; Zhang, Tong

2007-11-06

To investigate the differences of regional grey matter volume between adults with persistent developmental stuttering and fluent speaking adults, and to determine whether stutterers have anomalous anatomy of speech-relevant brain areas that possibly affect speech fluency. High-resolution magnetic resonance imaging (MRI) scanning was performed on 10 adults with developmental stuttering, aged 26 (21 - 35) with the onset age of 4 (3 - 7) and 12 age, sex, hand preference, and education-matched controls. The customized brain templates were created in order to improve spatial normalization and segmentation. Then automated preprocessing of MRI data was conducted using an optimized version of VBM, a fully automated unbiased and objective whole-brain MRI analysis technique. VBM analysis revealed that compared with the controls, the stuttering adults had significant clusters of locally gray matter volume increased in the superior temporal, middle temporal, precentral and postcentral gyrus, and inferior parietal lobule of the bilateral hemisphere (P < 0.001), the numbers of increased gray matter volume in the right and left hemispheres were 60,247 and 48,782 voxels respectively. The, Grey matter decrease was shown with an overall decreased gray matter volume of 32 394 voxels, mainly in the bilateral cerebella posterior lobe and dorsal part of medulla, especially inferior semi-lunar lobule, followed by cerebellar tonsil and bilateral medulla in comparison with the controls (P < 0.001). The reduction of the regional gray matter volume of bilateral cerebella and medulla is related to the neural mechanism of the controlling disorder of speech production and may be the essential cause of stuttering. Some areas with increased gray matter volume in temporal lobe, parietal lobe, and frontal lobe, may be the result of long term functional compensation for the cerebella and medulla function deficiency.

A failure of left temporal cortex to specialize for language is an early emerging and fundamental property of autism

PubMed Central

Pierce, Karen; Courchesne, Eric

2012-01-01

Failure to develop normal language comprehension is an early warning sign of autism, but the neural mechanisms underlying this signature deficit are unknown. This is because of an almost complete absence of functional studies of the autistic brain during early development. Using functional magnetic resonance imaging, we previously observed a trend for abnormally lateralized temporal responses to language (i.e. greater activation on the right, rather than the expected left) in a small sample (n = 12) of sleeping 2–3 year olds with autism in contrast to typically developing children, a finding also reported in autistic adults and adolescents. It was unclear, however, if findings of atypical laterality would be observed in a larger sample, and at even earlier ages in autism, such as around the first birthday. Answers to these questions would provide the foundation for understanding how neurofunctional defects of autism unfold, and provide a foundation for studies using patterns of brain activation as a functional early biomarker of autism. To begin to examine these issues, a prospective, cross-sectional design was used in which brain activity was measured in a large sample of toddlers (n = 80) during the presentation of a bedtime story during natural sleep. Forty toddlers with autism spectrum disorder and 40 typically developing toddlers ranging in age between 12–48 months participated. Any toddler with autism who participated in the imaging experiment prior to final diagnosis was tracked and diagnoses confirmed at a later age. Results indicated that at-risk toddlers later diagnosed as autistic display deficient left hemisphere response to speech sounds and have abnormally right-lateralized temporal cortex response to language; this defect worsens with age, becoming most severe in autistic 3- and 4-year-olds. Typically developing children show opposite developmental trends with a tendency towards greater temporal cortex response with increasing age and maintenance of left-lateralized activation with age. We have now demonstrated lateralized abnormalities of temporal cortex processing of language in autism across two separate samples, including a large sample of young infants who later are diagnosed with autism, suggesting that this pattern may reflect a fundamental early neural developmental pathology in autism. PMID:22350062

Neurodevelopmental Reflex Testing in Neonatal Rat Pups.

PubMed

Nguyen, Antoinette T; Armstrong, Edward A; Yager, Jerome Y

2017-04-24

Neurodevelopmental reflex testing is commonly used in clinical practice to assess the maturation of the nervous system. Neurodevelopmental reflexes are also referred to as primitive reflexes. They are sensitive and consistent with later outcomes. Abnormal reflexes are described as an absence, persistence, reappearance, or latency of reflexes, which are predictive indices of infants that are at high risk for neurodevelopmental disorders. Animal models of neurodevelopmental disabilities, such as cerebral palsy, often display aberrant developmental reflexes, as would be observed in human infants. The techniques described assess a variety of neurodevelopmental reflexes in neonatal rats. Neurodevelopmental reflex testing offers the investigator a testing method that is not otherwise available in such young animals. The methodology presented here aims to assist investigators in examining developmental milestones in neonatal rats as a method of detecting early-onset brain injury and/or determining the effectiveness of therapeutic interventions. The methodology presented here aims to provide a general guideline for investigators.

Direct brain recordings reveal impaired neural function in infants with single-suture craniosynostosis: a future modality for guiding management?

PubMed

Hashim, Peter W; Brooks, Eric D; Persing, John A; Reuman, Hannah; Naples, Adam; Travieso, Roberto; Terner, Jordan; Steinbacher, Derek; Landi, Nicole; Mayes, Linda; McPartland, James C

2015-01-01

Patients with single-suture craniosynostosis (SSC) are at an elevated risk for long-term learning disabilities. Such adverse outcomes indicate that the early development of neural processing in SSC may be abnormal. At present, however, the precise functional derangements of the developing brain remain largely unknown. Event-related potentials (ERPs) are a form of noninvasive neuroimaging that provide direct measurements of cortical activity and have shown value in predicting long-term cognitive functioning. The current study used ERPs to examine auditory processing in infants with SSC to help clarify the developmental onset of delays in this population. Fifteen infants with untreated SSC and 23 typically developing controls were evaluated. ERPs were recorded during the presentation of speech sounds. Analyses focused on the P150 and N450 components of auditory processing. Infants with SSC demonstrated attenuated P150 amplitudes relative to typically developing controls. No differences in the N450 component were identified between untreated SSC and controls. Infants with untreated SSC demonstrate abnormal speech sound processing. Atypicalities are detectable as early as 6 months of age and may represent precursors to long-term language delay. Electrophysiological assessments provide a precise examination of neural processing in SSC and hold potential as a future modality to examine the effects of surgical treatment on brain development.

The Utility of Chromosomal Microarray Analysis in Developmental and Behavioral Pediatrics

ERIC Educational Resources Information Center

Beaudet, Arthur L.

2013-01-01

Chromosomal microarray analysis (CMA) has emerged as a powerful new tool to identify genomic abnormalities associated with a wide range of developmental disabilities including congenital malformations, cognitive impairment, and behavioral abnormalities. CMA includes array comparative genomic hybridization (CGH) and single nucleotide polymorphism…

Dandy-Walker malformation: analysis of 19 cases.

PubMed

Alexiou, George A; Sfakianos, George; Prodromou, Neofytos

2010-02-01

Dandy-Walker malformation is a congenital disorder that involves the cerebellum and fourth ventricle. Regarding treatment, there is still controversy over the optimum surgical management. In the current study, we present 19 consecutive cases of Dandy-Walker malformation diagnosed between January 1992 and January 2008 that were treated in our institute. All patients presented with hydrocephalus at the time of diagnosis and were treated surgically. Combined drainage of the ventricular system and posterior fossa cyst, using a 3-way connector was performed in 5 patients. Posterior fossa cyst drainage alone was performed in 10 patients and the remaining 4 patients were treated by ventricular drainage alone. All patients improved after treatment. Dandy-Walker malformation is a developmental abnormality of the central nervous system associated with various brain and extracranial abnormalities. Surgical treatment remains controversial, whereas prognosis varies greatly according to the severity of syndrome and associated comorbidities.

Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders.

PubMed

Zhao, Y; Fung, C; Shin, D; Shin, B-C; Thamotharan, S; Sankar, R; Ehninger, D; Silva, A; Devaskar, S U

2010-03-01

Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristics of autism spectrum disorders. This clinical presentation occurred despite metabolic adaptations consisting of an increase in microvascular/glial GLUT1, neuronal GLUT8 and monocarboxylate transporter isoform 2 concentrations, with minimal to no change in brain glucose uptake but an increase in lactate uptake. Neuron-specific glucose deficiency has a negative impact on neurodevelopment interfering with functional competence. This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans.

Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.

PubMed

Gripp, Karen W; Zand, Dina J; Demmer, Laurie; Anderson, Carol E; Dobyns, William B; Zackai, Elaine H; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L; Sol-Church, Katia

2013-10-01

Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. Copyright © 2013 Wiley Periodicals, Inc.

Prevalence of prenatal brain abnormalities in fetuses with congenital heart disease: a systematic review.

PubMed

Khalil, A; Bennet, S; Thilaganathan, B; Paladini, D; Griffiths, P; Carvalho, J S

2016-09-01

Studies have shown an association between congenital heart defects (CHDs) and postnatal brain abnormalities and neurodevelopmental delay. Recent evidence suggests that some of these brain abnormalities are present before birth. The primary aim of this study was to perform a systematic review to quantify the prevalence of prenatal brain abnormalities in fetuses with CHDs. MEDLINE, EMBASE and The Cochrane Library were searched electronically. Reference lists within each article were hand-searched for additional reports. The outcomes observed included structural brain abnormalities (on magnetic resonance imaging (MRI)) and changes in brain volume (on MRI, three-dimensional (3D) volumetric MRI, 3D ultrasound and phase-contrast MRI), brain metabolism or maturation (on magnetic resonance spectroscopy and phase-contrast MRI) and brain blood flow (on Doppler ultrasound, phase-contrast MRI and 3D power Doppler ultrasound) in fetuses with CHDs. Cohort and case-control studies were included and cases of chromosomal or genetic abnormalities, case reports and editorials were excluded. Proportion meta-analysis was used for analysis. Between-study heterogeneity was assessed using the I(2) test. The search yielded 1943 citations, and 20 studies (n = 1175 cases) were included in the review. Three studies reported data on structural brain abnormalities, while data on altered brain volume, metabolism and blood flow were reported in seven, three and 14 studies, respectively. The three studies (221 cases) reporting on structural brain abnormalities were suitable for inclusion in a meta-analysis. The prevalence of prenatal structural brain abnormalities in fetuses with CHD was 28% (95% CI, 18-40%), with a similar prevalence (25% (95% CI, 14-39%)) when tetralogy of Fallot was considered alone. These abnormalities included ventriculomegaly (most common), agenesis of the corpus callosum, ventricular bleeding, increased extra-axial space, vermian hypoplasia, white-matter abnormalities and delayed brain development. Fetuses with CHD were more likely than those without CHD to have reduced brain volume, delay in brain maturation and altered brain circulation, most commonly in the form of reduced middle cerebral artery pulsatility index and cerebroplacental ratio. These changes were usually evident in the third trimester, but some studies reported them from as early as the second trimester. In the absence of known major aneuploidy or genetic syndromes, fetuses with CHD are at increased risk of brain abnormalities, which are discernible prenatally. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

The motivation for very early intervention for infants at high risk for autism spectrum disorders.

PubMed

Webb, Sara Jane; Jones, Emily J H; Kelly, Jean; Dawson, Geraldine

2014-02-01

The first Autism Research Matrix (IACC, 2003) listed the identification of behavioural and biological markers of risk for autism as a top priority. This emphasis was based on the hypothesis that intervention with infants at-risk, at an early age when the brain is developing and before core autism symptoms have emerged, could significantly alter the developmental trajectory of children at risk for the disorder and impact long-range outcome. Research has provided support for specific models of early autism intervention (e.g., Early Start Denver Model) for improving outcomes in young children with autism, based on both behavioural and brain activity measures. Although great strides have been made in ability to identify risk markers for autism in younger infant/toddler samples, how and when to intervene during the prodromal state remains a critical question. Emerging evidence suggests that abnormal brain circuitry in autism precedes altered social behaviours; thus, an intervention designed to promote early social engagement and reciprocity potentially could steer brain development back toward the normal trajectory and remit or reduce the expression of symptoms.

Cranial thickness changes in early childhood

NASA Astrophysics Data System (ADS)

Gajawelli, Niharika; Deoni, Sean; Shi, Jie; Dirks, Holly; Linguraru, Marius George; Nelson, Marvin D.; Wang, Yalin; Lepore, Natasha

2017-11-01

The neurocranium changes rapidly in early childhood to accommodate the developing brain. However, developmental disorders may cause abnormal growth of the neurocranium, the most common one being craniosynostosis, affecting about 1 in 2000 children. It is important to understand how the brain and neurocranium develop together to understand the role of the neurocranium in neurodevelopmental outcomes. However, the neurocranium is not as well studied as the human brain in early childhood, due to a lack of imaging data. CT is typically employed to investigate the cranium, but, due to ionizing radiation, may only be used for clinical cases. However, the neurocranium is also visible on magnetic resonance imaging (MRI). Here, we used a large dataset of MRI images from healthy children in the age range of 1 to 2 years old and extracted the neurocranium. A conformal geometry based analysis pipeline is implemented to determine a set of statistical atlases of the neurocranium. A growth model of the neurocranium will help us understand cranial bone and suture development with respect to the brain, which will in turn inform better treatment strategies for neurocranial disorders.

Prenatal alcohol exposure affects vasculature development in the neonatal brain.

PubMed

Jégou, Sylvie; El Ghazi, Faiza; de Lendeu, Pamela Kwetieu; Marret, Stéphane; Laudenbach, Vincent; Uguen, Arnaud; Marcorelles, Pascale; Roy, Vincent; Laquerrière, Annie; Gonzalez, Bruno José

2012-12-01

In humans, antenatal alcohol exposure elicits various developmental disorders, in particular in the brain. Numerous studies focus on the deleterious effects of alcohol on neural cells. Although recent studies suggest that alcohol can affect angiogenesis in adults, the impact of prenatal alcohol exposure on brain microvasculature remains poorly understood. We used a mouse model to investigate effects of prenatal alcohol exposure on the cortical microvascular network in vivo and ex vivo and the action of alcohol, glutamate, and vascular endothelial growth factor A (VEGF) on activity, plasticity, and survival of microvessels. We used quantitative reverse transcriptase polymerase chain reaction, Western blot, immunohistochemistry, calcimetry, and videomicroscopy. We characterized the effect of prenatal alcohol exposure on the cortical microvascular network in human controls and fetal alcohol syndrome (FAS)/partial FAS (pFAS) patients at different developmental stages. In mice, prenatal alcohol exposure induced a reduction of cortical vascular density, loss of the radial orientation of microvessels, and altered expression of VEGF receptors. Time-lapse experiments performed on brain slices revealed that ethanol inhibited glutamate-induced calcium mobilization in endothelial cells, affected plasticity, and promoted death of microvessels. These effects were prevented by VEGF. In humans, we evidenced a stage-dependent alteration of the vascular network in the cortices of fetuses with pFAS/FAS. Whereas no modification was observed from gestational week 20 (WG20) to WG22, the radial organization of cortical microvessels was clearly altered in pFAS/FAS patients from WG30 to WG38. Prenatal alcohol exposure affects cortical angiogenesis both in mice and in pFAS/FAS patients, suggesting that vascular defects contribute to alcohol-induced brain abnormalities. Copyright © 2012 American Neurological Association.

Effects of 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) injected into the yolks of chicken (Gallus domesticus) eggs prior to incubation

USGS Publications Warehouse

Powell, D.C.; Aulerich, R.J.; Meadows, J.C.; Tillitt, D.E.; Giesy, J.P.; Stromborg, K.L.; Bursian, S.J.

1996-01-01

The yolks of White Leghorn chicken (Gallus domesticus) eggs were injected prior to incubation with either 3,3′,4,4′,5- pentachlorobiphenyl (PCB 126) at doses ranging from 0.1 to 12.8 μg/kg egg or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at doses ranging from 0.04 to 0.64 μg/kg egg. Chicks were subjected to necropsy within 24 h of hatching. The brain, bursa, heart, liver, and spleen were removed and weighed. Assessment of the rate of hatching indicated an LD50±S.E. of 2.3±0.19 μg/kg egg (7.1±0.58 nmol/kg egg) for PCB 126 and 0.15±0.012 μg/kg egg (0.47±0.037 nmol/kg egg) for TCDD. No significant differences in the incidence of developmental abnormalities (structural defects and edema) were observed in TCDD-exposed embryos, while PCB 126 caused significantly more developmental abnormalities at 3.2, 6.4, and 12.8 μg/kg egg than the vehicle control. PCB 126 caused lower hatchling weights and greater relative brain, heart, and liver weights when compared to the vehicle control group at a dose of 3.2 μg/kg egg which is greater than the LD50. TCDD at 0.08 μg/kg egg caused relative bursa weights to be less than those of the vehicle control. A toxic equivalency factor (TEF) of 0.07 was determined for PCB 126 in relation to TCDD based on overt lethality.

Low nitric oxide: a key factor underlying copper-deficiency teratogenicity.

PubMed

Yang, Soo Jin; Keen, Carl L; Lanoue, Louise; Rucker, Robert B; Uriu-Adams, Janet Y

2007-12-15

Copper (Cu)-deficiency-induced teratogenicity is characterized by major cardiac, brain, and vascular anomalies; however, the underlying mechanisms are poorly understood. Cu deficiency decreases superoxide dismutase activity and increases superoxide anions, which can interact with nitric oxide (NO), reducing the NO pool size. Given the role of NO as a developmental signaling molecule, we tested the hypothesis that low NO levels, secondary to Cu deficiency, represent a developmental challenge. Gestation day 8.5 embryos from Cu-adequate (Cu+) or Cu-deficient (Cu-) dams were cultured for 48 h in Cu+ or Cu- medium, respectively. We report that NO levels were low in conditioned medium from Cu-/Cu- embryos and yolk sacs, compared to Cu+/Cu+ controls under basal conditions and with NO synthase (NOS) agonists. The low NO production was associated with low endothelial NOS phosphorylation at serine 1177 and cyclic guanosine-3',5'-monophosphate (cGMP) concentrations in the Cu-/Cu- group. The altered NO levels in Cu-deficient embryos are functionally significant, as the administration of the NO donor DETA/NONOate increased cGMP and ameliorated embryo and yolk sac abnormalities. These data support the concept that Cu deficiency limits NO availability and alters NO-dependent signaling, which contributes to abnormal embryo and yolk sac development.

Low nitric oxide: a key factor underlying copper deficiency teratogenicity

PubMed Central

Yang, Soo Jin; Keen, Carl L.; Lanoue, Louise; Rucker, Robert B.; Uriu-Adams, Janet Y.

2008-01-01

Copper (Cu) deficiency-induced teratogenicity is characterized by major cardiac, brain and vascular anomalies, however, the underlying mechanisms are poorly understood. Cu deficiency decreases superoxide dismutase activity, and increases superoxide anions which can interact with nitric oxide (NO), reducing the NO pool size. Given the role of NO as a developmental signaling molecule, we tested the hypothesis that low NO levels, secondary to Cu deficiency, represent a developmental challenge. Gestation day 8.5 embryos from Cu adequate (Cu+) or Cu deficient (Cu−) dams were cultured for 48 h in Cu+ or Cu− medium, respectively. We report that NO levels were low in conditioned media from Cu−/Cu− embryos and yolk sacs, compared to Cu+/Cu+ controls under basal conditions, and with NO synthase (NOS) agonists. The low NO production was associated with low endothelial NOS phosphorylation at serine 1177 and cyclic guanosine-3′,5′-monophosphate (cGMP) concentrations in the Cu−/Cu− group. The altered NO levels in Cu deficient embryos are functionally significant, as the administration of the NO donor, DETA/NONOate, increased cGMP and ameliorated embryo and yolk sac abnormalities. These data support the concept that Cu deficiency limits NO availability and alters NO-dependent signaling which contributes to abnormal embryo and yolk sac development. PMID:18037129

Larval Red Drum (Sciaenops ocellatus) Sublethal Exposure to Weathered Deepwater Horizon Crude Oil: Developmental and Transcriptomic Consequences.

PubMed

Xu, Elvis Genbo; Khursigara, Alex J; Magnuson, Jason; Hazard, E Starr; Hardiman, Gary; Esbaugh, Andrew J; Roberts, Aaron P; Schlenk, Daniel

2017-09-05

The Deepwater Horizon (DWH) incident resulted in extensive oiling of the pelagic zone and shoreline habitats of many commercially important fish species. Exposure to the water-accommodated fraction (WAF) of oil from the spill causes developmental toxicity through cardiac defects in pelagic fish species. However, few studies have evaluated the effects of the oil on near-shore estuarine fish species such as red drum (Sciaenops ocellatus). Following exposure to a certified weathered slick oil (4.74 μg/L ∑PAH 50 ) from the DWH event, significant sublethal impacts were observed ranging from impaired nervous system development [average 17 and 22% reductions in brain and eye area at 48 h postfertilization (hpf), respectively] to abnormal cardiac morphology (100% incidence at 24, 48, and 72 hpf) in red drum larvae. Consistent with the phenotypic responses, significantly differentially expressed transcripts, enriched gene ontology, and altered functions and canonical pathways predicted adverse outcomes in nervous and cardiovascular systems, with more pronounced changes at later larval stages. Our study demonstrated that the WAF of weathered slick oil of DWH caused morphological abnormalities predicted by a suite of advanced bioinformatic tools in early developing red drum and also provided the basis for a better understanding of molecular mechanisms of crude oil toxicity in fish.

The Interplay between Emotion and Cognition in Autism Spectrum Disorder: Implications for Developmental Theory

PubMed Central

Gaigg, Sebastian B.

2012-01-01

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is clinically defined by abnormalities in reciprocal social and communicative behaviors and an inflexible adherence to routinised patterns of thought and behavior. Laboratory studies repeatedly demonstrate that autistic individuals experience difficulties in recognizing and understanding the emotional expressions of others and naturalistic observations show that they use such expressions infrequently and inappropriately to regulate social exchanges. Dominant theories attribute this facet of the ASD phenotype to abnormalities in a social brain network that mediates social-motivational and social-cognitive processes such as face processing, mental state understanding, and empathy. Such theories imply that only emotion related processes relevant to social cognition are compromised in ASD but accumulating evidence suggests that the disorder may be characterized by more widespread anomalies in the domain of emotions. In this review I summarize the relevant literature and argue that the social-emotional characteristics of ASD may be better understood in terms of a disruption in the domain-general interplay between emotion and cognition. More specifically I will suggest that ASD is the developmental consequence of early emerging anomalies in how emotional responses to the environment modulate a wide range of cognitive processes including those that are relevant to navigating the social world. PMID:23316143

Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment

PubMed Central

Celen, Cemre; Chuang, Jen-Chieh; Luo, Xin; Nijem, Nadine; Walker, Angela K; Chen, Fei; Zhang, Shuyuan; Chung, Andrew S; Nguyen, Liem H; Nassour, Ibrahim; Budhipramono, Albert; Sun, Xuxu; Bok, Levinus A; McEntagart, Meriel; Gevers, Evelien F; Birnbaum, Shari G; Eisch, Amelia J; Powell, Craig M; Ge, Woo-Ping; Santen, Gijs WE; Chahrour, Maria; Zhu, Hao

2017-01-01

Sequencing studies have implicated haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al., 2013). We generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified Insulin-like growth factor (IGF1) deficiency with inadequate compensation by Growth hormone-releasing hormone (GHRH) and Growth hormone (GH), underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders, and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling. DOI: http://dx.doi.org/10.7554/eLife.25730.001 PMID:28695822

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces apoptotic cell death and cytochrome P4501A expression in developing Fundulus heteroclitus embryos

USGS Publications Warehouse

Toomey, B.H.; Bello, S.; Hahn, M.E.; Cantrell, S.; Wright, P.; Tillitt, D.E.; Di Giulio, R.T.

2001-01-01

Fundulus heteroclitus embryos were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early development using nanoinjection or water bath exposure. TCDD caused developmental abnormalities that included hemorrhaging, loss of vascular integrity, edema, stunted development and death. The LC50 and LD50 of TCDD for Fundulus embryos were ???19.7??9.5 pg TCDD/??l (water bath) and 0.25??0.09 ng TCDD/g embryo (nanoinjection). To identify a possible cause for these developmental abnormalities we analyzed the effects of TCDD on apoptotic cell death and cytochrome P4501A (CYP1A) expression in the embryos. TCDD exposure increased apoptotic cell death in several tissues including brain, eye, gill, kidney, tail, intestine, heart, and vascular tissue. CYP1A expression was also increased in the TCDD-exposed embryos predominantly in liver, kidney, gill, heart, intestine, and in vascular tissues throughout the embryo. There was co-occurrence of TCDD-induced apoptosis and CYP1A expression in some, but not all, cell types. In addition the dose response relationships for apoptosis and mortality were similar, while CYP1A expression appeared more sensitive to TCDD induction. Copyright ?? 2001 Elsevier Science B.V.

The Interplay between Emotion and Cognition in Autism Spectrum Disorder: Implications for Developmental Theory.

PubMed

Gaigg, Sebastian B

2012-01-01

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is clinically defined by abnormalities in reciprocal social and communicative behaviors and an inflexible adherence to routinised patterns of thought and behavior. Laboratory studies repeatedly demonstrate that autistic individuals experience difficulties in recognizing and understanding the emotional expressions of others and naturalistic observations show that they use such expressions infrequently and inappropriately to regulate social exchanges. Dominant theories attribute this facet of the ASD phenotype to abnormalities in a social brain network that mediates social-motivational and social-cognitive processes such as face processing, mental state understanding, and empathy. Such theories imply that only emotion related processes relevant to social cognition are compromised in ASD but accumulating evidence suggests that the disorder may be characterized by more widespread anomalies in the domain of emotions. In this review I summarize the relevant literature and argue that the social-emotional characteristics of ASD may be better understood in terms of a disruption in the domain-general interplay between emotion and cognition. More specifically I will suggest that ASD is the developmental consequence of early emerging anomalies in how emotional responses to the environment modulate a wide range of cognitive processes including those that are relevant to navigating the social world.

Neural signature of developmental coordination disorder in the structural connectome independent of comorbid autism.

PubMed

Caeyenberghs, Karen; Taymans, Tom; Wilson, Peter H; Vanderstraeten, Guy; Hosseini, Hadi; van Waelvelde, Hilde

2016-07-01

Children with autism spectrum disorders (ASD) often exhibit motor clumsiness (Developmental Coordination Disorder, DCD), i.e. they struggle with everyday tasks that require motor coordination like dressing, self-care, and participating in sport and leisure activities. Previous studies in these neurodevelopmental disorders have demonstrated functional abnormalities and alterations of white matter microstructural integrity in specific brain regions. These findings suggest that the global organization of brain networks is affected in DCD and ASD and support the hypothesis of a 'dys-connectivity syndrome' from a network perspective. No studies have compared the structural covariance networks between ASD and DCD in order to look for the signature of DCD independent of comorbid autism. Here, we aimed to address the question of whether abnormal connectivity in DCD overlaps that seen in autism or comorbid DCD-autism. Using graph theoretical analysis, we investigated differences in global and regional topological properties of structural brain networks in 53 children: 8 ASD children with DCD (DCD+ASD), 15 ASD children without DCD (ASD), 11 with DCD only, and 19 typically developing (TD) children. We constructed separate structural correlation networks based on cortical thickness derived from Freesurfer. The children were assessed on the Movement-ABC and the Beery Test of Visual Motor Integration. Behavioral results demonstrated that the DCD group and DCD+ASD group scored on average poorer than the TD and ASD groups on various motor measures. Furthermore, although the brain networks of all groups exhibited small-world properties, the topological architecture of the networks was significantly altered in children with ASD compared with DCD and TD. ASD children showed increased normalized path length and higher values of clustering coefficient. Also, paralimbic regions exhibited nodal clustering coefficient alterations in singular disorders. These changes were disorder-specific, and included alterations in clustering coefficient in the isthmus of the right cingulate gyrus and the pars orbitalis of the right inferior frontal gyrus in ASD children, and DCD-related increases in the lateral orbitofrontal cortex. Children meeting criteria for both DCD and ASD exhibited topological changes that were more widespread from those seen in children with only DCD, i.e. children with DCD+ASD showed alterations of clustering coefficient in (para)limbic regions, primary areas, and association areas. The DCD+ASD group showed changes in clustering coefficient in the left association cortex relative to the ASD group. Finally, the DCD+ASD group shared ASD-specific abnormalities in the pars orbitalis of right inferior frontal gyrus, which was hypothesized to reflect atypical emotional-cognitive processing. Our results provide evidence that DCD and ASD are neurodevelopmental disorders with a low degree of overlap in abnormalities in connectivity. The co-occurrence of DCD+ASD was also associated with a distinct topological pattern, highlighting the unique neural signature of comorbid neurodevelopmental disorders. © 2016 John Wiley & Sons Ltd.

Common genetic variants influence human subcortical brain structures.

PubMed

Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M; Weale, Michael E; Weinberger, Daniel R; Adams, Hieab H H; Launer, Lenore J; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L; Becker, James T; Yanek, Lisa; van der Lee, Sven J; Ebling, Maritza; Fischl, Bruce; Longstreth, W T; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N; van Duijn, Cornelia M; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M Arfan; Martin, Nicholas G; Wright, Margaret J; Schumann, Gunter; Franke, Barbara; Thompson, Paul M; Medland, Sarah E

2015-04-09

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Chromosomal Aneuploidies and Early Embryonic Developmental Arrest

PubMed Central

Maurer, Maria; Ebner, Thomas; Puchner, Manuela; Mayer, Richard Bernhard; Shebl, Omar; Oppelt, Peter; Duba, Hans-Christoph

2015-01-01

Background Selecting the best embryo for transfer, with the highest chance of achieving a vital pregnancy, is a major goal in current in vitro fertilization (IVF) technology. The high rate of embryonic developmental arrest during IVF treatment is one of the limitations in achieving this goal. Chromosomal abnormalities are possibly linked with chromosomal arrest and selection against abnormal fertilization products. The objective of this study was to evaluate the frequency and type of chromosomal abnormalities in preimplantation embryos with developmental arrest. Materials and Methods This cohort study included blastomeres of embryos with early developmental arrest that were biopsied and analyzed by fluorescence in-situ hybridization (FISH) with probes for chromosomes 13, 16, 18, 21 and 22. Forty-five couples undergoing IVF treatment were included, and 119 arrested embryos were biopsied. All probes were obtained from the Kinderwunsch Zentrum, Linz, Austria, between August 2009 and August 2011. Results Of these embryos, 31.6% were normal for all chromosomes tested, and 68.4% were abnormal. Eleven embryos were uniformly aneuploid, 20 were polyploid, 3 were haploid, 11 displayed mosaicism and 22 embryos exhibited chaotic chromosomal complement. Conclusion Nearly 70% of arrested embryos exhibit chromosomal errors, making chromosomal abnormalities a major cause of embryonic arrest and may be a further explanation for the high developmental failure rates during culture of the embryos in the IVF setting. PMID:26644858

Preserved local but disrupted contextual figure-ground influences in an individual with abnormal function of intermediate visual areas

PubMed Central

Brooks, Joseph L.; Gilaie-Dotan, Sharon; Rees, Geraint; Bentin, Shlomo; Driver, Jon

2012-01-01

Visual perception depends not only on local stimulus features but also on their relationship to the surrounding stimulus context, as evident in both local and contextual influences on figure-ground segmentation. Intermediate visual areas may play a role in such contextual influences, as we tested here by examining LG, a rare case of developmental visual agnosia. LG has no evident abnormality of brain structure and functional neuroimaging showed relatively normal V1 function, but his intermediate visual areas (V2/V3) function abnormally. We found that contextual influences on figure-ground organization were selectively disrupted in LG, while local sources of figure-ground influences were preserved. Effects of object knowledge and familiarity on figure-ground organization were also significantly diminished. Our results suggest that the mechanisms mediating contextual and familiarity influences on figure-ground organization are dissociable from those mediating local influences on figure-ground assignment. The disruption of contextual processing in intermediate visual areas may play a role in the substantial object recognition difficulties experienced by LG. PMID:22947116

Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency

PubMed Central

Stephen, Joshi; Vilboux, Thierry; Mian, Luhe; Kuptanon, Chulaluck; Sinclair, Courtney M.; Yildirimli, Deniz; Maynard, Dawn M.; Bryant, Joy; Fischer, Roxanne; Vemulapalli, Meghana; Mullikin, James C.; Huizing, Marjan; Gahl, William A.

2017-01-01

Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic “molar tooth sign” on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients’ fibroblasts. PMID:28220259

Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency.

PubMed

Stephen, Joshi; Vilboux, Thierry; Mian, Luhe; Kuptanon, Chulaluck; Sinclair, Courtney M; Yildirimli, Deniz; Maynard, Dawn M; Bryant, Joy; Fischer, Roxanne; Vemulapalli, Meghana; Mullikin, James C; Huizing, Marjan; Gahl, William A; Malicdan, May Christine V; Gunay-Aygun, Meral

2017-04-01

Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic "molar tooth sign" on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients' fibroblasts.

[Amblyopia].

PubMed

Orssaud, C

2014-06-01

Amblyopia is a developmental disorder of the entire visual system, including the extra-striate cortex. It manifests mainly by impaired visual acuity in the amblyopic eye. However, other abnormalities of visual function can be observed, such as decreased contrast sensitivity and stereoscopic vision, and some abnormalities can be found in the "good" eye. Amblyopia occurs during the critical period of brain development. It may be due to organic pathology of the visual pathways, visual deprivation or functional abnormalities, mainly anisometropia or strabismus. The diagnosis of amblyopia must be confirmed prior to treatment. Confirmation is based on cycloplegic refraction, visual acuity measurement and orthoptic assessment. However, screening for amblyopia and associated risk factors permits earlier diagnosis and treatment. The younger the child, the more effective the treatment, and it can only be achieved during the critical period. It requires parental cooperation in order to be effective and is based on occlusion or penalization of the healthy eye. The amblyopic eye may then develop better vision. Maintenance therapy must be performed until the end of the critical period to avoid recurrence. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

The interaction between maternal immune activation and alpha 7 nicotinic acetylcholine receptor in regulating behaviors in the offspring

PubMed Central

Wu, Wei-Li; Adams, Catherine E.; Stevens, Karen E.; Chow, Ke-Huan; Freedman, Robert; Patterson, Paul H.

2015-01-01

Mutation of human chromosome 15q13.3 increases the risk for autism and schizophrenia. One of the noteworthy genes in 15q13.3 is CHRNA7, which encodes the nicotinic acetylcholine receptor alpha 7 subunit (α7nAChR) associated with schizophrenia in clinical studies and rodent models. This study investigates the role of α7nAChR in maternal immune activation (MIA) mice model, a murine model of environmental risk factor for autism and schizophrenia. We provided choline, a selective α7nAChR agonist among its several developmental roles, in the diet of C57BL/6N wild-type dams throughout the gestation and lactation period and induced MIA at mid-gestation. The adult offspring behavior and gene expression profile in the maternal spleen-placenta-fetal brain axis at mid-gestation were investigated. We found that choline supplementation prevented several MIA-induced behavioral abnormalities in the wild-type offspring. Pro-inflammatory cytokine interleukin-6 (IL-6) and Chrna7 gene expression in the wild-type fetal brain were elevated by poly(I:C) injection and were suppressed by gestational choline supplementation. We further investigated the gene expression level of IL-6 in Chrna7 mutant mice. We found that the basal level of IL-6 was higher in Chrna7 mutant fetal brain, which suggests that α7nAChR may serve an anti-inflammatory role in the fetal brain during development. Lastly, we induced MIA in Chrna7+/− offspring. The Chrna7+/− offspring were more vulnerable to MIA, with increased behavioral abnormalities. Our study shows that α7nAChR modulates inflammatory response affecting the fetal brain and demonstrates its effects on offspring behavior development after MIA. PMID:25683697

Fetal and Neonatal Iron Deficiency Exacerbates Mild Thyroid Hormone Insufficiency Effects on Male Thyroid Hormone Levels and Brain Thyroid Hormone-Responsive Gene Expression

PubMed Central

Bastian, Thomas W.; Prohaska, Joseph R.; Georgieff, Michael K.

2014-01-01

Fetal/neonatal iron (Fe) and iodine/TH deficiencies lead to similar brain developmental abnormalities and often coexist in developing countries. We recently demonstrated that fetal/neonatal Fe deficiency results in a mild neonatal thyroidal impairment, suggesting that TH insufficiency contributes to the neurodevelopmental abnormalities associated with Fe deficiency. We hypothesized that combining Fe deficiency with an additional mild thyroidal perturbation (6-propyl-2-thiouracil [PTU]) during development would more severely impair neonatal thyroidal status and brain TH-responsive gene expression than either deficiency alone. Early gestation pregnant rats were assigned to 7 different treatment groups: control, Fe deficient (FeD), mild TH deficient (1 ppm PTU), moderate TH deficient (3 ppm PTU), severe TH deficient (10 ppm PTU), FeD/1 ppm PTU, or FeD/3 ppm PTU. FeD or 1 ppm PTU treatment alone reduced postnatal day 15 serum total T4 concentrations by 64% and 74%, respectively, without significantly altering serum total T3 concentrations. Neither treatment alone significantly altered postnatal day 16 cortical or hippocampal T3 concentrations. FeD combined with 1 ppm PTU treatment produced a more severe effect, reducing serum total T4 by 95%, and lowering hippocampal and cortical T3 concentrations by 24% and 31%, respectively. Combined FeD/PTU had a more severe effect on brain TH-responsive gene expression than either treatment alone, significantly altering Pvalb, Dio2, Mbp, and Hairless hippocampal and/or cortical mRNA levels. FeD/PTU treatment more severely impacted cortical and hippocampal parvalbumin protein expression compared with either individual treatment. These data suggest that combining 2 mild thyroidal insults during development significantly disrupts thyroid function and impairs TH-regulated brain gene expression. PMID:24424046

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

PubMed Central

Falgoust, Lindsay; Pan, Jullie W.; Sun, Dandan; Zhang, Zhongling

2016-01-01

Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid–base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na+/H+ exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H+ in exchange for Na+ influx. Altering NHE function significantly influences neuronal excitability and plays a role in epilepsy. This review gives an overview of pH regulatory mechanisms in the brain with a special focus on the NHE family and the relationship between epilepsy and dysfunction of NHE isoforms. We first discuss how cells translocate acids and bases across the membrane and establish pH homeostasis as a result of the concerted effort of enzymes and ion transporters. We focus on the specific roles of the NHE family by detailing how the loss of NHE1 in two NHE mutant mice results in enhanced neuronal excitability in these animals. Furthermore, we highlight new findings on the link between mutations of NHE6 and NHE9 and developmental brain disorders including epilepsy, autism, and attention deficit hyperactivity disorder (ADHD). These studies demonstrate the importance of NHE proteins in maintaining H+ homeostasis and their intricate roles in the regulation of neuronal function. A better understanding of the mechanisms underlying NHE1, 6, and 9 dysfunctions in epilepsy formation may advance the development of new epilepsy treatment strategies. PMID:26965387

Expression pattern of the thrombopoietin receptor (Mpl) in the murine central nervous system.

PubMed

Ivanova, Anna; Wuerfel, Jens; Zhang, Juan; Hoffmann, Olaf; Ballmaier, Matthias; Dame, Christof

2010-07-28

Thrombopoietin (Thpo) and its receptor (Mpl), which regulate megakaryopoiesis, are expressed in the central nervous system (CNS), where Thpo is thought to exert pro-apoptotic effects on newly generated neurons. Mpl expression has been analysed in brain tissue on transcript level and in cultured primary rat neurons and astrocytes on protein level. Herein, we analysed Mpl expression in the developing and adult murine CNS by immunohistochemistry and investigated the brain of mice with homozygous Mpl deficiency (Mpl-/-) by MRI. Mpl was not detectable at developmental stages E12 to E15 in any resident cells of the CNS. From E18 onwards, robust Mpl expression was found in various brain areas, including cerebral cortex, olfactory bulb, thalamus, hypothalamus, medulla, pons, and the grey matter of spinal cord. However, major developmental changes became obvious: In the subventricular zone of the cerebral cortex Mpl expression occurred only during late gestation, while in the hippocampus Mpl expression was detectable for first time at stage P4. In the white matter of the cerebellum Mpl expression was restricted to the perinatal period. In the adult cerebellum, Mpl expression switched to Purkinje cell. The majority of other Mpl-positive cells were NeuN-positive neurons. None of the cells could be double-labelled with astrocyte marker GFAP. Mpl-/- mice showed no gross abnormalities of the brain. Our data locate Mpl expression to neurons at different subdivisions of the spinal cord, rhombencephalon, midbrain and prosencephalon. Besides neuronal cells Mpl protein is also expressed in Purkinje cells of the adult cerebellum.

Emerging roles of Na⁺/H⁺ exchangers in epilepsy and developmental brain disorders.

PubMed

Zhao, Hanshu; Carney, Karen E; Falgoust, Lindsay; Pan, Jullie W; Sun, Dandan; Zhang, Zhongling

2016-01-01

Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid-base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na(+)/H(+) exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H(+) in exchange for Na(+) influx. Altering NHE function significantly influences neuronal excitability and plays a role in epilepsy. This review gives an overview of pH regulatory mechanisms in the brain with a special focus on the NHE family and the relationship between epilepsy and dysfunction of NHE isoforms. We first discuss how cells translocate acids and bases across the membrane and establish pH homeostasis as a result of the concerted effort of enzymes and ion transporters. We focus on the specific roles of the NHE family by detailing how the loss of NHE1 in two NHE mutant mice results in enhanced neuronal excitability in these animals. Furthermore, we highlight new findings on the link between mutations of NHE6 and NHE9 and developmental brain disorders including epilepsy, autism, and attention deficit hyperactivity disorder (ADHD). These studies demonstrate the importance of NHE proteins in maintaining H(+) homeostasis and their intricate roles in the regulation of neuronal function. A better understanding of the mechanisms underlying NHE1, 6, and 9 dysfunctions in epilepsy formation may advance the development of new epilepsy treatment strategies. Published by Elsevier Ltd.

Pericentric inversion of chromosome 11 (p14.3q21) associated with developmental delays, hypopigmented skin lesions and abnormal brain MRI findings - a new case report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zachor, D.A.; Lofton, M.

1994-09-01

We report 3 year old male, referred for evaluation of developmental delays. Pregnancy was complicated by oligohydramnios, proteinuria and prematurity. Medical history revealed: bilateral inguinal hernia, small scrotal sac, undescended testes, developmental delays and behavioral problems. The child had: microcephaly, facial dysmorphic features, single palmar creases, hypopigmented skin lesions of variable size, intermittent exotropia and small retracted testes. Neurological examination was normal. Cognitive level was at the average range with mild delay in his adaptive behavior. Expressive language delays and severe articulation disorder were noted, as well as clumsiness, poor control and precision of gross and fine motor skills. Chromosomalmore » analysis of peripheral leukocytes indicated that one of the number 11 chromosomes had undergone a pericentric inversion with breakpoints on the short (p) arm at band p14.3 and the long (q) arm at band q21. An MRI of the brain showed mild delay in myelinization pattern of white matter. Chromosome 11 inversion in other sites was associated with Beckwith-Wiedemann syndrome and several malignancies. To our knowledge this is the first description of inv(11)(p14.3q21) that is associated with microcephaly, dysmorphic features, hypopigmented skin lesions and speech delay. This inversion may disrupt the expression of the involved genes. However, additional cases with the same cytogenetic anomaly are needed to explore the phenotypic significance of this disorder.« less

Clinical Correlation between Perverted Nystagmus and Brain MRI Abnormal Findings

PubMed Central

Han, Won-Gue; Yoon, Hee-Chul; Kim, Tae-Min; Rah, Yoon Chan

2016-01-01

Background and Objectives To analyze the clinical correlation between perverted nystagmus and brain magnetic resonance imaging (MRI) abnormal findings and to evaluate whether perverted nystagmus is clinically significant results of brain abnormal lesions or not. Subjects and Methods We performed medical charts review from January 2008 to July 2014, retrospectively. Patients who were suspected central originated vertigo at Frenzel goggles test were included among patients who visited our hospital. To investigate the correlation with nystagmus suspected central originated vertigo and brain MRI abnormal findings, we confirmed whether performing brain MRI or not. Then we exclude that patients not performed brain MRI. Results The number of patients with perverted nystagmus was 15, upbeating was 1 and down-beating was 14. Among these patients, 5 patients have brain MRI abnormal findings. However, 2 patients with MRI abnormal findings were not associated correctly with perverted nystagmus and only 3 patients with perverted nystagmus were considered central originated vertigo and further evaluation and treatment was performed by the department of neurology. Conclusions Perverted nystagmus was considered to the abnormalities at brain lesions, especially cerebellum, but neurologic symptoms and further evaluation were needed for exact diagnosis of central originated vertigo. PMID:27626081

Altered retrieval of melodic information in congenital amusia: insights from dynamic causal modeling of MEG data.

PubMed

Albouy, Philippe; Mattout, Jérémie; Sanchez, Gaëtan; Tillmann, Barbara; Caclin, Anne

2015-01-01

Congenital amusia is a neuro-developmental disorder that primarily manifests as a difficulty in the perception and memory of pitch-based materials, including music. Recent findings have shown that the amusic brain exhibits altered functioning of a fronto-temporal network during pitch perception and short-term memory. Within this network, during the encoding of melodies, a decreased right backward frontal-to-temporal connectivity was reported in amusia, along with an abnormal connectivity within and between auditory cortices. The present study investigated whether connectivity patterns between these regions were affected during the short-term memory retrieval of melodies. Amusics and controls had to indicate whether sequences of six tones that were presented in pairs were the same or different. When melodies were different only one tone changed in the second melody. Brain responses to the changed tone in "Different" trials and to its equivalent (original) tone in "Same" trials were compared between groups using Dynamic Causal Modeling (DCM). DCM results confirmed that congenital amusia is characterized by an altered effective connectivity within and between the two auditory cortices during sound processing. Furthermore, right temporal-to-frontal message passing was altered in comparison to controls, with notably an increase in "Same" trials. An additional analysis in control participants emphasized that the detection of an unexpected event in the typically functioning brain is supported by right fronto-temporal connections. The results can be interpreted in a predictive coding framework as reflecting an abnormal prediction error sent by temporal auditory regions towards frontal areas in the amusic brain.

Brain Dysplasia Associated with Ciliary Dysfunction In Infants with Congenital Heart Disease

PubMed Central

Panigrahy, Ashok; Lee, Vincent; Ceschin, Rafael; Zuccoli, Giulio; Beluk, Nancy; Khalifa, Omar; Votava-Smith, Jodie K; DeBrunner, Mark; Munoz, Ricardo; Domnina, Yuliya; Morell, Victor; Wearden, Peter; De Toledo, Joan Sanchez; Devine, William; Zahid, Maliha; Lo, Cecilia W.

2016-01-01

Objective To test for associations between abnormal respiratory ciliary motion (CM) and brain abnormalities in infants with congenital heart disease (CHD) Study design We recruited 35 infants with CHD preoperatively and performed nasal tissue biopsy to assess respiratory CM by videomicroscopy. Cranial ultrasound and brain magnetic resonance imaging were obtained pre- and/or post-operatively and systematically reviewed for brain abnormalities. Segmentation was used to quantitate cerebrospinal fluid and regional brain volumes. Perinatal and perioperative clinical variables were collected. Results A total of 10 (28.5%) patients with CHD had abnormal CM. Abnormal CM was not associated with brain injury, but was correlated with increased extra-axial CSF volume (p<0.001), delayed brain maturation (p<0.05), and a spectrum of subtle dysplasia including the hippocampus (p<0.0078) and olfactory bulb (p<0.034). Abnormal CM was associated with higher composite dysplasia score (p<0.001) and both were correlated with elevated pre-operative serum lactate (p <0.001). Conclusion Abnormal respiratory CM in infants with CHD is associated with a spectrum of brain dysplasia. These findings suggest that ciliary defects may play a role in brain dysplasia in patients with CHD and have the potential to prognosticate neurodevelopmental risks. PMID:27574995

Differentiation of Speech Delay and Global Developmental Delay in Children Using DTI Tractography-Based Connectome.

PubMed

Jeong, J-W; Sundaram, S; Behen, M E; Chugani, H T

2016-06-01

Pure speech delay is a common developmental disorder which, according to some estimates, affects 5%-8% of the population. Speech delay may not only be an isolated condition but also can be part of a broader condition such as global developmental delay. The present study investigated whether diffusion tensor imaging tractography-based connectome can differentiate global developmental delay from speech delay in young children. Twelve children with pure speech delay (39.1 ± 20.9 months of age, 9 boys), 14 children with global developmental delay (39.3 ± 18.2 months of age, 12 boys), and 10 children with typical development (38.5 ± 20.5 months of age, 7 boys) underwent 3T DTI. For each subject, whole-brain connectome analysis was performed by using 116 cortical ROIs. The following network metrics were measured at individual regions: strength (number of the shortest paths), efficiency (measures of global and local integration), cluster coefficient (a measure of local aggregation), and betweeness (a measure of centrality). Compared with typical development, global and local efficiency were significantly reduced in both global developmental delay and speech delay (P < .0001). The nodal strength of the cognitive network is reduced in global developmental delay, whereas the nodal strength of the language network is reduced in speech delay. This finding resulted in a high accuracy of >83% ± 4% to discriminate global developmental delay from speech delay. The network abnormalities identified in the present study may underlie the neurocognitive and behavioral consequences commonly identified in children with global developmental delay and speech delay. Further validation studies in larger samples are required. © 2016 by American Journal of Neuroradiology.

Inhibitors of choline uptake and metabolism cause developmental abnormalities in neurulating mouse embryos.

PubMed

Fisher, M C; Zeisel, S H; Mar, M H; Sadler, T W

2001-08-01

Choline is an essential nutrient in methylation, acetylcholine and phospholipid biosynthesis, and in cell signaling. The demand by an embryo or fetus for choline may place a pregnant woman and, subsequently, the developing conceptus at risk for choline deficiency. To determine whether a disruption in choline uptake and metabolism results in developmental abnormalities, early somite staged mouse embryos were exposed in vitro to either an inhibitor of choline uptake and metabolism, 2-dimethylaminoethanol (DMAE), or an inhibitor of phosphatidylcholine synthesis, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH(3)). Cell death following inhibitor exposure was investigated with LysoTracker Red and histology. Embryos exposed to 250-750 microM DMAE for 26 hr developed craniofacial hypoplasia and open neural tube defects in the forebrain, midbrain, and hindbrain regions. Embryos exposed to 125-275 microM ET-18-OCH(3) exhibited similar defects or expansion of the brain vesicles. ET-18-OCH(3)-affected embryos also had a distended neural tube at the posterior neuropore. Embryonic growth was reduced in embryos treated with either DMAE (375, 500, and 750 microM) or ET-18-OCH(3) (200 and 275 microM). Whole mount staining with LysoTracker Red and histological sections showed increased areas of cell death in embryos treated with 275 microM ET-18-OCH(3) for 6 hr, but there was no evidence of cell death in DMAE-exposed embryos. Inhibition of choline uptake and metabolism during neurulation results in growth retardation and developmental defects that affect the neural tube and face. Copyright 2001 Wiley-Liss, Inc.

Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders.

PubMed

Paterson, Clare; Wang, Yanhong; Hyde, Thomas M; Weinberger, Daniel R; Kleinman, Joel E; Law, Amanda J

2017-03-01

Genes implicated in schizophrenia are enriched in networks differentially regulated during human CNS development. Neuregulin 3 (NRG3), a brain-enriched neurotrophin, undergoes alternative splicing and is implicated in several neurological disorders with developmental origins. Isoform-specific increases in NRG3 are observed in schizophrenia and associated with rs10748842, a NRG3 risk polymorphism, suggesting NRG3 transcriptional dysregulation as a molecular mechanism of risk. The authors quantitatively mapped the temporal trajectories of NRG3 isoforms (classes I-IV) in the neocortex throughout the human lifespan, examined whether tissue-specific regulation of NRG3 occurs in humans, and determined if abnormalities in NRG3 transcriptomics occur in mood disorders and are genetically determined. NRG3 isoform classes I-IV were quantified using quantitative real-time polymerase chain reaction in human postmortem dorsolateral prefrontal cortex from 286 nonpsychiatric control individuals, from gestational week 14 to 85 years old, and individuals diagnosed with either bipolar disorder (N=34) or major depressive disorder (N=69). Tissue-specific mapping was investigated in several human tissues. rs10748842 was genotyped in individuals with mood disorders, and association with NRG3 isoform expression examined. NRG3 classes displayed individually specific expression trajectories across human neocortical development and aging; classes I, II, and IV were significantly associated with developmental stage. NRG3 class I was increased in bipolar and major depressive disorder, consistent with observations in schizophrenia. NRG3 class II was increased in bipolar disorder, and class III was increased in major depression. The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3. Mapping the temporal expression of genes during human brain development provides vital insight into gene function and identifies critical sensitive periods whereby genetic factors may influence risk for psychiatric disease. Here the authors provide comprehensive insight into the transcriptional landscape of the psychiatric risk gene, NRG3, in human neocortical development and expand on previous findings in schizophrenia to identify increased expression of developmentally and genetically regulated isoforms in the brain of patients with mood disorders. Principally, the finding that NRG3 classes II and III are brain-specific isoforms predicted by rs10748842 risk genotype and are increased in mood disorders further implicates a molecular mechanism of psychiatric risk at the NRG3 locus and identifies a potential developmental role for NRG3 in bipolar disorder and major depression. These observations encourage investigation of the neurobiology of NRG3 isoforms and highlight inhibition of NRG3 signaling as a potential target for psychiatric treatment development.

Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders

PubMed Central

Paterson, Clare; Wang, Yanhong; Hyde, Thomas M.; Weinberger, Daniel R.; Kleinman, Joel E.; Law, Amanda J.

2018-01-01

Objective Genes implicated in schizophrenia are enriched in networks differentially regulated during human CNS development. Neuregulin 3 (NRG3), a brain-enriched neurotrophin, undergoes alternative splicing and is implicated in several neurological disorders with developmental origins. Isoform-specific increases in NRG3 are observed in schizophrenia and associated with rs10748842, a NRG3 risk polymorphism, suggesting NRG3 transcriptional dysregulation as a molecular mechanism of risk. The authors quantitatively mapped the temporal trajectories of NRG3 isoforms (classes I–IV) in the neocortex throughout the human lifespan, examined whether tissue-specific regulation of NRG3 occurs in humans, and determined if abnormalities in NRG3 transcriptomics occur in mood disorders and are genetically determined. Method NRG3 isoform classes I–IV were quantified using quantitative real-time polymerase chain reaction in human postmortem dorsolateral prefrontal cortex from 286 nonpsychiatric control individuals, from gestational week 14 to 85 years old, and individuals diagnosed with either bipolar disorder (N=34) or major depressive disorder (N=69). Tissue-specific mapping was investigated in several human tissues. rs10748842 was genotyped in individuals with mood disorders, and association with NRG3 isoform expression examined. Results NRG3 classes displayed individually specific expression trajectories across human neocortical development and aging; classes I, II, and IV were significantly associated with developmental stage. NRG3 class I was increased in bipolar and major depressive disorder, consistent with observations in schizophrenia. NRG3 class II was increased in bipolar disorder, and class III was increased in major depression. The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3. Conclusions Mapping the temporal expression of genes during human brain development provides vital insight into gene function and identifies critical sensitive periods whereby genetic factors may influence risk for psychiatric disease. Here the authors provide comprehensive insight into the transcriptional landscape of the psychiatric risk gene, NRG3, in human neocortical development and expand on previous findings in schizophrenia to identify increased expression of developmentally and genetically regulated isoforms in the brain of patients with mood disorders. Principally, the finding that NRG3 classes II and III are brain-specific isoforms predicted by rs10748842 risk genotype and are increased in mood disorders further implicates a molecular mechanism of psychiatric risk at the NRG3 locus and identifies a potential developmental role for NRG3 in bipolar disorder and major depression. These observations encourage investigation of the neurobiology of NRG3 isoforms and highlight inhibition of NRG3 signaling as a potential target for psychiatric treatment development. PMID:27771971

Perinatal Influences of Valproate on Brain and Behaviour: An Animal Model for Autism.

PubMed

Ranger, Peter; Ellenbroek, Bart A

Valproic acid or valproate (VPA) is an anti-convulsant and mood stabiliser effective in treating epilepsy and bipolar disorders. Although in adults VPA is well tolerated and safe, there is convincing evidence that it has teratogenic properties, ranging from mild neurodevelopmental changes to severe congenital malformations. In particular, studies involving humans and other animals have shown that prenatal exposure to VPA can induce developmental abnormalities reminiscent of autism spectrum disorder (ASD). In this chapter, we discuss the connection between VPA and ASD, evaluate the VPA animal model of ASD, and describe the possible molecular mechanisms underlying VPA's teratogenic properties.

The Translational Role of Diffusion Tensor Image Analysis in Animal Models of Developmental Pathologies

PubMed Central

Oguz, Ipek; McMurray, Matthew S.; Styner, Martin; Johns, Josephine M.

2013-01-01

Diffusion Tensor Magnetic Resonance Imaging (DTI) has proven itself a powerful technique for clinical investigation of the neurobiological targets and mechanisms underlying developmental pathologies. The success of DTI in clinical studies has demonstrated its great potential for understanding translational animal models of clinical disorders, and preclinical animal researchers are beginning to embrace this new technology to study developmental pathologies. In animal models, genetics can be effectively controlled, drugs consistently administered, subject compliance ensured, and image acquisition times dramatically increased to reduce between-subject variability and improve image quality. When pairing these strengths with the many positive attributes of DTI, such as the ability to investigate microstructural brain organization and connectivity, it becomes possible to delve deeper into the study of both normal and abnormal development. The purpose of this review is to provide new preclinical investigators with an introductory source of information about the analysis of data resulting from small animal DTI studies to facilitate the translation of these studies to clinical data. In addition to an in depth review of translational analysis techniques, we present a number of relevant clinical and animal studies using DTI to investigate developmental insults in order to further illustrate techniques and to highlight where small animal DTI could potentially provide a wealth of translational data to inform clinical researchers. PMID:22627095

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure.

PubMed

Gavin, David P; Grayson, Dennis R; Varghese, Sajoy P; Guizzetti, Marina

2017-05-11

Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure. Prenatal alcohol exposure influences neuronal and astrocyte development, permanently altering brain connectivity. Prenatal alcohol exposure also alters chromatin structure through histone and DNA modifications. However, the data linking alcohol-induced differentiation changes with developmental alterations in chromatin structure remain to be elucidated. In the first part of this review, we discuss the sequence of chromatin structural changes involved in neural cell differentiation during normal development. We then discuss the effects of prenatal alcohol on developmental histone modifications and DNA methylation in the context of neurogenesis and astrogliogenesis. We attempt to synthesize the developmental literature with the FASD literature, proposing that alcohol-induced changes to chromatin structure account for altered neurogenesis and astrogliogenesis as well as altered neuron and astrocyte differentiation. Together these changes may contribute to the cognitive and behavioral abnormalities in FASD. Future studies using standardized alcohol exposure paradigms at specific developmental stages will advance the understanding of how chromatin structural changes impact neural cell fate and maturation in FASD.

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure

PubMed Central

Gavin, David P.; Grayson, Dennis R.; Varghese, Sajoy P.; Guizzetti, Marina

2017-01-01

Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure. Prenatal alcohol exposure influences neuronal and astrocyte development, permanently altering brain connectivity. Prenatal alcohol exposure also alters chromatin structure through histone and DNA modifications. However, the data linking alcohol-induced differentiation changes with developmental alterations in chromatin structure remain to be elucidated. In the first part of this review, we discuss the sequence of chromatin structural changes involved in neural cell differentiation during normal development. We then discuss the effects of prenatal alcohol on developmental histone modifications and DNA methylation in the context of neurogenesis and astrogliogenesis. We attempt to synthesize the developmental literature with the FASD literature, proposing that alcohol-induced changes to chromatin structure account for altered neurogenesis and astrogliogenesis as well as altered neuron and astrocyte differentiation. Together these changes may contribute to the cognitive and behavioral abnormalities in FASD. Future studies using standardized alcohol exposure paradigms at specific developmental stages will advance the understanding of how chromatin structural changes impact neural cell fate and maturation in FASD. PMID:28492482

Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry

NASA Astrophysics Data System (ADS)

Ateca-Cabarga, Juan C.; Cosa, Alejandro; Pallarés, Vicente; López-Atalaya, José P.; Barco, Ángel; Canals, Santiago; Moratal, David

2015-11-01

The Rubinstein-Taybi Syndrome (RSTS) is a congenital disease that affects brain development causing severe cognitive deficits. In most cases the disease is associated with dominant mutations in the gene encoding the CREB binding protein (CBP). In this work, we present the first quantitative analysis of brain abnormalities in a mouse model of RSTS using magnetic resonance imaging (MRI) and two novel self-developed automated algorithms for image volumetric analysis. Our results quantitatively confirm key syndromic features observed in RSTS patients, such as reductions in brain size (-16.31%, p < 0.05), white matter volume (-16.00%, p < 0.05), and corpus callosum (-12.40%, p < 0.05). Furthermore, they provide new insight into the developmental origin of the disease. By comparing brain tissues in a region by region basis between cbp+/- and cbp+/+ littermates, we found that cbp haploinsufficiency is specifically associated with significant reductions in prosencephalic tissue, such us in the olfactory bulb and neocortex, whereas regions evolved from the embryonic rhombencephalon were spared. Despite the large volume reductions, the proportion between gray-, white-matter and cerebrospinal fluid were conserved, suggesting a role of CBP in brain size regulation. The commonalities with holoprosencephaly and arhinencephaly conditions suggest the inclusion of RSTS in the family of neuronal migration disorders.

The brain finger protein gene (ZNF179), a member of the RING finger family, maps within the Smith-Magenis syndrome region at 17p11.2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kimura, Toshiyuki; Arakawa, Yoshiki; Inazawa, Johji

1997-03-31

Smith-Magenis syndrome (SAIS) is caused by a microdeletion of 17p11.2 and comprises developmental and growth delay, facial abnormalities, unusual behavior and sleep problems. This phenotype may be due to haploinsufficiency of several contiguous genes. The human brain finger protein gene (ZNF179), a member of the RING finger protein family, has been isolated and mapped to l7p11.2. FISH analyses of metaphase or interphase chromosomes of 6 patients with SMS show that ZNF179 was deleted in one of the 2 homologs (17p11.2), indicating a possible association of the defect of this gene with the pathogenesis of SMS. Furthermore, using a prophase FISHmore » ordering system, we sublocalized ZNF179 proximally to LLGL which lies on the critical region for SMS. 27 refs., 2 figs.« less

A review of brain circuitries involved in stuttering

PubMed Central

Craig-McQuaide, Anna; Akram, Harith; Zrinzo, Ludvic; Tripoliti, Elina

2014-01-01

Stuttering has been the subject of much research, nevertheless its etiology remains incompletely understood. This article presents a critical review of the literature on stuttering, with particular reference to the role of the basal ganglia (BG). Neuroimaging and lesion studies of developmental and acquired stuttering, as well as pharmacological and genetic studies are discussed. Evidence of structural and functional changes in the BG in those who stutter indicates that this motor speech disorder is due, at least in part, to abnormal BG cues for the initiation and termination of articulatory movements. Studies discussed provide evidence of a dysfunctional hyperdopaminergic state of the thalamocortical pathways underlying speech motor control in stuttering. Evidence that stuttering can improve, worsen or recur following deep brain stimulation for other indications is presented in order to emphasize the role of BG in stuttering. Further research is needed to fully elucidate the pathophysiology of this speech disorder, which is associated with significant social isolation. PMID:25452719

Drugs of abuse that cause developing neurons to commit suicide.

PubMed

Farber, Nuri B; Olney, John W

2003-12-30

When neuronal activity is abnormally suppressed during the developmental period of synaptogenesis, the timing and sequence of synaptic connections is disrupted, and this causes nerve cells to receive an internal signal to commit suicide, a form of cell death known as "apoptosis". By altering glutamate and GABA transmission alcohol suppresses neuronal activity, causing millions of nerve cells to commit suicide in the developing brain. This proapoptotic effect of alcohol provides a likely explanation for the diminished brain size and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome. These findings have public health significance, not only in relation to fetal alcohol syndrome, but also in relation to several other drugs of abuse and various drugs used in obstetric and pediatric medicine, because these additional drugs (e.g. phencyclidine, ketamine, benzodiazepines, barbiturates) also suppress neuronal activity and drive developing neurons to commit suicide.

Developmentally stable whole-brain volume reductions and developmentally sensitive caudate and putamen volume alterations in those with attention-deficit/hyperactivity disorder and their unaffected siblings.

PubMed

Greven, Corina U; Bralten, Janita; Mennes, Maarten; O'Dwyer, Laurence; van Hulzen, Kimm J E; Rommelse, Nanda; Schweren, Lizanne J S; Hoekstra, Pieter J; Hartman, Catharina A; Heslenfeld, Dirk; Oosterlaan, Jaap; Faraone, Stephen V; Franke, Barbara; Zwiers, Marcel P; Arias-Vasquez, Alejandro; Buitelaar, Jan K

2015-05-01

Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder. It has been linked to reductions in total brain volume and subcortical abnormalities. However, owing to heterogeneity within and between studies and limited sample sizes, findings on the neuroanatomical substrates of ADHD have shown considerable variability. Moreover, it remains unclear whether neuroanatomical alterations linked to ADHD are also present in the unaffected siblings of those with ADHD. To examine whether ADHD is linked to alterations in whole-brain and subcortical volumes and to study familial underpinnings of brain volumetric alterations in ADHD. In this cross-sectional study, we included participants from the large and carefully phenotyped Dutch NeuroIMAGE sample (collected from September 2009-December 2012) consisting of 307 participants with ADHD, 169 of their unaffected siblings, and 196 typically developing control individuals (mean age, 17.21 years; age range, 8-30 years). Whole-brain volumes (total brain and gray and white matter volumes) and volumes of subcortical regions (nucleus accumbens, amygdala, caudate nucleus, globus pallidus, hippocampus, putamen, thalamus, and brainstem) were derived from structural magnetic resonance imaging scans using automated tissue segmentation. Regression analyses revealed that relative to control individuals, participants with ADHD had a 2.5% smaller total brain (β = -31.92; 95% CI, -52.69 to -11.16; P = .0027) and a 3% smaller total gray matter volume (β = -22.51; 95% CI, -35.07 to -9.96; P = .0005), while total white matter volume was unaltered (β = -10.10; 95% CI, -20.73 to 0.53; P = .06). Unaffected siblings had total brain and total gray matter volumes intermediate to participants with ADHD and control individuals. Significant age-by-diagnosis interactions showed that older age was linked to smaller caudate (P < .001) and putamen (P = .01) volumes (both corrected for total brain volume) in control individuals, whereas age was unrelated to these volumes in participants with ADHD and their unaffected siblings. Attention-deficit/hyperactivity disorder was not significantly related to the other subcortical volumes. Global differences in gray matter volume may be due to alterations in the general mechanisms underlying normal brain development in ADHD. The age-by-diagnosis interaction in the caudate and putamen supports the relevance of different brain developmental trajectories in participants with ADHD vs control individuals and supports the role of subcortical basal ganglia alterations in the pathophysiology of ADHD. Alterations in total gray matter and caudate and putamen volumes in unaffected siblings suggest that these volumes are linked to familial risk for ADHD.

Triple X syndrome: a review of the literature.

PubMed

Otter, Maarten; Schrander-Stumpel, Constance T R M; Curfs, Leopold M G

2010-03-01

The developmental and clinical aspects in the literature on triple X syndrome are reviewed. Prenatal diagnosis depends on karyotyping. The incidence is 1 of 1000 females. At birth, 47,XXX girls have a lower mean birth weight and a smaller head circumference. Triple X diagnosis was not suspected at birth. The maternal age seems to be increased. Toddlers with triple X syndrome show delayed language development. The youngest girls show accelerated growth until puberty. EEG abnormalities seem to be rather common. Many girls show motor-coordination problems and auditory-processing disorders are not rare. Scoliosis is probably more common in adolescent cases. The IQ levels are 20 points below that of controls, and verbal IQ is lowest. The girls struggle with low self-esteem and they need psychological, behavioural and educational support. They perform best in stable families. After leaving school they seem to feel better. In adults, premature ovarian failure seems to be more prevalent than in controls. MRIs of the brain seem to show decreased brain volumes. The 47,XXX women most often find jobs that reflect their performance abilities. Psychotic illness seems to be more prevalent in triple X adult women than in controls. Psychotic disorders respond well to psychotropic drugs. Triple X adults suffer more frequently from cyclothymic and labile personality traits. Research on triple X syndrome may yield more insight into brain and behaviour relations, developmental psychopathology, auditory-processing disorders, EEG disorders, personality and psychotic disorders, etc.

Idiopathic toe walking.

PubMed

Oetgen, Matthew E; Peden, Sean

2012-05-01

Toe walking is a bilateral gait abnormality in which a normal heel strike is absent and most weight bearing occurs through the forefoot. This abnormality may not be pathologic in patients aged <2 years, but it is a common reason for referral to an orthopaedic surgeon. Toe walking can be caused by several neurologic and developmental abnormalities and may be the first sign of a global developmental problem. Cases that lack a definitive etiology are categorized as idiopathic. A detailed history, with careful documentation of the developmental history, and a thorough physical examination are required in the child with a primary report of toe walking. Treatment is based on age and the severity of the abnormality. Management includes observation, stretching, casting, bracing, chemodenervation, and surgical lengthening of the gastrocnemius-soleus complex and/or Achilles tendon. An understanding of idiopathic toe walking as well as treatment options and their outcomes can help the physician individualize treatment to achieve optimal results.

Prevalence and spectrum of in utero structural brain abnormalities in fetuses with complex congenital heart disease.

PubMed

Brossard-Racine, M; du Plessis, A J; Vezina, G; Robertson, R; Bulas, D; Evangelou, I E; Donofrio, M; Freeman, D; Limperopoulos, C

2014-08-01

Brain injury is a major complication in neonates with complex congenital heart disease. Preliminary evidence suggests that fetuses with congenital heart disease are at greater risk for brain abnormalities. However, the nature and frequency of these brain abnormalities detected by conventional fetal MR imaging has not been examined prospectively. Our primary objective was to determine the prevalence and spectrum of brain abnormalities detected on conventional clinical MR imaging in fetuses with complex congenital heart disease and, second, to compare the congenital heart disease cohort with a control group of fetuses from healthy pregnancies. We prospectively recruited pregnant women with a confirmed fetal congenital heart disease diagnosis and healthy volunteers with normal fetal echocardiogram findings who underwent a fetal MR imaging between 18 and 39 weeks gestational age. A total of 338 fetuses (194 controls; 144 with congenital heart disease) were studied at a mean gestational age of 30.61 ± 4.67 weeks. Brain abnormalities were present in 23% of the congenital heart disease group compared with 1.5% in the control group (P < .001). The most common abnormalities in the congenital heart disease group were mild unilateral ventriculomegaly in 12/33 (36.4%) and increased extra-axial spaces in 10/33 (30.3%). Subgroup analyses comparing the type and frequency of brain abnormalities based on cardiac physiology did not reveal significant associations, suggesting that the brain abnormalities were not limited to those with the most severe congenital heart disease. This is the first large prospective study reporting conventional MR imaging findings in fetuses with congenital heart disease. Our results suggest that brain abnormalities are prevalent but relatively mild antenatally in fetuses with congenital heart disease. The long-term predictive value of these findings awaits further study. © 2014 by American Journal of Neuroradiology.

Amplitude-integrated EEG in newborns with critical congenital heart disease predicts preoperative brain magnetic resonance imaging findings.

PubMed

Mulkey, Sarah B; Yap, Vivien L; Bai, Shasha; Ramakrishnaiah, Raghu H; Glasier, Charles M; Bornemeier, Renee A; Schmitz, Michael L; Bhutta, Adnan T

2015-06-01

The study aims are to evaluate cerebral background patterns using amplitude-integrated electroencephalography in newborns with critical congenital heart disease, determine if amplitude-integrated electroencephalography is predictive of preoperative brain injury, and assess the incidence of preoperative seizures. We hypothesize that amplitude-integrated electroencephalography will show abnormal background patterns in the early preoperative period in infants with congenital heart disease that have preoperative brain injury on magnetic resonance imaging. Twenty-four newborns with congenital heart disease requiring surgery at younger than 30 days of age were prospectively enrolled within the first 3 days of age at a tertiary care pediatric hospital. Infants had amplitude-integrated electroencephalography for 24 hours beginning close to birth and preoperative brain magnetic resonance imaging. The amplitude-integrated electroencephalographies were read to determine if the background pattern was normal, mildly abnormal, or severely abnormal. The presence of seizures and sleep-wake cycling were noted. The preoperative brain magnetic resonance imaging scans were used for brain injury and brain atrophy assessment. Fifteen of 24 infants had abnormal amplitude-integrated electroencephalography at 0.71 (0-2) (mean [range]) days of age. In five infants, the background pattern was severely abnormal. (burst suppression and/or continuous low voltage). Of the 15 infants with abnormal amplitude-integrated electroencephalography, 9 (60%) had brain injury. One infant with brain injury had a seizure on amplitude-integrated electroencephalography. A severely abnormal background pattern on amplitude-integrated electroencephalography was associated with brain atrophy (P = 0.03) and absent sleep-wake cycling (P = 0.022). Background cerebral activity is abnormal on amplitude-integrated electroencephalography following birth in newborns with congenital heart disease who have findings of brain injury and/or brain atrophy on preoperative brain magnetic resonance imaging. Copyright © 2015 Elsevier Inc. All rights reserved.

The influence of brain abnormalities on psychosocial development, criminal history and paraphilias in sexual murderers.

PubMed

Briken, Peer; Habermann, Niels; Berner, Wolfgang; Hill, Andreas

2005-09-01

The aim of this study was to investigate the number and type of brain abnormalities and their influence on psychosocial development, criminal history and paraphilias in sexual murderers. We analyzed psychiatric court reports of 166 sexual murderers and compared a group with notable signs of brain abnormalities (N = 50) with those without any signs (N = 116). Sexual murderers with brain abnormalities suffered more from early behavior problems. They were less likely to cohabitate with the victim at the time of the homicide and had more victims at the age of six years or younger. Psychiatric diagnoses revealed a higher total number of paraphilias: Transvestic fetishism and paraphilias not otherwise specified were more frequent in offenders with brain abnormalities. A binary logistic regression identified five predictors that accounted for 46.8% of the variance explaining the presence of brain abnormalities. Our results suggest the importance of a comprehensive neurological and psychological examination of this special offender group.

Capitalizing on Basic Brain Processes in Developmental Algebra--Part 2

ERIC Educational Resources Information Center

Laughbaum, Edward D.

2011-01-01

Basic brain function is not a mystery. Given that neuroscientists understand its basic functioning processes, one wonders what their research suggests to teachers of developmental algebra. What if we knew how to teach so as to improve understanding of the algebra taught to developmental algebra students? What if we knew how the brain processes…

Capitalizing on Basic Brain Processes in Developmental Algebra--Part One

ERIC Educational Resources Information Center

Laughbaum, Edward D.

2011-01-01

Basic brain function is not a mystery. Given that neuroscientists understand the brain's basic functioning processes, one wonders what their research suggests to teachers of developmental algebra. What if we knew how to teach so as to improve understanding of the algebra taught to developmental algebra students? What if we knew how the brain…

Abnormalities on the Neurological Examination and EEG in Young Children with Pervasive Developmental Disorders

ERIC Educational Resources Information Center

Akshoomoff, Natacha; Farid, Nikdokht; Courchesne, Eric; Haas, Richard

2007-01-01

This study examined the nature and frequency of neurological and EEG abnormalities in 60 young children (ages 2-6 years) with pervasive developmental disorders. A number of standard neurological functions could not be adequately assessed due to the young age of the children and/or limited comprehension and cooperation. The most common neurological…

An Investigation of Sleep Characteristics, EEG Abnormalities and Epilepsy in Developmentally Regressed and Non-Regressed Children with Autism

ERIC Educational Resources Information Center

Giannotti, Flavia; Cortesi, Flavia; Cerquiglini, Antonella; Miraglia, Daniela; Vagnoni, Cristina; Sebastiani, Teresa; Bernabei, Paola

2008-01-01

This study investigated sleep of children with autism and developmental regression and the possible relationship with epilepsy and epileptiform abnormalities. Participants were 104 children with autism (70 non-regressed, 34 regressed) and 162 typically developing children (TD). Results suggested that the regressed group had higher incidence of…

Environmental enrichment increases the GFAP+ stem cell pool and reverses hypoxia-induced cognitive deficits in juvenile mice.

PubMed

Salmaso, Natalina; Silbereis, John; Komitova, Mila; Mitchell, Patrick; Chapman, Katherine; Ment, Laura R; Schwartz, Michael L; Vaccarino, Flora M

2012-06-27

Premature children born with very low birth weight (VLBW) can suffer chronic hypoxic injury as a consequence of abnormal lung development and cardiovascular abnormalities, often leading to grave neurological and behavioral consequences. Emerging evidence suggests that environmental enrichment improves outcome in animal models of adult brain injury and disease; however, little is known about the impact of environmental enrichment following developmental brain injury. Intriguingly, data on socio-demographic factors from longitudinal studies that examined a number of VLBW cohorts suggest that early environment has a substantial impact on neurological and behavioral outcomes. In the current study, we demonstrate that environmental enrichment significantly enhances behavioral and neurobiological recovery from perinatal hypoxic injury. Using a genetic fate-mapping model that allows us to trace the progeny of GFAP+ astroglial cells, we show that hypoxic injury increases the proportion of astroglial cells that attain a neuronal fate. In contrast, environmental enrichment increases the stem cell pool, both through increased stem cell proliferation and stem cell survival. In mice subjected to hypoxia and subsequent enrichment there is an additive effect of both conditions on hippocampal neurogenesis from astroglia, resulting in a robust increase in the number of neurons arising from GFAP+ cells by the time these mice reach full adulthood.

Converging early responses to brain injury pave the road to epileptogenesis.

PubMed

Neuberger, Eric J; Gupta, Akshay; Subramanian, Deepak; Korgaonkar, Akshata A; Santhakumar, Vijayalakshmi

2017-11-29

Epilepsy, characterized by recurrent seizures and abnormal electrical activity in the brain, is one of the most prevalent brain disorders. Over two million people in the United States have been diagnosed with epilepsy and 3% of the general population will be diagnosed with it at some point in their lives. While most developmental epilepsies occur due to genetic predisposition, a class of "acquired" epilepsies results from a variety of brain insults. A leading etiological factor for epilepsy that is currently on the rise is traumatic brain injury (TBI), which accounts for up to 20% of all symptomatic epilepsies. Remarkably, the presence of an identified early insult that constitutes a risk for development of epilepsy provides a therapeutic window in which the pathological processes associated with brain injury can be manipulated to limit the subsequent development of recurrent seizure activity and epilepsy. Recent studies have revealed diverse pathologies, including enhanced excitability, activated immune signaling, cell death, and enhanced neurogenesis within a week after injury, suggesting a period of heightened adaptive and maladaptive plasticity. An integrated understanding of these processes and their cellular and molecular underpinnings could lead to novel targets to arrest epileptogenesis after trauma. This review attempts to highlight and relate the diverse early changes after trauma and their role in development of epilepsy and suggests potential strategies to limit neurological complications in the injured brain. © 2017 Wiley Periodicals, Inc.

Common genetic variants influence human subcortical brain structures

PubMed Central

Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

2015-01-01

The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

The Gini coefficient: a methodological pilot study to assess fetal brain development employing postmortem diffusion MRI.

PubMed

Viehweger, Adrian; Riffert, Till; Dhital, Bibek; Knösche, Thomas R; Anwander, Alfred; Stepan, Holger; Sorge, Ina; Hirsch, Wolfgang

2014-10-01

Diffusion-weighted imaging (DWI) is important in the assessment of fetal brain development. However, it is clinically challenging and time-consuming to prepare neuromorphological examinations to assess real brain age and to detect abnormalities. To demonstrate that the Gini coefficient can be a simple, intuitive parameter for modelling fetal brain development. Postmortem fetal specimens(n = 28) were evaluated by diffusion-weighted imaging (DWI) on a 3-T MRI scanner using 60 directions, 0.7-mm isotropic voxels and b-values of 0, 150, 1,600 s/mm(2). Constrained spherical deconvolution (CSD) was used as the local diffusion model. Fractional anisotropy (FA), apparent diffusion coefficient (ADC) and complexity (CX) maps were generated. CX was defined as a novel diffusion metric. On the basis of those three parameters, the Gini coefficient was calculated. Study of fetal brain development in postmortem specimens was feasible using DWI. The Gini coefficient could be calculated for the combination of the three diffusion parameters. This multidimensional Gini coefficient correlated well with age (Adjusted R(2) = 0.59) between the ages of 17 and 26 gestational weeks. We propose a new method that uses an economics concept, the Gini coefficient, to describe the whole brain with one simple and intuitive measure, which can be used to assess the brain's developmental state.

Brain and bone abnormalities of thanatophoric dwarfism.

PubMed

Miller, Elka; Blaser, Susan; Shannon, Patrick; Widjaja, Elysa

2009-01-01

The purpose of this article is to present the imaging findings of skeletal and brain abnormalities in thanatophoric dwarfism, a lethal form of dysplastic dwarfism. The bony abnormalities associated with thanatophoric dwarfism include marked shortening of the tubular bones and ribs. Abnormal temporal lobe development is a common associated feature and can be visualized as early as the second trimester. It is important to assess the brains of fetuses with suspected thanatophoric dwarfism because the presence of associated brain malformations can assist in the antenatal diagnosis of thanatophoric dwarfism.

Cytogenetic Studies of Rwandan Pediatric Patients Presenting with Global Developmental Delay, Intellectual Disability and/or Multiple Congenital Anomalies

PubMed Central

Uwineza, Annette; Hitayezu, Janvier; Jamar, Mauricette; Caberg, Jean-Hubert; Murorunkwere, Seraphine; Janvier, Ndinkabandi; Bours, Vincent

2016-01-01

Global developmental delay (GDD) is defined as a significant delay in two or more developmental domains: gross or fine motor, speech/language, cognitive, social/personal and activities of daily living. Many of these children will go on to be diagnosed with intellectual disability (ID), which is most commonly defined as having an IQ <75 in addition to impairment in adaptive functioning. Cytogenetic studies have been performed in 664 Rwandan pediatric patients presenting GDD/ID and/or multiple congenital abnormalities (MCA). Karyotype analysis was performed in all patients and revealed 260 chromosomal abnormalities. The most frequent chromosomal abnormality was Down syndrome and then Edward syndrome and Patau syndrome. Other identified chromosomal abnormalities included 47,XX,+del(9)(q11), 46,XY,del(13)(q34) and 46,XX,der(22)t(10;22)(p10;p10)mat. In conclusion, our results highlight the high frequency of cytogenetically detectable abnormalities in this series, with implications for the burden on the healthcare. This study demonstrates the importance of cytogenetic analysis in patients with GDD/ID and MCA. PMID:26507407

EEG complexity as a biomarker for autism spectrum disorder risk

PubMed Central

2011-01-01

Background Complex neurodevelopmental disorders may be characterized by subtle brain function signatures early in life before behavioral symptoms are apparent. Such endophenotypes may be measurable biomarkers for later cognitive impairments. The nonlinear complexity of electroencephalography (EEG) signals is believed to contain information about the architecture of the neural networks in the brain on many scales. Early detection of abnormalities in EEG signals may be an early biomarker for developmental cognitive disorders. The goal of this paper is to demonstrate that the modified multiscale entropy (mMSE) computed on the basis of resting state EEG data can be used as a biomarker of normal brain development and distinguish typically developing children from a group of infants at high risk for autism spectrum disorder (ASD), defined on the basis of an older sibling with ASD. Methods Using mMSE as a feature vector, a multiclass support vector machine algorithm was used to classify typically developing and high-risk groups. Classification was computed separately within each age group from 6 to 24 months. Results Multiscale entropy appears to go through a different developmental trajectory in infants at high risk for autism (HRA) than it does in typically developing controls. Differences appear to be greatest at ages 9 to 12 months. Using several machine learning algorithms with mMSE as a feature vector, infants were classified with over 80% accuracy into control and HRA groups at age 9 months. Classification accuracy for boys was close to 100% at age 9 months and remains high (70% to 90%) at ages 12 and 18 months. For girls, classification accuracy was highest at age 6 months, but declines thereafter. Conclusions This proof-of-principle study suggests that mMSE computed from resting state EEG signals may be a useful biomarker for early detection of risk for ASD and abnormalities in cognitive development in infants. To our knowledge, this is the first demonstration of an information theoretic analysis of EEG data for biomarkers in infants at risk for a complex neurodevelopmental disorder. PMID:21342500

Autism, an overwhelming condition: history, etiopathogenesis, types, diagnosis, therapy and prognosis.

PubMed

Amihăesei, Ioana Cristina; Stefanachi, Elena

2013-01-01

Autism is defined as a neurologic developmental disorder affecting brain and behavior, becoming usually apparent before 3 years of age, with stable evolution and no remission. No neurologic morphologic abnormality was associated with the disease. Several types of disease being described, autism is part of a larger spectrum known as autism spectrum disorders (ASD), or pervasive developmental disorders (PDD). The disease was first described long before it was defined and it has received its modern name. Main cause in the development of autism is considered to be genetic, up to 90 %. However, environmental factors could be incriminated, sometimes. The five types included in ASD are: Asperger syndrome, pervasive developmental disorder-not otherwise specified (PDD-NOS), typical autism, Rett syndrome and childhood disintegrative disorder (CDD). The classical triad of symptoms includes: social interaction impairments, communication impairments and repetitive, stereotype behavior. Diagnosis is based on interview of the parents and specialized observation of the suspected children. Main tools used in therapy are the family and the educational system. Well established, specialized programs of therapy were developed in time. Prognosis of autism is severe, since no cure is possible; nevertheless spontaneous recoveries do occur, in some cases.

Endocrine disruptors: from Wingspread to environmental developmental biology.

PubMed

Markey, Caroline M; Rubin, Beverly S; Soto, Ana M; Sonnenschein, Carlos

2002-12-01

The production and release of synthetic chemicals into the environment has been a hallmark of the "Second Industrial Revolution" and the "Green Revolution." Soon after the inception of these chemicals, anecdotal evidence began to emerge linking environmental contamination of rivers and lakes with a variety of developmental and reproductive abnormalities in wildlife species. The accumulation of evidence suggesting that these synthetic chemicals were detrimental to wildlife, and potentially humans, as a result of their hormonal activity, led to the proposal of the endocrine disruptor hypothesis at the 1991 Wingspread Conference. Since that time, experimental and epidemiological data have shown that exposure of the developing fetus or neonate to environmentally-relevant concentrations of certain synthetic chemicals causes morphological, biochemical, physiological and behavioral anomalies in both vertebrate and invertebrate species. The ubiquitous use, and subsequent human exposure, of one particular chemical, the estrogen mimic bisphenol A (BPA), is the subject of this present review. We have highlighted this chemical since it provides an arresting model of how chemical exposure impacts developmental processes involved in the morphogenesis of tissues and organs, including those of the male and female reproductive systems, the mammary glands and the brain.

TBBPA induces developmental toxicity, oxidative stress, and apoptosis in embryos and zebrafish larvae (Danio rerio).

PubMed

Wu, Shengmin; Ji, Guixiang; Liu, Jining; Zhang, Shenghu; Gong, Yang; Shi, Lili

2016-10-01

Tetrabromobisphenol A (TBBPA) is currently one of the most frequently used brominated flame retardants and can be considered as a high production volume chemical. In this study, zebrafish embryos and larvae served as a biological model to evaluate TBBPA-induced developmental toxicity, oxidative stress, oxidant-associated gene expression, and cell apoptosis. Abnormalities, including hyperemia and pericardial edema, were induced in zebrafish larvae. The results showed that toxicity endpoints such as hatching rate, survival rate, malformation rate, and growth rate had a significant dose-response relationship with TBBPA. Further studies revealed that TBBPA did not alter the enzyme activities of Copper/Zinc Superoxide dismutase (Cu/Zn-SOD), catalase (CAT), and glutathioneperoxidase (GPx) at 0.10 mg/L, but decreased activities following exposure to 0.40, 0.70, and 1.00 mg/L. Despite the significantly decreased gene expression of Cu/Zn-SOD, CAT, and GPx1a in the 1.00 mg/L treatment group, other treatments (0.10, 0.40, 0.70 mg/L) did not alter gene expression. Moreover, Acridine orange staining results showed that apoptotic cells mainly accumulated in the brain, heart, and tail, indicating possible TBBPA-induced brain, cardiac, and blood circulation system impairment in zebrafish embryos and larvae. Histological analysis also showed evidence of obvious heart impairment in TBBPA-treated groups. This study provides new evidence on the developmental toxicity, oxidative stress, and apoptosis of embryos and zebrafish larvae, which is important for the evaluation of environmental toxicity and chemical risk. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1241-1249, 2016. © 2015 Wiley Periodicals, Inc.

Oligodendroglial Alterations and the Role of Microglia in White Matter Injury: Relevance to Schizophrenia

PubMed Central

Chew, Li-Jin; Fusar-Poli, Paolo; Schmitz, Thomas

2015-01-01

Schizophrenia is a chronic and debilitating mental illness characterized by a broad range of abnormal behaviors, including delusions and hallucinations, impaired cognitive function, as well as mood disturbances and social withdrawal. Due to the heterogeneous nature of the disease, the causes of schizophrenia are very complex; its etiology is believed to involve multiple brain regions and the connections between them, and includes alterations in both gray and white matter regions. The onset of symptoms varies with age and severity, and there is some debate over a degenerative or developmental etiology. Longitudinal magnetic resonance imaging studies have detected progressive gray matter loss in the first years of disease, suggesting neurodegeneration; but there is also increasing recognition of a temporal association between clinical complications at birth and disease onset that supports a neurodevelopmental origin. Presently, neuronal abnormalities in schizophrenia are better understood than alterations in myelin-producing cells of the brain, the oligodendrocytes, which are the predominant constituents of white matter structures. Proper white matter development and its structural integrity critically impacts brain connectivity, which affects sensorimotor coordination and cognitive ability. Evidence of defective white matter growth and compromised white matter integrity has been found in individuals at high risk of psychosis, and decreased numbers of mature oligodendrocytes are detected in schizophrenia patients. Inflammatory markers, including proinflammatory cytokines and chemokines, are also associated with psychosis. A relationship between risk of psychosis, white matter defects and prenatal inflammation is being established. Animal models of perinatal brain injury are successful in producing white matter damage in the brain, typified by hypomyelination and/or dysmyelination, impaired motor coordination and prepulse inhibition of the acoustic startle reflex, recapitulating structural and functional characteristics observed in schizophrenia. In addition, elevated expression of inflammation-related genes in brain tissue and increased production of cytokines by blood cells from patients with schizophrenia indicate immunological dysfunction and abnormal inflammatory responses, which are also important underlying features in experimental models. Microglia, resident immune defenders of the central nervous system, play important roles in the development and protection of neural cells, but can contribute to injury under pathological conditions. This article discusses oligodendroglial changes in schizophrenia and focuses on microglial activity in the context of the disease, in neonatal brain injury and in various experimental models of white matter damage. These include disorders associated with premature birth, and animal models of perinatal bacterial and viral infection, oxygen deprivation (hypoxia) and excess (hyperoxia), and elevated systemic proinflammatory cytokine levels. We briefly review the effects of treatment with antipsychotic and anti-inflammatory agents in models of perinatal brain injury, and comment on the therapeutic potential of these strategies. By understanding the neurobiological basis of oligodendroglial abnormalities in schizophrenia, it is hoped that patients will benefit from the availability of targeted and more efficacious treatment options. PMID:23446060

Oxytocin, vasopressin, and autism: is there a connection?

PubMed

Insel, T R; O'Brien, D J; Leckman, J F

1999-01-15

Autism is a poorly understood developmental disorder characterized by social impairment, communication deficits, and compulsive behavior. The authors review evidence from animal studies demonstrating that the nonapeptides, oxytocin and vasopressin, have unique effects on the normal expression of species-typical social behavior, communication, and rituals. Based on this evidence, they hypothesize that an abnormality in oxytocin or vasopressin neurotransmission may account for several features of autism. As autism appears to be a genetic disorder, mutations in the various peptide, peptide receptor, or lineage-specific developmental genes could lead to altered oxytocin or vasopressin neurotransmission. Many of these genes have been cloned and sequenced, and several polymorphisms have been identified. Recent gene targeting studies that alter expression of either the peptides or their receptors in the rodent brain partially support the autism hypothesis. While previous experience suggests caution in hypothesizing a cause or suggesting a treatment for autism, the available preclinical evidence with oxytocin and vasopressin recommends the need for clinical studies using gene scanning, pharmacological and neurobiological approaches.

Electroencephalographic Abnormalities during Sleep in Children with Developmental Speech-Language Disorders: A Case-Control Study

ERIC Educational Resources Information Center

Parry-Fielder, Bronwyn; Collins, Kevin; Fisher, John; Keir, Eddie; Anderson, Vicki; Jacobs, Rani; Scheffer, Ingrid E.; Nolan, Terry

2009-01-01

Earlier research has suggested a link between epileptiform activity in the electroencephalogram (EEG) and developmental speech-language disorder (DSLD). This study investigated the strength of this association by comparing the frequency of EEG abnormalities in 45 language-normal children (29 males, 16 females; mean age 6y 11mo, SD 1y 10mo, range…

Can pharmacological and psychological treatment change brain structure and function in PTSD? A systematic review.

PubMed

Thomaes, Kathleen; Dorrepaal, Ethy; Draijer, Nel; Jansma, Elise P; Veltman, Dick J; van Balkom, Anton J

2014-03-01

While there is evidence of clinical improvement of posttraumatic stress disorder (PTSD) with treatment, its neural underpinnings are insufficiently clear. Moreover, it is unknown whether similar neurophysiological changes occur in PTSD specifically after child abuse, given its enduring nature and the developmental vulnerability of the brain during childhood. We systematically reviewed PTSD treatment effect studies on structural and functional brain changes from PubMed, EMBASE, PsycINFO, PILOTS and the Cochrane Library. We included studies on adults with (partial) PTSD in Randomized Controlled Trials (RCT) or pre-post designs (excluding case studies) on pharmacotherapy and psychotherapy. Risk of bias was evaluated independently by two raters. Brain coordinates and effect sizes were standardized for comparability. We included 15 studies (6 RCTs, 9 pre-post), four of which were on child abuse. Results showed that pharmacotherapy improved structural abnormalities (i.e., increased hippocampus volume) in both adult-trauma and child abuse related PTSD (3 pre-post studies). Functional changes were found to distinguish between groups. Adult-trauma PTSD patients showed decreased amygdala and increased dorsolateral prefrontal activations post-treatment (4 RCTs, 5 pre-post studies). In one RCT, child abuse patients showed no changes in the amygdala, but decreased dorsolateral prefrontal, dorsal anterior cingulate and insula activation post-treatment. In conclusion, pharmacotherapy may reduce structural abnormalities in PTSD, while psychotherapy may decrease amygdala activity and increase prefrontal, dorsal anterior cingulate and hippocampus activations, that may relate to extinction learning and re-appraisal. There is some evidence for a distinct activation pattern in child abuse patients, which clearly awaits further empirical testing. Copyright © 2013 Elsevier Ltd. All rights reserved.

Neurocytotoxic effects of iron-ions on the developing brain measured in vivo using medaka (Oryzias latipes), a vertebrate model

PubMed Central

Yasuda, Takako; Oda, Shoji; Yasuda, Hiroshi; Hibi, Yusuke; Anzai, Kazunori; Mitani, Hiroshi

2011-01-01

Purpose: Exposure to heavy-ion radiation is considered a critical health risk on long-term space missions. The developing central nervous system (CNS) is a highly radiosensitive tissue; however, the biological effects of heavy-ion radiation, which are greater than those of low-linear energy transfer (LET) radiation, are not well studied, especially in vivo in intact organisms. Here, we examined the effects of iron-ions on the developing CNS using vertebrate organism, fish embryos of medaka (Oryzias latipes). Materials and methods: Medaka embryos at developmental stage 28 were irradiated with iron-ions at various doses of 0-1.5 Gy. At 24 h after irradiation, radiation-induced apoptosis was examined using an acridine orange (AO) assay and histo-logically. To estimate the relative biological effectiveness (RBE), we quantified only characteristic AO-stained rosette-shaped apoptosis in the developing optic tectum (OT). At the time of hatching, morphological abnormalities in the irradiated brain were examined histologically. Results: The dose-response curve utilizing an apoptotic index for the iron-ion irradiated embryos was much steeper than that for X-ray irradiated embryos, with RBE values of 3.7-4.2. Histological examinations of irradiated medaka brain at 24 h after irradiation showed AO-positive rosette-shaped clusters as aggregates of condensed nuclei, exhibiting a circular hole, mainly in the marginal area of the OT and in the retina. However, all of the irradiated embryos hatched normally without apparent histological abnormalities in their brains. Conclusion: Our present study indicates that the medaka embryo is a useful model for evaluating neurocytotoxic effects on the developing CNS induced by exposure to heavy iron-ions relevant to the aerospace radiation environment. PMID:21770703

Prevention of Blast-Related Injuries

DTIC Science & Technology

2017-09-01

allow early screening and assessment of brain abnormality in soldiers to enable timely therapeutic intervention. The current study reports on the...use of qEEG in blast-induced brain injury using a swine model. The purposes are to determine if qEEG can detect brain activity abnormalities early...brain functional abnormalities and deficits in absence of any clinical mTBI symptoms. Methods such as EEG-wavelet entropy measures [36] and Shannon

Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia.

PubMed

Hadar, R; Bikovski, L; Soto-Montenegro, M L; Schimke, J; Maier, P; Ewing, S; Voget, M; Wieske, F; Götz, T; Desco, M; Hamani, C; Pascau, J; Weiner, I; Winter, C

2018-04-01

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia's neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.

Changes in neurocranium thickness in early childhood

NASA Astrophysics Data System (ADS)

Gajawelli, Niharika; Deoni, Sean; Shi, Jie; Xu, Liang; Dirks, Holly; Dean, Douglas; O'Muircheartaigh, Jonathan; Sawardekar, Siddhant; Ezis, Andrea; Nelson, Marvin D.; Wang, Yalin; Lepore, Natasha

2015-12-01

Several developmental disorders involve shape abnormalities of the neurocranium, the most common one being craniosynostosis, that affects about 1 in 2000 infants. A key step in determining how these disorders affect neurodevelopment is to establish how the brain and neurocranium co-evolve in the normally developing child. However, due to the scarcity of normally developing infant and pediatric imaging data, there have been a lack of imaging studies pertaining to normal neurocranial development. Here, taking advantage of a large data bank of high quality brain MRI from healthy children ages 0-4 years old, and of a novel conformal geometry-based analysis pipeline, we have been determining a set of statistical atlases of the neurocranium, divided into age groups. In this first part of the study, we focus more specifically on a comparison of 1 and 2 year old infants. Characterizing neurocranium shape changes will enable us to understand how the cranial bones develop in relation to brain development. This in turn will allow a better determination of the effects of neurocranial disorders, which will help inform treatment strategies.

Task positive and default mode networks during a working memory in children with primary monosymptomatic nocturnal enuresis and healthy controls.

PubMed

Zhang, Kaihua; Ma, Jun; Lei, Du; Wang, Mengxing; Zhang, Jilei; Du, Xiaoxia

2015-10-01

Nocturnal enuresis is a common developmental disorder in children, and primary monosymptomatic nocturnal enuresis (PMNE) is the dominant subtype. This study investigated brain functional abnormalities that are specifically related to working memory in children with PMNE using function magnetic resonance imaging (fMRI) in combination with an n-back task. Twenty children with PMNE and 20 healthy children, group-matched for age and sex, participated in this experiment. Several brain regions exhibited reduced activation during the n-back task in children with PMNE, including the right precentral gyrus and the right inferior parietal lobule extending to the postcentral gyrus. Children with PMNE exhibited decreased cerebral activation in the task-positive network, increased task-related cerebral deactivation during a working memory task, and longer response times. Patients exhibited different brain response patterns to different levels of working memory and tended to compensate by greater default mode network deactivation to sustain normal working memory function. Our results suggest that children with PMNE have potential working memory dysfunction.

Evaluating changes in brain vasculature of murine embryos in utero due to maternal alcohol consumption using optical coherence tomography

NASA Astrophysics Data System (ADS)

Raghunathan, Raksha; Wu, Chen; Singh, Manmohan; Liu, Chih-Hao; Miranda, Rajesh C.; Larin, Kirill V.

2017-04-01

Fetal Alcohol Syndrome (FAS) refers to the broad spectrum of developmental and behavioral effects caused due to prenatal alcohol exposure (PAE). Wide range of abnormalities vary depending on the amount of alcohol consumed and the period of consumption during gestation. PAE during early stages of pregnancy is very common. However a large number of women continue to consume alcohol even during the second trimester, a critical period for fetal neurogenesis and angiogenesis. Optical coherence tomography (OCT) has shown to be extremely useful in embryonic imaging. Our previous work showed that OCT is capable of quantitative assessment of ventriculomegaly caused by maternal alcohol consumption. Although structural changes and changes in blood flow in the fetal brain after maternal alcohol consumption have been studied, acute vasculature changes are not well documented. Speckle variance OCT (SVOCT), is a functional extension of OCT that has been used to study vasculature development in embryos. We use SVOCT, to detect vasculature changes in the embryonic brain in utero, minutes after maternal alcohol consumption.

Effects of exogenous agents on brain development: stress, abuse and therapeutic compounds.

PubMed

Archer, Trevor

2011-10-01

The range of exogenous agents likely to affect, generally detrimentally, the normal development of the brain and central nervous system defies estimation although the amount of accumulated evidence is enormous. The present review is limited to certain types of chemotherapeutic and "use-and-abuse" compounds and environmental agents, exemplified by anesthetic, antiepileptic, sleep-inducing and anxiolytic compounds, nicotine and alcohol, and stress as well as agents of infection; each of these agents have been investigated quite extensively and have been shown to contribute to the etiopathogenesis of serious neuropsychiatric disorders. To greater or lesser extent, all of the exogenous agents discussed in the present treatise have been investigated for their influence upon neurodevelopmental processes during the period of the brain growth spurt and during other phases uptill adulthood, thereby maintaining the notion of critical phases for the outcome of treatment whether prenatal, postnatal, or adolescent. Several of these agents have contributed to the developmental disruptions underlying structural and functional brain abnormalities that are observed in the symptom and biomarker profiles of the schizophrenia spectrum disorders and the fetal alcohol spectrum disorders. In each case, the effects of the exogenous agents upon the status of the affected brain, within defined parameters and conditions, is generally permanent and irreversible. © 2010 Blackwell Publishing Ltd.

Autism, oxytocin and interoception

PubMed Central

Quattrocki, E.; Friston, Karl

2014-01-01

Autism is a pervasive developmental disorder characterized by profound social and verbal communication deficits, stereotypical motor behaviors, restricted interests, and cognitive abnormalities. Autism affects approximately 1% of children in developing countries. Given this prevalence, identifying risk factors and therapeutic interventions are pressing objectives—objectives that rest on neurobiologically grounded and psychologically informed theories about the underlying pathophysiology. In this article, we review the evidence that autism could result from a dysfunctional oxytocin system early in life. As a mediator of successful procreation, not only in the reproductive system, but also in the brain, oxytocin plays a crucial role in sculpting socio-sexual behavior. Formulated within a (Bayesian) predictive coding framework, we propose that oxytocin encodes the saliency or precision of interoceptive signals and enables the neuronal plasticity necessary for acquiring a generative model of the emotional and social ‘self.’ An aberrant oxytocin system in infancy could therefore help explain the marked deficits in language and social communication – as well as the sensory, autonomic, motor, behavioral, and cognitive abnormalities – seen in autism. PMID:25277283

Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy.

PubMed

Iannetti, Paola; Parisi, Pasquale; Spalice, Alberto; Ruggieri, Martino; Zara, Federico

2009-07-01

We report on the use of the voltage-gated calcium channel blocker (Vg-CCB), verapamil, as an add-on anticonvulsant medication in two girls, 4 and 14 years of age, who were affected by severe myoclonic epilepsy in infancy (SMEI) or Dravet syndrome, a channelopathy caused by abnormalities in the voltage-gated sodium channel neuronal type alpha1 subunit (SCN1A) gene at 2q24. Both girls had pharmacoresistant epilepsy and developmental delay. Mutation analysis for the SCN1A gene revealed a missense mutation in exon 2 in the 4-year-old girl. Verapamil was co-administered in both children with a prompt response in controlling status epilepticus, myoclonic jerks, and partial and generalized seizures. The therapeutic effect lasted 13 months in the 14-year-old girl, while it is still present after a 20-month follow-up period in the 4-year-old girl who, in addition, has experienced improvement in motor and language development. The verapamil vVg-CCB, which crosses the blood-brain barrier (BBB): (a) inhibits the P-glycoprotein, an active efflux transporter protein expressed in normal tissue, including the brain, which is believed to contribute to the in situ phenomenon of multidrug resistance; and (b) may regulate membrane depolarization induced by abnormal sodium channels functions by modulating the abnormal Ca++ influxes into neurons with subsequent cell resting. This is the first report on long-lasting verapamil therapy in SMEI. The functional consequences of such in vivo modulating effects on Ca++ channels could contribute to rational targeting for future molecular therapeutic approaches in pharmacoresistant epileptic channelopathies.

Microglia and Inflammation: Impact on Developmental Brain Injuries

ERIC Educational Resources Information Center

Chew, Li-Jin; Takanohashi, Asako; Bell, Michael

2006-01-01

Inflammation during the perinatal period has become a recognized risk factor for developmental brain injuries over the past decade or more. To fully understand the relationship between inflammation and brain development, a comprehensive knowledge about the immune system within the brain is essential. Microglia are resident immune cells within the…

Temporal Lobe Epilepsy in Children

PubMed Central

Nickels, Katherine C.; Wong-Kisiel, Lily C.; Moseley, Brian D.; Wirrell, Elaine C.

2012-01-01

The temporal lobe is a common focus for epilepsy. Temporal lobe epilepsy in infants and children differs from the relatively homogeneous syndrome seen in adults in several important clinical and pathological ways. Seizure semiology varies by age, and the ictal EEG pattern may be less clear cut than what is seen in adults. Additionally, the occurrence of intractable seizures in the developing brain may impact neurocognitive function remote from the temporal area. While many children will respond favorably to medical therapy, those with focal imaging abnormalities including cortical dysplasia, hippocampal sclerosis, or low-grade tumors are likely to be intractable. Expedient workup and surgical intervention in these medically intractable cases are needed to maximize long-term developmental outcome. PMID:22957247

Added Value of Including Entire Brain on Body Imaging With FDG PET/MRI.

PubMed

Franceschi, Ana M; Matthews, Robert; Bangiyev, Lev; Relan, Nand; Chaudhry, Ammar; Franceschi, Dinko

2018-05-24

FDG PET/MRI examination of the body is routinely performed from the skull base to the mid thigh. Many types of brain abnormalities potentially could be detected on PET/MRI if the head was included. The objective of this study was therefore to identify and characterize brain findings incidentally detected on PET/MRI of the body with the head included. We retrospectively identified 269 patients with FDG PET/MRI whole-body scans that included the head. PET/MR images of the brain were reviewed by a nuclear medicine physician and neuroradiologist, first individually and then concurrently. Both PET and MRI findings were identified, including abnormal FDG uptake, standardized uptake value, lesion size, and MRI signal characteristics. For each patient, relevant medical history and prior imaging were reviewed. Of the 269 subjects, 173 were women and 96 were men (mean age, 57.4 years). Only the initial PET/MR image of each patient was reviewed. A total of 37 of the 269 patients (13.8%) had abnormal brain findings noted on the PET/MRI whole-body scan. Sixteen patients (5.9%) had vascular disease, nine patients (3.3%) had posttherapy changes, and two (0.7%) had benign cystic lesions in the brain. Twelve patients (4.5%) had serious nonvascular brain abnormalities, including cerebral metastasis in five patients and pituitary adenomas in two patients. Only nine subjects (3.3%) had a new neurologic or cognitive symptom suggestive of a brain abnormality. Routine body imaging with FDG PET/MRI of the area from the skull base to the mid thigh may miss important brain abnormalities when the head is not included. The additional brain abnormalities identified on whole-body imaging may provide added clinical value to the management of oncology patients.

Neural conduction abnormality in the brain stem and prevalence of the abnormality in late preterm infants with perinatal problems.

PubMed

Jiang, Ze Dong

2013-08-01

Neurodevelopment in late preterm infants has recently attracted considerable interest. The prevalence of brain stem conduction abnormality remains unknown. We examined maximum length sequence brain stem auditory evoked response in 163 infants, born at 33-36 weeks gestation, who had various perinatal problems. Compared with 49 normal term infants without problems, the late preterm infants showed a significant increase in III-V and I-V interpeak intervals at all 91-910/s clicks, particularly at 455 and 910/s (p < 0.01-0.001). The I-III interval was slightly increased, without statistically significant difference from the controls at any click rates. These results suggest that neural conduction along the, mainly more central or rostral part of, auditory brain stem is abnormal in late preterm infants with perinatal problems. Of the 163 late preterm infant, the number (and percentage rate) of infants with abnormal I-V interval at 91, 227, 455, and 910/s clicks was, respectively, 11 (6.5%), 17 (10.2%), 37 (22.3%), and 31 (18.7%). The number (and percentage rate) of infants with abnormal III-V interval at these rates was, respectively, 10 (6.0%), 17 (10.2%), 28 (16.9), and 36 (21.2%). Apparently, the abnormal rates were much higher at 455 and 910/s clicks than at lower rates 91 and 227/s. In total, 42 (25.8%) infants showed abnormal I-V and/or III-V intervals. Conduction in, mainly in the more central part, the brain stem is abnormal in late preterm infants with perinatal problems. The abnormality is more detectable at high- than at low-rate sensory stimulation. A quarter of late preterm infants with perinatal problems have brain stem conduction abnormality.

ENVIRONMENTAL CONTAMINATION AND DEVELOPMENTAL ABNORMALITIES IN EGGS AND HATCHLINGS OF THE COMMON SNAPPING TURTLE (CHELYDRA SERPENTINA SERPENTINA) FROM THE GREAT LAKES-ST. LAWRENCE RIVER BASIN (1989-91). (R827102)

EPA Science Inventory

Abstract

During 1989-91, we assessed developmental abnormalities in embryos and hatchlings from eggs of the common snapping turtle (Chelydra serpentina serpentina). Eggs were collected and artificially incubated from eight sites in Ontario, Canada and Akwesasne/...

Continuum of neurobehaviour and its associations with brain MRI in infants born preterm

PubMed Central

Eeles, Abbey L; Walsh, Jennifer M; Olsen, Joy E; Cuzzilla, Rocco; Thompson, Deanne K; Anderson, Peter J; Doyle, Lex W; Cheong, Jeanie L Y; Spittle, Alicia J

2017-01-01

Background Infants born very preterm (VPT) and moderate-to-late preterm (MLPT) are at increased risk of long-term neurodevelopmental deficits, but how these deficits relate to early neurobehaviour in MLPT children is unclear. The aims of this study were to compare the neurobehavioural performance of infants born across three different gestational age groups: preterm <30 weeks’ gestational age (PT<30); MLPT (32–36 weeks’ gestational age) and term age (≥37 weeks’ gestational age), and explore the relationships between MRI brain abnormalities and neurobehaviour at term-equivalent age. Methods Neurobehaviour was assessed at term-equivalent age in 149 PT<30, 200 MLPT and 200 term-born infants using the Neonatal Intensive Care UnitNetwork Neurobehavioral Scale (NNNS), the Hammersmith Neonatal Neurological Examination (HNNE) and Prechtl’s Qualitative Assessment of General Movements (GMA). A subset of 110 PT<30 and 198 MLPT infants had concurrent brain MRI. Results Proportions with abnormal neurobehaviour on the NNNS and the HNNE, and abnormal GMA all increased with decreasing gestational age. Higher brain MRI abnormality scores in some regions were associated with suboptimal neurobehaviour on the NNNS and HNNE. The relationships between brain MRI abnormality scores and suboptimal neurobehaviour were similar in both PT<30 and MLPT infants. The relationship between brain MRI abnormality scores and abnormal GMA was stronger in PT<30 infants. Conclusions There was a continuum of neurobehaviour across gestational ages. The relationships between brain abnormality scores and suboptimal neurobehaviour provide evidence that neurobehavioural assessments offer insight into the integrity of the developing brain, and may be useful in earlier identification of the highest-risk infants. PMID:29637152

A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity

PubMed Central

Costa, Lucio G.; de Laat, Rian; Tagliaferri, Sara; Pellacani, Claudia

2013-01-01

Polybrominated diphenyl ethers (PBDEs), extensively used in the past few decades as flame retardants in a variety of consumer products, have become world-wide persistent environmental pollutants. Levels in North America are usually higher than those in Europe and Asia, and body burden is 3 to 9-fold higher in infants and toddlers than in adults. The latter has raised concern for potential developmental toxicity and neurotoxicity of PBDEs. Experimental studies in animals and epidemiological observations in humans suggest that PBDEs may be developmental neurotoxicants. Pre- and/or post-natal exposure to PBDEs may cause long-lasting behavioral abnormalities, particularly in the domains of motor activity and cognition. The mechanisms underlying the developmental neurotoxic effects of PBDEs are not known, though several hypotheses have been put forward. One general mode of action relates to the ability of PBDEs to impair thyroid hormone homeostasis, thus indirectly affecting the developing brain. An alternative or additional mode of action involves a direct effect of PBDEs on nervous system cells; PBDEs can cause oxidative stress-related damage (DNA damage, mitochondrial dysfunction, apoptosis), and interfere with signal transduction (particularly calcium signaling), and with neurotransmitter systems. Important issues such as bioavailability and metabolism of PBDEs, extrapolation of results to low level of exposures, and the potential effects of interactions among PBDE congeners and between PBDEs and other contaminants also need to be taken into account. PMID:24270005

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

PubMed Central

Hanson, Daniel R; Gottesman, Irving I

2005-01-01

Background Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. Discussion A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. Summary A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons. PMID:15707482

A Primer on Brain Imaging in Developmental Psychopathology: What Is It Good For?

ERIC Educational Resources Information Center

Pine, Daniel S.

2006-01-01

This primer introduces a Special Section on brain imaging, which includes a commentary and 10 data papers presenting applications of brain imaging to questions on developmental psychopathology. This primer serves two purposes. First, the article summarizes the strength and weaknesses of various brain-imaging techniques typically employed in…

Prenatal ethanol exposure-induced adrenal developmental abnormality of male offspring rats and its possible intrauterine programming mechanisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Hegui; He, Zheng; Zhu, Chunyan

Fetal adrenal developmental status is the major determinant of fetal tissue maturation and offspring growth. We have previously proposed that prenatal ethanol exposure (PEE) suppresses fetal adrenal corticosterone (CORT) synthesis. Here, we focused on PEE-induced adrenal developmental abnormalities of male offspring rats before and after birth, and aimed to explore its intrauterine programming mechanisms. A rat model of intrauterine growth retardation (IUGR) was established by PEE (4 g/kg·d). In PEE fetus, increased serum CORT concentration and decreased insulin-like growth factor 1 (IGF1) concentration, with lower bodyweight and structural abnormalities as well as a decreased Ki67 expression (proliferative marker), were observedmore » in the male fetal adrenal cortex. Adrenal glucocorticoid (GC)-metabolic activation system was enhanced while gene expression of IGF1 signaling pathway with steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD) was decreased. Furthermore, in the male adult offspring of PEE, serum CORT level was decreased but IGF1 was increased with partial catch-up growth, and Ki67 expression demonstrated no obvious change. Adrenal GC-metabolic activation system was inhibited, while IGF1 signaling pathway and 3β-HSD was enhanced with the steroidogenic factor 1 (SF1), and StAR was down-regulated in the adult adrenal. Based on these findings, we propose a “two-programming” mechanism for PEE-induced adrenal developmental toxicity: “the first programming” is a lower functional programming of adrenal steroidogenesis, and “the second programming” is GC-metabolic activation system-related GC-IGF1 axis programming. - Highlights: • Prenatal ethanol exposure induces adrenal developmental abnormality in offspring rats. • Prenatal ethanol exposure induces intrauterine programming of adrenal steroidogenesis. • Intrauterine GC-IGF1 axis programming might mediate adrenal developmental abnormality.« less

Behavioural and neural basis of anomalous motor learning in children with autism.

PubMed

Marko, Mollie K; Crocetti, Deana; Hulst, Thomas; Donchin, Opher; Shadmehr, Reza; Mostofsky, Stewart H

2015-03-01

Autism spectrum disorder is a developmental disorder characterized by deficits in social and communication skills and repetitive and stereotyped interests and behaviours. Although not part of the diagnostic criteria, individuals with autism experience a host of motor impairments, potentially due to abnormalities in how they learn motor control throughout development. Here, we used behavioural techniques to quantify motor learning in autism spectrum disorder, and structural brain imaging to investigate the neural basis of that learning in the cerebellum. Twenty children with autism spectrum disorder and 20 typically developing control subjects, aged 8-12, made reaching movements while holding the handle of a robotic manipulandum. In random trials the reach was perturbed, resulting in errors that were sensed through vision and proprioception. The brain learned from these errors and altered the motor commands on the subsequent reach. We measured learning from error as a function of the sensory modality of that error, and found that children with autism spectrum disorder outperformed typically developing children when learning from errors that were sensed through proprioception, but underperformed typically developing children when learning from errors that were sensed through vision. Previous work had shown that this learning depends on the integrity of a region in the anterior cerebellum. Here we found that the anterior cerebellum, extending into lobule VI, and parts of lobule VIII were smaller than normal in children with autism spectrum disorder, with a volume that was predicted by the pattern of learning from visual and proprioceptive errors. We suggest that the abnormal patterns of motor learning in children with autism spectrum disorder, showing an increased sensitivity to proprioceptive error and a decreased sensitivity to visual error, may be associated with abnormalities in the cerebellum. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Unraveling the Miswired Connectome: A Developmental Perspective

PubMed Central

Di Martino, Adriana; Fair, Damien A.; Kelly, Clare; Satterthwaite, Theodore D.; Castellanos, F. Xavier; Thomason, Moriah E.; Craddock, R. Cameron; Luna, Beatriz; Leventhal, Bennett L.; Zuo, Xi-Nian; Milham, Michael P.

2014-01-01

Summary The vast majority of mental illnesses can be conceptualized as developmental disorders of neural interactions within the connectome, or developmental miswiring. The recent maturation of pediatric in vivo brain imaging is bringing within reach the identification of clinically meaningful brain-based biomarkers of developmental disorders. Even more auspicious, is the ability to study the evolving connectome throughout life, beginning in utero, which promises to move the field from topological phenomenology to etiological nosology. Here, we scope advances in pediatric imaging of the brain connectome as the field faces the challenge of unraveling developmental miswiring. We highlight promises while also providing a pragmatic review of the many obstacles ahead that must be overcome to significantly impact public health. PMID:25233316

Cortical and Subcortical Brain Morphometry Differences Between Patients With Autism Spectrum Disorder and Healthy Individuals Across the Lifespan: Results From the ENIGMA ASD Working Group.

PubMed

van Rooij, Daan; Anagnostou, Evdokia; Arango, Celso; Auzias, Guillaume; Behrmann, Marlene; Busatto, Geraldo F; Calderoni, Sara; Daly, Eileen; Deruelle, Christine; Di Martino, Adriana; Dinstein, Ilan; Duran, Fabio Luis Souza; Durston, Sarah; Ecker, Christine; Fair, Damien; Fedor, Jennifer; Fitzgerald, Jackie; Freitag, Christine M; Gallagher, Louise; Gori, Ilaria; Haar, Shlomi; Hoekstra, Liesbeth; Jahanshad, Neda; Jalbrzikowski, Maria; Janssen, Joost; Lerch, Jason; Luna, Beatriz; Martinho, Mauricio Moller; McGrath, Jane; Muratori, Filippo; Murphy, Clodagh M; Murphy, Declan G M; O'Hearn, Kirsten; Oranje, Bob; Parellada, Mara; Retico, Alessandra; Rosa, Pedro; Rubia, Katya; Shook, Devon; Taylor, Margot; Thompson, Paul M; Tosetti, Michela; Wallace, Gregory L; Zhou, Fengfeng; Buitelaar, Jan K

2018-04-01

Neuroimaging studies show structural differences in both cortical and subcortical brain regions in children and adults with autism spectrum disorder (ASD) compared with healthy subjects. Findings are inconsistent, however, and it is unclear how differences develop across the lifespan. The authors investigated brain morphometry differences between individuals with ASD and healthy subjects, cross-sectionally across the lifespan, in a large multinational sample from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) ASD working group. The sample comprised 1,571 patients with ASD and 1,651 healthy control subjects (age range, 2-64 years) from 49 participating sites. MRI scans were preprocessed at individual sites with a harmonized protocol based on a validated automated-segmentation software program. Mega-analyses were used to test for case-control differences in subcortical volumes, cortical thickness, and surface area. Development of brain morphometry over the lifespan was modeled using a fractional polynomial approach. The case-control mega-analysis demonstrated that ASD was associated with smaller subcortical volumes of the pallidum, putamen, amygdala, and nucleus accumbens (effect sizes [Cohen's d], 0.13 to -0.13), as well as increased cortical thickness in the frontal cortex and decreased thickness in the temporal cortex (effect sizes, -0.21 to 0.20). Analyses of age effects indicate that the development of cortical thickness is altered in ASD, with the largest differences occurring around adolescence. No age-by-ASD interactions were observed in the subcortical partitions. The ENIGMA ASD working group provides the largest study of brain morphometry differences in ASD to date, using a well-established, validated, publicly available analysis pipeline. ASD patients showed altered morphometry in the cognitive and affective parts of the striatum, frontal cortex, and temporal cortex. Complex developmental trajectories were observed for the different regions, with a developmental peak around adolescence. These findings suggest an interplay in the abnormal development of the striatal, frontal, and temporal regions in ASD across the lifespan.

Urea cycle disorders: brain MRI and neurological outcome.

PubMed

Bireley, William R; Van Hove, Johan L K; Gallagher, Renata C; Fenton, Laura Z

2012-04-01

Urea cycle disorders encompass several enzyme deficiencies that can result in cerebral damage, with a wide clinical spectrum from asymptomatic to severe. The goal of this study was to correlate brain MRI abnormalities in urea cycle disorders with clinical neurological sequelae to evaluate whether MRI abnormalities can assist in guiding difficult treatment decisions. We performed a retrospective chart review of patients with urea cycle disorders and symptomatic hyperammonemia. Brain MRI images were reviewed for abnormalities that correlated with severity of clinical neurological sequelae. Our case series comprises six urea cycle disorder patients, five with ornithine transcarbamylase deficiency and one with citrullinemia type 1. The observed trend in distribution of brain MRI abnormalities as the severity of neurological sequelae increased was the peri-insular region first, extending into the frontal, parietal, temporal and, finally, the occipital lobes. There was thalamic restricted diffusion in three children with prolonged hyperammonemia. Prior to death, this site is typically reported to be spared in urea cycle disorders. The pattern and extent of brain MRI abnormalities correlate with clinical neurological outcome in our case series. This suggests that brain MRI abnormalities may assist in determining prognosis and helping clinicians with subsequent treatment decisions.

Lenticular abnormalities in children.

PubMed

Khokhar, Sudarshan; Agarwal, Tushar; Kumar, Gaurav; Kushmesh, Rakhi; Tejwani, Lalit Kumar

2012-01-01

To study the lenticular problems in children presenting at an apex institute. Retrospective analysis of records (< 14 years) of new lens clinic cases was done. Of 1,047 children, 687 were males. Mean age at presentation was 6.35 ± 4.13 years. Developmental cataract was seen in 45.6% and posttraumatic cataract in 29.7% of patients. Other abnormalities were cataract with retinal detachment, persistent hyperplastic primary vitreous, subluxated lens, micro/spherophakia, cataract secondary to uveitis, intraocular lens complications, cataract with choroidal coloboma, and visual axis opacification. Developmental and posttraumatic cataracts were the most common abnormalities. Delayed presentation is of concern. Copyright 2012, SLACK Incorporated.

Cytogenetic Studies of Rwandan Pediatric Patients Presenting with Global Developmental Delay, Intellectual Disability and/or Multiple Congenital Anomalies.

PubMed

Uwineza, Annette; Hitayezu, Janvier; Jamar, Mauricette; Caberg, Jean-Hubert; Murorunkwere, Seraphine; Janvier, Ndinkabandi; Bours, Vincent; Mutesa, Leon

2016-02-01

Global developmental delay (GDD) is defined as a significant delay in two or more developmental domains: gross or fine motor, speech/language, cognitive, social/personal and activities of daily living. Many of these children will go on to be diagnosed with intellectual disability (ID), which is most commonly defined as having an IQ <75 in addition to impairment in adaptive functioning. Cytogenetic studies have been performed in 664 Rwandan pediatric patients presenting GDD/ID and/or multiple congenital abnormalities (MCA). Karyotype analysis was performed in all patients and revealed 260 chromosomal abnormalities. The most frequent chromosomal abnormality was Down syndrome and then Edward syndrome and Patau syndrome. Other identified chromosomal abnormalities included 47,XX,+del(9)(q11), 46,XY,del(13)(q34) and 46,XX,der(22)t(10;22)(p10;p10)mat. In conclusion, our results highlight the high frequency of cytogenetically detectable abnormalities in this series, with implications for the burden on the healthcare. This study demonstrates the importance of cytogenetic analysis in patients with GDD/ID and MCA. © The Author [2015]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Irreversible barrier to the reprogramming of donor cells in cloning with mouse embryos and embryonic stem cells.

PubMed

Ono, Yukiko; Kono, Tomohiro

2006-08-01

Somatic cloning does not always result in ontogeny in mammals, and development is often associated with various abnormalities and embryo loss with a high frequency. This is considered to be due to aberrant gene expression resulting from epigenetic reprogramming errors. However, a fundamental question in this context is whether the developmental abnormalities reported to date are specific to somatic cloning. The aim of this study was to determine the stage of nuclear differentiation during development that leads to developmental abnormalities associated with embryo cloning. In order to address this issue, we reconstructed cloned embryos using four- and eight-cell embryos, morula embryos, inner cell mass (ICM) cells, and embryonic stem cells as donor nuclei and determined the occurrence of abnormalities such as developmental arrest and placentomegaly, which are common characteristics of all mouse somatic cell clones. The present analysis revealed that an acute decline in the full-term developmental competence of cloned embryos occurred with the use of four- and eight-cell donor nuclei (22.7% vs. 1.8%) in cases of standard embryo cloning and with morula and ICM donor nuclei (11.4% vs. 6.6%) in serial nuclear transfer. Histological observation showed abnormal differentiation and proliferation of trophoblastic giant cells in the placentae of cloned concepti derived from four-cell to ICM cell donor nuclei. Enlargement of placenta along with excessive proliferation of the spongiotrophoblast layer and glycogen cells was observed in the clones derived from morula embryos and ICM cells. These results revealed that irreversible epigenetic events had already started to occur at the four-cell stage. In addition, the expression of genes involved in placentomegaly is regulated at the blastocyst stage by irreversible epigenetic events, and it could not be reprogrammed by the fusion of nuclei with unfertilized oocytes. Hence, developmental abnormalities such as placentomegaly as well as embryo loss during development may occur even in cloned embryos reconstructed with nuclei from preimplantation-stage embryos, and these abnormalities are not specific to somatic cloning.

Abnormal functional connectivity density in children with anisometropic amblyopia at resting-state.

PubMed

Wang, Tianyue; Li, Qian; Guo, Mingxia; Peng, Yanmin; Li, Qingji; Qin, Wen; Yu, Chunshui

2014-05-14

Amblyopia is a developmental disorder resulting from anomalous binocular visual input in early life. Task-based neuroimaging studies have widely investigated cortical functional impairments in amblyopia, but changes in spontaneous neuronal functional activities in amblyopia remain largely unknown. In the present study, functional connectivity density (FCD) mapping, an ultrafast data-driven method based on fMRI, was applied for the first time to investigate changes in cortical functional connectivities in amblyopia during the resting-state. We quantified and compared both short- and long-range FCD in both the brains of children with anisometropic amblyopia (AAC) and normal sighted children (NSC). In contrast to the NSC, the AAC showed significantly decreased short-range FCD in the inferior temporal/fusiform gyri, parieto-occipital and rostrolateral prefrontal cortices, as well as decreased long-range FCD in the premotor cortex, dorsal inferior parietal lobule, frontal-insular and dorsal prefrontal cortices. Furthermore, most regions with reduced long-range FCD in the AAC showed decreased functional connectivity with occipital and posterior parietal cortices in the AAC. The results suggest that chronically poor visual input in amblyopia not only impairs the brain's short-range functional connections in visual pathways and in the frontal cortex, which is important for cognitive control, but also affects long-range functional connections among the visual areas, posterior parietal and frontal cortices that subserve visuomotor and visual-guided actions, visuospatial attention modulation and the integration of salient information. This study provides evidence for abnormal spontaneous brain activities in amblyopia. Copyright © 2014 Elsevier B.V. All rights reserved.

RHEB1 insufficiency in aged male mice is associated with stress-induced seizures.

PubMed

Tian, Qi; Gromov, Pavel; Clement, Joachim H; Wang, Yingming; Riemann, Marc; Weih, Falk; Sun, Xiao-Xin; Dai, Mu-Shui; Fedorov, Lev M

2017-12-01

The mechanistic target of rapamycin (mTOR), a protein kinase, is a central regulator of mammalian metabolism and physiology. Protein mTOR complex 1 (mTORC1) functions as a major sensor for the nutrient, energy, and redox state of a cell and is activated by ras homolog enriched in brain (RHEB1), a GTP-binding protein. Increased activation of mTORC1 pathway has been associated with developmental abnormalities, certain form of epilepsy (tuberous sclerosis), and cancer. Clinically, those mTOR-related disorders are treated with the mTOR inhibitor rapamycin and its rapalogs. Because the effects of chronic interference with mTOR signaling in the aged brain are yet unknown, we used a genetic strategy to interfere with mTORC1 signaling selectively by introducing mutations of Rheb1 into the mouse. We created conventional knockout (Rheb1 +/- ) and gene trap (Rheb1 Δ/+ ) mutant mouse lines. Rheb1-insufficient mice with different combinations of mutant alleles were monitored over a time span of 2 years. The mice did not show any behavioral/neurological changes during the first 18 months of age. However, after aging (> 18 months of age), both the Rheb1 +/- and Rheb1 Δ /- hybrid males developed rare stress-induced seizures, whereas Rheb1 +/- and Rheb1 Δ /- females and Rheb1 Δ/+ and Rheb1 Δ/Δ mice of both genders did not show any abnormality. Our findings suggest that chronic intervention with mTORC1 signaling in the aged brain might be associated with major adverse events.

[Forensic application of brainstem auditory evoked potential in patients with brain concussion].

PubMed

Zheng, Xing-Bin; Li, Sheng-Yan; Huang, Si-Xing; Ma, Ke-Xin

2008-12-01

To investigate changes of brainstem auditory evoked potential (BAEP) in patients with brain concussion. Nineteen patients with brain concussion were studied with BAEP examination. The data was compared to the healthy persons reported in literatures. The abnormal rate of BAEP for patients with brain concussion was 89.5%. There was a statistically significant difference between the abnormal rate of patients and that of healthy persons (P<0.05). The abnormal rate of BAEP in the brainstem pathway for patients with brain concussion was 73.7%, indicating dysfunction of the brainstem in those patients. BAEP might be helpful in forensic diagnosis of brain concussion.

Comparison of SPET brain perfusion and 18F-FDG brain metabolism in patients with chronic fatigue syndrome.

PubMed

Abu-Judeh, H H; Levine, S; Kumar, M; el-Zeftawy, H; Naddaf, S; Lou, J Q; Abdel-Dayem, H M

1998-11-01

Chronic fatigue syndrome is a clinically defined condition of uncertain aetiology. We compared 99Tcm-HMPAO single photon emission tomography (SPET) brain perfusion with dual-head 18F-FDG brain metabolism in patients with chronic fatigue syndrome. Eighteen patients (14 females, 4 males), who fulfilled the diagnostic criteria of the Centers for Disease Control for chronic fatigue syndrome, were investigated. Thirteen patients had abnormal SPET brain perfusion scans and five had normal scans. Fifteen patients had normal glucose brain metabolism scans and three had abnormal scans. We conclude that, in chronic fatigue syndrome patients, there is discordance between SPET brain perfusion and 18F-FDG brain uptake. It is possible to have brain perfusion abnormalities without corresponding changes in glucose uptake.

Frontal networks in adults with autism spectrum disorder

PubMed Central

Catani, Marco; Dell’Acqua, Flavio; Budisavljevic, Sanja; Howells, Henrietta; Thiebaut de Schotten, Michel; Froudist-Walsh, Seán; D’Anna, Lucio; Thompson, Abigail; Sandrone, Stefano; Bullmore, Edward T.; Suckling, John; Baron-Cohen, Simon; Lombardo, Michael V.; Wheelwright, Sally J.; Chakrabarti, Bhismadev; Lai, Meng-Chuan; Ruigrok, Amber N. V.; Leemans, Alexander; Ecker, Christine; Consortium, MRC AIMS; Craig, Michael C.

2016-01-01

Abstract It has been postulated that autism spectrum disorder is underpinned by an ‘atypical connectivity’ involving higher-order association brain regions. To test this hypothesis in a large cohort of adults with autism spectrum disorder we compared the white matter networks of 61 adult males with autism spectrum disorder and 61 neurotypical controls, using two complementary approaches to diffusion tensor magnetic resonance imaging. First, we applied tract-based spatial statistics, a ‘whole brain’ non-hypothesis driven method, to identify differences in white matter networks in adults with autism spectrum disorder. Following this we used a tract-specific analysis, based on tractography, to carry out a more detailed analysis of individual tracts identified by tract-based spatial statistics. Finally, within the autism spectrum disorder group, we studied the relationship between diffusion measures and autistic symptom severity. Tract-based spatial statistics revealed that autism spectrum disorder was associated with significantly reduced fractional anisotropy in regions that included frontal lobe pathways. Tractography analysis of these specific pathways showed increased mean and perpendicular diffusivity, and reduced number of streamlines in the anterior and long segments of the arcuate fasciculus, cingulum and uncinate—predominantly in the left hemisphere. Abnormalities were also evident in the anterior portions of the corpus callosum connecting left and right frontal lobes. The degree of microstructural alteration of the arcuate and uncinate fasciculi was associated with severity of symptoms in language and social reciprocity in childhood. Our results indicated that autism spectrum disorder is a developmental condition associated with abnormal connectivity of the frontal lobes. Furthermore our findings showed that male adults with autism spectrum disorder have regional differences in brain anatomy, which correlate with specific aspects of autistic symptoms. Overall these results suggest that autism spectrum disorder is a condition linked to aberrant developmental trajectories of the frontal networks that persist in adult life. PMID:26912520

Brain Injury in Neonates with Complex Congenital Heart Disease: What Is the Predictive Value of MRI in the Fetal Period?

PubMed

Brossard-Racine, M; du Plessis, A; Vezina, G; Robertson, R; Donofrio, M; Tworetzky, W; Limperopoulos, C

2016-07-01

Brain injury in neonates with congenital heart disease is an important predictor of adverse neurodevelopmental outcome. Impaired brain development in congenital heart disease may have a prenatal origin, but the sensitivity and specificity of fetal brain MR imaging for predicting neonatal brain lesions are currently unknown. We sought to determine the value of conventional fetal MR imaging for predicting abnormal findings on neonatal preoperative MR imaging in neonates with complex congenital heart disease. MR imaging studies were performed in 103 fetuses with confirmed congenital heart disease (mean gestational age, 31.57 ± 3.86 weeks) and were repeated postnatally before cardiac surgery (mean age, 6.8 ± 12.2 days). Each MR imaging study was read by a pediatric neuroradiologist. Brain abnormalities were detected in 17/103 (16%) fetuses by fetal MR imaging and in 33/103 (32%) neonates by neonatal MR imaging. Only 9/33 studies with abnormal neonatal findings were preceded by abnormal findings on fetal MR imaging. The sensitivity and specificity of conventional fetal brain MR imaging for predicting neonatal brain abnormalities were 27% and 89%, respectively. Brain abnormalities detected by in utero MR imaging in fetuses with congenital heart disease are associated with higher risk of postnatal preoperative brain injury. However, a substantial proportion of anomalies on postnatal MR imaging were not present on fetal MR imaging; this result is likely due to the limitations of conventional fetal MR imaging and the emergence of new lesions that occurred after the fetal studies. Postnatal brain MR imaging studies are needed to confirm the presence of injury before open heart surgery. © 2016 by American Journal of Neuroradiology.

MRI as a tool to study brain structure from mouse models for mental retardation

NASA Astrophysics Data System (ADS)

Verhoye, Marleen; Sijbers, Jan; Kooy, R. F.; Reyniers, E.; Fransen, E.; Oostra, B. A.; Willems, Peter; Van der Linden, Anne-Marie

1998-07-01

Nowadays, transgenic mice are a common tool to study brain abnormalities in neurological disorders. These studies usually rely on neuropathological examinations, which have a number of drawbacks, including the risk of artefacts introduced by fixation and dehydration procedures. Here we present 3D Fast Spin Echo Magnetic Resonance Imaging (MRI) in combination with 2D and 3D segmentation techniques as a powerful tool to study brain anatomy. We set up MRI of the brain in mouse models for the fragile X syndrome (FMR1 knockout) and Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus (CRASH) syndrome (L1CAM knockout). Our major goal was to determine qualitative and quantitative differences in specific brain structures. MRI of the brain of fragile X and CRASH patients has revealed alterations in the size of specific brain structures, including the cerebellar vermis and the ventricular system. In the present MRI study of the brain from fragile X knockout mice, we have measured the size of the brain, cerebellum and 4th ventricle, which were reported as abnormal in human fragile X patients, but found no evidence for altered brain regions in the mouse model. In CRASH syndrome, the most specific brain abnormalities are vermis hypoplasia and abnormalities of the ventricular system with some degree of hydrocephalus. With the MRI study of L1CAM knockout mice we found vermis hypoplasia, abnormalities of the ventricular system including dilatation of the lateral and the 4th ventricles. These subtle abnormalities were not detected upon standard neuropathological examination. Here we proved that this sensitive MRI technique allows to measure small differences which can not always be detected by means of pathology.

Developmental Thyroid Hormone Insufficiency Reduces Expression of Brain-Derived Neurotrophic Factor (BDNF) in Adults But Not in Neonates

EPA Science Inventory

Brain-derived neurotrophic factor (BDNF) is a neurotrophin critical for many developmental and physiological aspects of CNS function. Severe hypothyroidism in the early neonatal period results in developmental and cognitive impairments and reductions in mRNA and protein expressio...

In utero and lactational exposure to low-doses of the pyrethroid insecticide cypermethrin leads to neurodevelopmental defects in male mice—An ethological and transcriptomic study

PubMed Central

Herzine, Ameziane; Perche, Olivier; Richard, Olivier; Montecot-Dubourg, Céline; Menuet, Arnaud; Mazaud-Guittot, Séverine; Lesné, Laurianne; Jegou, Bernard; Mortaud, Stéphane

2017-01-01

Accumulating evidence suggests that developmental exposure to environmental chemicals may modify the course of brain development, ultimately leading to neuropsychiatric / neurodegenerative disorders later in life. In the present study, we assessed the impact of one of the most frequently used pesticides in both residential and agricultural applications − the synthetic pyrethroid cypermethrin (CYP) − on developmental neurotoxicity (DNT). Female mice were perinatally exposed to low doses of CYP (5 and 20 mg/kg body weight) from gestation to postnatal day 15. Behavioral analyses were performed during the offspring’s early life and during adulthood. Postnatal analyses revealed that perinatal exposure to CYP disturbed motor development without modifying sensory and communicative skills. We found that later in life, CYP-exposed offspring expressed maladaptive behaviors in response to highly challenging tasks and abnormal sociability. Transcriptomic analyses performed in the offspring’s brain at the end of the exposure, highlighted mitochondrial dysfunction as a relevant pathomechanism underlying CYP-induced DNT. Interestingly, several genes involved in proteostasis maintenance were also shown to be dysregulated suggesting that alterations in biogenesis, folding, trafficking and degradation of proteins may significantly contribute to CYP-related DNT. From a regulatory perspective, this study highlights that behavioral and transcriptomic analyses are complementary tools providing useful direction for better DNT characterization, and as such, should be used together more systematically. PMID:29020013

Brain surface contraction mapped in first-episode schizophrenia: a longitudinal magnetic resonance imaging study

PubMed Central

Sun, D; Stuart, GW; Jenkinson, M; Wood, SJ; McGorry, PD; Velakoulis, D; van Erp, TGM; Thompson, PM; Toga, AW; Smith, DJ; Cannon, TD; Pantelis, C

2009-01-01

Schizophrenia is associated with structural brain abnormalities, but the timing of onset and course of these changes remains unclear. Longitudinal magnetic resonance imaging (MRI) studies have demonstrated progressive brain volume decreases in patients around and after the onset of illness, although considerable discrepancies exist regarding which brain regions are affected. The anatomical pattern of these progressive changes in schizophrenia is largely unknown. In this study, MRI scans were acquired repeatedly from 16 schizophrenia patients approximately 2 years apart following their first episode of illness, and also from 14 age-matched healthy subjects. Cortical Pattern Matching, in combination with Structural Image Evaluation, using Normalisation, of Atrophy, was applied to compare the rates of cortical surface contraction between patients and controls. Surface contraction in the dorsal surfaces of the frontal lobe was significantly greater in patients with first-episode schizophrenia (FESZ) compared with healthy controls. Overall, brain surface contraction in patients and healthy controls showed similar anatomical patterns, with that of the former group exaggerated in magnitude across the entire brain surface. That the pattern of structural change in the early course of schizophrenia corresponds so closely to that associated with normal development is consistent with the hypothesis that a schizophrenia-related factor interacts with normal adolescent brain developmental processes in the pathophysiology of schizophrenia. The exaggerated progressive changes seen in patients with schizophrenia may reflect an increased rate of synaptic pruning, resulting in excessive loss of neuronal connectivity, as predicted by the late neurodevelopmental hypothesis of the illness. PMID:18607377

Brain evolution and development: adaptation, allometry and constraint

PubMed Central

Barton, Robert A.

2016-01-01

Phenotypic traits are products of two processes: evolution and development. But how do these processes combine to produce integrated phenotypes? Comparative studies identify consistent patterns of covariation, or allometries, between brain and body size, and between brain components, indicating the presence of significant constraints limiting independent evolution of separate parts. These constraints are poorly understood, but in principle could be either developmental or functional. The developmental constraints hypothesis suggests that individual components (brain and body size, or individual brain components) tend to evolve together because natural selection operates on relatively simple developmental mechanisms that affect the growth of all parts in a concerted manner. The functional constraints hypothesis suggests that correlated change reflects the action of selection on distributed functional systems connecting the different sub-components, predicting more complex patterns of mosaic change at the level of the functional systems and more complex genetic and developmental mechanisms. These hypotheses are not mutually exclusive but make different predictions. We review recent genetic and neurodevelopmental evidence, concluding that functional rather than developmental constraints are the main cause of the observed patterns. PMID:27629025

Primary headache pathophysiology in children: the contribution of clinical neurophysiology.

PubMed

Pro, S; Tarantino, S; Capuano, A; Vigevano, F; Valeriani, M

2014-01-01

Although primary headaches are very prevalent also in pediatric age, most neurophysiologic studies in these diseases concerned only the adulthood. The neurophysiologic investigation of the pathophysiological mechanisms subtending migraine and tension-type headache in children and adolescents could be particularly interesting, since during the developmental age the migrainous phenotype is scarcely influenced by many environmental factors that can typically act on adult headache patients. The neurophysiologic abnormality most frequently found in adult migraineurs, that is the reduced habituation of evoked potentials, was confirmed also in migraine children, although it was shown to involve also children with tension-type headache. Some studies showed abnormalities in the maturation of brain functions in migraine children and adolescents. While the visual system maturation seems slowed in young migraineurs, the psychophysiological mechanisms subtending somatosensory spatial attention in migraine children are more similar to those of healthy adults than to those of age-matched controls. There are some still unexplored fields that will have to be subjects of future studies. The nociceptive modality, which has been investigated in adult patients with primary headaches, should be studied also in pediatric migraine. Moreover, the technique of transcranial magnetic stimulation, not yet used in young migraineurs, will possibly provide further elements about brain excitability in migraine children. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Developmental Thyroid Hormone Insufficiency Induces Cortical Brain Malformation and Learning Impairments: A Cross-Fostering Study

EPA Science Inventory

Thyroid hormones (TH) are essential for brain development, but animal models of well-defined and sensitive downstream apical neurotoxic outcomes associated with developmental TH disruption are lacking. A structural anomaly, a cortical heterotopia, in the brains of hypothyroid rat...

Effective brain network analysis with resting-state EEG data: a comparison between heroin abstinent and non-addicted subjects

NASA Astrophysics Data System (ADS)

Hu, Bin; Dong, Qunxi; Hao, Yanrong; Zhao, Qinglin; Shen, Jian; Zheng, Fang

2017-08-01

Objective. Neuro-electrophysiological tools have been widely used in heroin addiction studies. Previous studies indicated that chronic heroin abuse would result in abnormal functional organization of the brain, while few heroin addiction studies have applied the effective connectivity tool to analyze the brain functional system (BFS) alterations induced by heroin abuse. The present study aims to identify the abnormality of resting-state heroin abstinent BFS using source decomposition and effective connectivity tools. Approach. The resting-state electroencephalograph (EEG) signals were acquired from 15 male heroin abstinent (HA) subjects and 14 male non-addicted (NA) controls. Multivariate autoregressive models combined independent component analysis (MVARICA) was applied for blind source decomposition. Generalized partial directed coherence (GPDC) was applied for effective brain connectivity analysis. Effective brain networks of both HA and NA groups were constructed. The two groups of effective cortical networks were compared by the bootstrap method. Abnormal causal interactions between decomposed source regions were estimated in the 1-45 Hz frequency domain. Main results. This work suggested: (a) there were clear effective network alterations in heroin abstinent subject groups; (b) the parietal region was a dominant hub of the abnormally weaker causal pathways, and the left occipital region was a dominant hub of the abnormally stronger causal pathways. Significance. These findings provide direct evidence that chronic heroin abuse induces brain functional abnormalities. The potential value of combining effective connectivity analysis and brain source decomposition methods in exploring brain alterations of heroin addicts is also implied.

Effective brain network analysis with resting-state EEG data: a comparison between heroin abstinent and non-addicted subjects.

PubMed

Hu, Bin; Dong, Qunxi; Hao, Yanrong; Zhao, Qinglin; Shen, Jian; Zheng, Fang

2017-08-01

Neuro-electrophysiological tools have been widely used in heroin addiction studies. Previous studies indicated that chronic heroin abuse would result in abnormal functional organization of the brain, while few heroin addiction studies have applied the effective connectivity tool to analyze the brain functional system (BFS) alterations induced by heroin abuse. The present study aims to identify the abnormality of resting-state heroin abstinent BFS using source decomposition and effective connectivity tools. The resting-state electroencephalograph (EEG) signals were acquired from 15 male heroin abstinent (HA) subjects and 14 male non-addicted (NA) controls. Multivariate autoregressive models combined independent component analysis (MVARICA) was applied for blind source decomposition. Generalized partial directed coherence (GPDC) was applied for effective brain connectivity analysis. Effective brain networks of both HA and NA groups were constructed. The two groups of effective cortical networks were compared by the bootstrap method. Abnormal causal interactions between decomposed source regions were estimated in the 1-45 Hz frequency domain. This work suggested: (a) there were clear effective network alterations in heroin abstinent subject groups; (b) the parietal region was a dominant hub of the abnormally weaker causal pathways, and the left occipital region was a dominant hub of the abnormally stronger causal pathways. These findings provide direct evidence that chronic heroin abuse induces brain functional abnormalities. The potential value of combining effective connectivity analysis and brain source decomposition methods in exploring brain alterations of heroin addicts is also implied.

Chronic ethanol exposure and folic acid supplementation: fetal growth and folate status in the maternal and fetal guinea pig.

PubMed

Hewitt, Amy J; Knuff, Amber L; Jefkins, Matthew J; Collier, Christine P; Reynolds, James N; Brien, James F

2011-05-01

Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus. Copyright © 2011 Elsevier Inc. All rights reserved.

High-Frequency EEG Variations in Children with Autism Spectrum Disorder during Human Faces Visualization

PubMed Central

Reategui, Camille; Costa, Bruna Karen de Sousa; da Fonseca, Caio Queiroz; da Silva, Luana; Morya, Edgard

2017-01-01

Autism spectrum disorder (ASD) is a neuropsychiatric disorder characterized by the impairment in the social reciprocity, interaction/language, and behavior, with stereotypes and signs of sensory function deficits. Electroencephalography (EEG) is a well-established and noninvasive tool for neurophysiological characterization and monitoring of the brain electrical activity, able to identify abnormalities related to frequency range, connectivity, and lateralization of brain functions. This research aims to evidence quantitative differences in the frequency spectrum pattern between EEG signals of children with and without ASD during visualization of human faces in three different expressions: neutral, happy, and angry. Quantitative clinical evaluations, neuropsychological evaluation, and EEG of children with and without ASD were analyzed paired by age and gender. The results showed stronger activation in higher frequencies (above 30 Hz) in frontal, central, parietal, and occipital regions in the ASD group. This pattern of activation may correlate with developmental characteristics in the children with ASD. PMID:29018811

Developmental social isolation affects adult behavior, social interaction, and dopamine metabolite levels in zebrafish.

PubMed

Shams, Soaleha; Amlani, Shahid; Buske, Christine; Chatterjee, Diptendu; Gerlai, Robert

2018-01-01

The zebrafish is a social vertebrate and an excellent translational model for a variety of human disorders. Abnormal social behavior is a hallmark of several human brain disorders. Social behavioral problems can arise as a result of adverse early social environment. Little is known about the effects of early social isolation in adult zebrafish. We compared zebrafish that were isolated for either short (7 days) or long duration (180 days) to socially housed zebrafish, testing their behavior across ontogenesis (ages 10, 30, 60, 90, 120, 180 days), and shoal cohesion and whole-brain monoamines and their metabolites in adulthood. Long social isolation increased locomotion and decreased shoal cohesion and anxiety in the open-field in adult. Additionally, both short and long social isolation reduced dopamine metabolite levels in response to social stimuli. Thus, early social isolation has lasting effects in zebrafish, and may be employed to generate zebrafish models of human neuropsychiatric conditions. © 2017 Wiley Periodicals, Inc.

What underlies the diversity of brain tumors?

PubMed Central

Swartling, Fredrik J.; Hede, Sanna-Maria; Weiss, William A.

2012-01-01

Glioma and medulloblastoma represent the most commonly occurring malignant brain tumors in adults and in children respectively. Recent genomic and transcriptional approaches present a complex group of diseases, and delineate a number of molecular subgroups within tumors that share a common histopathology. Differences in cells of origin, regional niches, developmental timing and genetic events all contribute to this heterogeneity. In an attempt to recapitulate the diversity of brain tumors, an increasing array of genetically engineered mouse models (GEMMs) has been developed. These models often utilize promoters and genetic drivers from normal brain development, and can provide insight into specific cells from which these tumors originate. GEMMs show promise in both developmental biology and developmental therapeutics. This review describes numerous murine brain tumor models in the context of normal brain development, and the potential for these animals to impact brain tumor research. PMID:23085857

Larger Brains in Medication Naive High-Functioning Subjects with Pervasive Developmental Disorder

ERIC Educational Resources Information Center

Palmen, Saskia J. M. C.; Pol, Hilleke E. Hulshoff; Kemner, Chantal; Schnack, Hugo G.; Janssen, Joost; Kahn, Rene S.; van Engeland, Herman

2004-01-01

Background: Are brain volumes of individuals with Pervasive Developmental Disorder (PDD) still enlarged in adolescence and adulthood, and if so, is this enlargement confined to the gray and/or the white matter and is it global or more prominent in specific brain regions. Methods: Brain MRI scans were made of 21 adolescents with PDD and 21 closely…

Growth and development of the brain and impact on cognitive outcomes.

PubMed

Hüppi, Petra S

2010-01-01

Understanding human brain development from the fetal life to adulthood is of great clinical importance as many neurological and neurobehavioral disorders have their origin in early structural and functional cerebral maturation. The developing brain is particularly prone to being affected by endogenous and exogenous events through the fetal and early postnatal life. The concept of 'developmental plasticity or disruption of the developmental program' summarizes these events. Increases in white matter, which speed up communication between brain cells, growing complexity of neuronal networks suggested by gray and white matter changes, and environmentally sensitive plasticity are all essential aspects in a child's ability to mentalize and maintain the adaptive flexibility necessary for achieving high sociocognitive functioning. Advancement in neuroimaging has opened up new ways for examining the developing human brain in vivo, the study of the effects of early antenatal, perinatal and neonatal events on later structural and functional brain development resulting in developmental disabilities or developmental resilience. In this review, methods of quantitative assessment of human brain development, such as 3D-MRI with image segmentation, diffusion tensor imaging to assess connectivity and functional MRI to visualize brain function will be presented. Copyright (c) 2010 S. Karger AG, Basel.

Isolated cortical visual loss with subtle brain MRI abnormalities in a case of hypoxic-ischemic encephalopathy.

PubMed

Margolin, Edward; Gujar, Sachin K; Trobe, Jonathan D

2007-12-01

A 16-year-old boy who was briefly asystolic and hypotensive after a motor vehicle accident complained of abnormal vision after recovering consciousness. Visual acuity was normal, but visual fields were severely constricted without clear hemianopic features. The ophthalmic examination was otherwise normal. Brain MRI performed 11 days after the accident showed no pertinent abnormalities. At 6 months after the event, brain MRI demonstrated brain volume loss in the primary visual cortex and no other abnormalities. One year later, visual fields remained severely constricted; neurologic examination, including formal neuropsychometric testing, was normal. This case emphasizes the fact that hypoxic-ischemic encephalopathy (HIE) may cause enduring damage limited to primary visual cortex and that the MRI abnormalities may be subtle. These phenomena should be recognized in the management of patients with HIE.

Development of quantitative analysis method for stereotactic brain image: assessment of reduced accumulation in extent and severity using anatomical segmentation.

PubMed

Mizumura, Sunao; Kumita, Shin-ichiro; Cho, Keiichi; Ishihara, Makiko; Nakajo, Hidenobu; Toba, Masahiro; Kumazaki, Tatsuo

2003-06-01

Through visual assessment by three-dimensional (3D) brain image analysis methods using stereotactic brain coordinates system, such as three-dimensional stereotactic surface projections and statistical parametric mapping, it is difficult to quantitatively assess anatomical information and the range of extent of an abnormal region. In this study, we devised a method to quantitatively assess local abnormal findings by segmenting a brain map according to anatomical structure. Through quantitative local abnormality assessment using this method, we studied the characteristics of distribution of reduced blood flow in cases with dementia of the Alzheimer type (DAT). Using twenty-five cases with DAT (mean age, 68.9 years old), all of whom were diagnosed as probable Alzheimer's disease based on NINCDS-ADRDA, we collected I-123 iodoamphetamine SPECT data. A 3D brain map using the 3D-SSP program was compared with the data of 20 cases in the control group, who age-matched the subject cases. To study local abnormalities on the 3D images, we divided the whole brain into 24 segments based on anatomical classification. We assessed the extent of an abnormal region in each segment (rate of the coordinates with a Z-value that exceeds the threshold value, in all coordinates within a segment), and severity (average Z-value of the coordinates with a Z-value that exceeds the threshold value). This method clarified orientation and expansion of reduced accumulation, through classifying stereotactic brain coordinates according to the anatomical structure. This method was considered useful for quantitatively grasping distribution abnormalities in the brain and changes in abnormality distribution.

Clinical and mutational spectrum in Korean patients with Rubinstein-Taybi syndrome: the spectrum of brain MRI abnormalities.

PubMed

Lee, Jin Sook; Byun, Christine K; Kim, Hunmin; Lim, Byung Chan; Hwang, Hee; Choi, Ji Eun; Hwang, Yong Seung; Seong, Moon-Woo; Park, Sung Sup; Kim, Ki Joong; Chae, Jong-Hee

2015-04-01

Rubinstein-Taybi syndrome (RSTS) is one of the neurodevelopmental disorders caused by mutations of epigenetic genes. The CREBBP gene is the most common causative gene, encoding the CREB-binding protein with histone acetyltransferase (HAT) activity, an epigenetic modulator. To date, there have been few reports on the structural abnormalities of the brain in RSTS patients. In addition, there are no reports on the analysis of CREBBP mutations in Korean RSTS patients. We performed mutational analyses on 16 unrelated patients with RSTS, with diagnosis based on the typical clinical features. Their medical records and brain MRI images were reviewed retrospectively. Ten of 16 patients (62.5%) had mutations in the CREBBP gene. The mutations included five frameshift mutations (31.2%), two nonsense mutations (12.5%), and three multiexon deletions (18.8%). There were no remarkable significant differences in the clinical features between those with and without a CREBBP mutation, although brain MRI abnormalities were more frequently observed in those with a CREBBP mutation. Seven of 10 patients in whom brain imaging was performed had structural abnormalities, including Chiari malformation type 1, thinning of the corpus callosum, and delayed myelination. There were no differences in delayed development or cognitive impairment between those with and without abnormal brain images, while epilepsy was involved in two patients who had abnormalities on brain MRI images. We investigated the spectrum of CREBBP mutations in Korean patients with RSTS for the first time. Eight novel mutations extended the genetic spectrum of CREBBP mutations in RSTS patients. This is also the first study showing the prevalence and spectrum of abnormalities on brain MRI in RSTS patients. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Impact of brain injury on functional measures of amplitude-integrated EEG at term equivalent age in premature infants.

PubMed

El Ters, N M; Vesoulis, Z A; Liao, S M; Smyser, C D; Mathur, A M

2017-08-01

To evaluate the association between qualitative and quantitative amplitude-integrated EEG (aEEG) measures at term equivalent age (TEA) and brain injury on magnetic resonance imaging (MRI) in preterm infants. A cohort of premature infants born at <30 weeks of gestation and with moderate-to-severe MRI injury on a TEA MRI scan was identified. A contemporaneous group of gestational age-matched control infants also born at <30 weeks of gestation with none/mild injury on MRI was also recruited. Quantitative aEEG measures, including maximum and minimum amplitudes, bandwidth span and spectral edge frequency (SEF 90 ), were calculated using an offline software package. The aEEG recordings were qualitatively scored using the Burdjalov system. MRI scans, performed on the same day as aEEG, occurred at a mean postmenstrual age of 38.0 (range 37 to 42) weeks and were scored for abnormality in a blinded manner using an established MRI scoring system. Twenty-eight (46.7%) infants had a normal MRI or mild brain abnormality, while 32 (53.3%) infants had moderate-to-severe brain abnormality. Univariate regression analysis demonstrated an association between severity of brain abnormality and quantitative measures of left and right SEF 90 and bandwidth span (β=-0.38, -0.40 and 0.30, respectively) and qualitative measures of cyclicity, continuity and total Burdjalov score (β=-0.10, -0.14 and -0.12, respectively). After correcting for confounding variables, the relationship between MRI abnormality score and aEEG measures of SEF 90 , bandwidth span and Burdjalov score remained significant. Brain abnormalities on MRI at TEA in premature infants are associated with abnormalities on term aEEG measures, suggesting that anatomical brain injury may contribute to delay in functional brain maturation as assessed using aEEG.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ema, Makoto, E-mail: ema-makoto@aist.go.jp; Gamo, Masashi; Honda, Kazumasa

We summarized significant effects reported in the literature on the developmental toxicity of engineered nanomaterials (ENMs) in rodents. The developmental toxicity of ENMs included not only structural abnormalities, but also death, growth retardation, and behavioral and functional abnormalities. Most studies were performed on mice using an injection route of exposure. Teratogenic effects were indicated when multi-walled carbon nanotubes (MWCNTs), single-walled carbon nanotubes (SWCNTs), and TiO{sub 2}-nanoparticles were administered to mice during early gestation. Reactive oxygen species levels were increased in placentas and malformed fetuses and their placentas after prenatal exposure to MWCNTs and SWCNTs, respectively. The pre- and postnatal mortalitiesmore » and growth retardation in offspring increased after prenatal exposure to ENMs. Histopathological and functional abnormalities were also induced in placentas after prenatal exposure to ENMs. Maternal exposure to ENMs induced behavioral alterations, histopathological and biochemical changes in the central nervous system, increased susceptibility to allergy, transplacental genotoxicity, and vascular, immunological, and reproductive effects in offspring. The size- and developmental stage-dependent placental transfer of ENMs was noted after maternal exposure. Silver accumulated in the visceral yolk sac after being injected with Ag-NPs during early gestation. Although currently available data has provided initial information on the potential developmental toxicity of ENMs, that on the developmental toxicity of ENMs is still very limited. Further studies using well-characterized ENMs, state-of the-art study protocols, and appropriate routes of exposure are required in order to clarify these developmental effects and provide information suitable for risk assessments of ENMs. - Highlights: • We review the developmental toxicity studies of engineered nanomaterials (ENMs). • Various developmental endpoints have been reported after exposure to ENMs. • Physico-chemical properties of ENMs are determinants of the developmental toxicity. • Oxidative stress/inflammation may be involved in the developmental toxicity of ENMs. • Further developmental toxicity studies of ENMs are needed to fill a data gap.« less

Reliability of magnetic resonance imaging for the detection of hypopituitarism in children with optic nerve hypoplasia.

PubMed

Ramakrishnaiah, Raghu H; Shelton, Julie B; Glasier, Charles M; Phillips, Paul H

2014-01-01

It is essential to identify hypopituitarism in children with optic nerve hypoplasia (ONH) because they are at risk for developmental delay, seizures, or death. The purpose of this study is to determine the reliability of neurohypophyseal abnormalities on magnetic resonance imaging (MRI) for the detection of hypopituitarism in children with ONH. Cross-sectional study. One hundred one children with clinical ONH who underwent MRI of the brain and orbits and a detailed pediatric endocrinologic evaluation. Magnetic resonance imaging studies were performed on 1.5-Tesla scanners. The imaging protocol included sagittal T1-weighted images, axial fast fluid-attenuated inversion-recovery/T2-weighted images, and diffusion-weighted images of the brain. Orbital imaging included fat-saturated axial and coronal images and high-resolution axial T2-weighted images. The MRI studies were reviewed by 2 pediatric neuroradiologists for optic nerve hypoplasia, absent or ectopic posterior pituitary, absent pituitary infundibulum, absent septum pellucidum, migration anomalies, and hemispheric injury. Medical records were reviewed for clinical examination findings and endocrinologic status. All patients underwent a clinical evaluation by a pediatric endocrinologist and a standardized panel of serologic testing that included serum insulin-like growth factor-1, insulin-like growth factor binding protein-3, prolactin, cortisol, adrenocorticotropic hormone, thyroid-stimulating hormone, and free thyroxine levels. Radiologists were masked to patients' endocrinologic status and funduscopic findings. Sensitivity and specificity of MRI findings for the detection of hypopituitarism. Neurohypophyseal abnormalities, including absent pituitary infundibulum, ectopic posterior pituitary bright spot, and absent posterior pituitary bright spot, occurred in 33 children. Magnetic resonance imaging disclosed neurohypophyseal abnormalities in 27 of the 28 children with hypopituitarism (sensitivity, 96%). A normal neurohypophysis occurred in 67 of 73 children with normal endocrinologic function (specificity, 92%). Neurohypophyseal abnormalities on MRI are sensitive and specific indicators of hypopituitarism in children with ONH. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Sex Differences in Intelligence and Brain Size: A Developmental Theory.

ERIC Educational Resources Information Center

Lynn, Richard

1999-01-01

Proposes a developmental theory of sex differences in intelligence that states that the faster maturation and brain size growth in girls up to age 15 compensates for their smaller brain size so that sex differences in intelligence are very small. Discusses evidence that supports this theory. (SLD)

Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species

PubMed Central

Semple, Bridgette D.; Blomgren, Klas; Gimlin, Kayleen; Ferriero, Donna M.; Noble-Haeusslein, Linda J.

2013-01-01

Hypoxic-ischemic and traumatic brain injuries are leading causes of long-term mortality and disability in infants and children. Although several preclinical models using rodents of different ages have been developed, species differences in the timing of key brain maturation events can render comparisons of vulnerability and regenerative capacities difficult to interpret. Traditional models of developmental brain injury have utilized rodents at postnatal day 7–10 as being roughly equivalent to a term human infant, based historically on the measurement of post-mortem brain weights during the 1970s. Here we will examine fundamental brain development processes that occur in both rodents and humans, to delineate a comparable time course of postnatal brain development across species. We consider the timing of neurogenesis, synaptogenesis, gliogenesis, oligodendrocyte maturation and age-dependent behaviors that coincide with developmentally regulated molecular and biochemical changes. In general, while the time scale is considerably different, the sequence of key events in brain maturation is largely consistent between humans and rodents. Further, there are distinct parallels in regional vulnerability as well as functional consequences in response to brain injuries. With a focus on developmental hypoxicischemic encephalopathy and traumatic brain injury, this review offers guidelines for researchers when considering the most appropriate rodent age for the developmental stage or process of interest to approximate human brain development. PMID:23583307

Quantitative Folding Pattern Analysis of Early Primary Sulci in Human Fetuses with Brain Abnormalities.

PubMed

Im, K; Guimaraes, A; Kim, Y; Cottrill, E; Gagoski, B; Rollins, C; Ortinau, C; Yang, E; Grant, P E

2017-07-01

Aberrant gyral folding is a key feature in the diagnosis of many cerebral malformations. However, in fetal life, it is particularly challenging to confidently diagnose aberrant folding because of the rapid spatiotemporal changes of gyral development. Currently, there is no resource to measure how an individual fetal brain compares with normal spatiotemporal variations. In this study, we assessed the potential for automatic analysis of early sulcal patterns to detect individual fetal brains with cerebral abnormalities. Triplane MR images were aligned to create a motion-corrected volume for each individual fetal brain, and cortical plate surfaces were extracted. Sulcal basins were automatically identified on the cortical plate surface and compared with a combined set generated from 9 normal fetal brain templates. Sulcal pattern similarities to the templates were quantified by using multivariate geometric features and intersulcal relationships for 14 normal fetal brains and 5 fetal brains that were proved to be abnormal on postnatal MR imaging. Results were compared with the gyrification index. Significantly reduced sulcal pattern similarities to normal templates were found in all abnormal individual fetuses compared with normal fetuses (mean similarity [normal, abnormal], left: 0.818, 0.752; P < .001; right: 0.810, 0.753; P < .01). Altered location and depth patterns of sulcal basins were the primary distinguishing features. The gyrification index was not significantly different between the normal and abnormal groups. Automated analysis of interrelated patterning of early primary sulci could outperform the traditional gyrification index and has the potential to quantitatively detect individual fetuses with emerging abnormal sulcal patterns. © 2017 by American Journal of Neuroradiology.

Exposure to benzidine caused apoptosis and malformation of telencephalon region in zebrafish.

PubMed

Chen, Mark Hung-Chih; Hsu, Li-Chi; Wu, Jia-Lun; Yeh, Chi-Wei; Tsai, Jen-Ning; Hseu, You-Cheng; Hsu, Li-Sung

2014-12-01

Exposure to benzidine has been known to induce human cancers, particularly bladder carcinomas. In this study, the zebrafish model was used to investigate the developmental toxicity of benzidine. Embryos at 6 h postfertilization (hpf) that were exposed to benzidine exhibited embryonic death in a dose- and time-dependent manner. Benzidine induced malformations in zebrafish, such as small brain development, shorter axes, and a slight pericardial edema. High concentrations (50, 100, and 200 µM) of benzidine triggered widespread apoptosis in the brain and dorsal neurons, as evidenced by acridine orange and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays. Real-time polymerase chain reaction analysis also showed that benzidine treatment affected p53, bax, and noxa expression. Decreases in specific brain markers, such as emx1 in the telencephalon, ngn1 in differentiated neurons, and otx2 in the midbrain, were observed in benzidine-treated embryos at 24 hpf. Conversely, no overt changes to pax2.1 expression in the midbrain-hindbrain boundary were found. Moreover, the use of Tg(HuC:GFP) zebrafish showed that benzidine caused a malformation of the telencephalon region. Our findings show that benzidine exposure triggers widespread apoptosis in the zebrafish brain and dorsal neurons, resulting in the development of an abnormal telencephalon. © 2013 Wiley Periodicals, Inc.

Subliminal trauma reminders impact neural processing of cognitive control in adults with developmental earthquake trauma: a preliminary report.

PubMed

Du, Xue; Li, Yu; Ran, Qian; Kim, Pilyoung; Ganzel, Barbara L; Liang, GuangSheng; Hao, Lei; Zhang, Qinglin; Meng, Huaqing; Qiu, Jiang

2016-03-01

Little is known about the effects of developmental trauma on the neural basis of cognitive control among adults who do not have posttraumatic stress disorder. To examine this question, we used functional magnetic resonance imaging to compare the effect of subliminal priming with earthquake-related images on attentional control during a Stroop task in survivors of the 2008 Wenchuan earthquake in China (survivor group, survivors were adolescents at the time of the earthquake) and in matched controls (control group). We found that the survivor group showed greater activation in the left ventral anterior cingulate cortex (vACC) and the bilateral parahippocampal gyrus during the congruent versus incongruent condition, as compared to the control group. Depressive symptoms were positively correlated with left vACC activation during the congruent condition. Moreover, psychophysiological interaction results showed that the survivor group had stronger functional connectivity between the left parahippocampal gyrus and the left vACC than the control group under the congruent-incongruent condition. These results suggested that trauma-related information was linked to abnormal activity in brain networks associated with cognitive control (e.g., vACC-parahippocampal gyrus). This may be a potential biomarker for depression following developmental trauma, and it may also provide a mechanism linking trauma reminders with depression.

Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism.

PubMed

Costa, Lucio G; Chang, Yu-Chi; Cole, Toby B

2017-06-01

Epidemiological and animal studies suggest that air pollution may negatively affect the central nervous system (CNS) and contribute to CNS diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component. Several studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity and that perinatal exposure may cause or contribute to developmental disabilities and behavioral abnormalities. In particular, a number of recent studies have found associations between exposures to traffic-related air pollution and autism spectrum disorders (ASD), which are characterized by impairment in socialization and in communication and by the presence of repetitive and unusual behaviors. The cause(s) of ASD are unknown, and while it may have a hereditary component, environmental factors are increasingly suspected as playing a pivotal role in its etiology, particularly in genetically susceptible individuals. Autistic children present higher levels of neuroinflammation and systemic inflammation, which are also hallmarks of exposure to traffic-related air pollution. Gene-environment interactions may play a relevant role in determining individual susceptibility to air pollution developmental neurotoxicity. Given the worldwide presence of elevated air pollution, studies on its effects and mechanisms on the developing brain, genetic susceptibility, role in neurodevelopmental disorders, and possible therapeutic interventions are certainly warranted.

Temporal abnormalities in children with developmental dyscalculia.

PubMed

Vicario, Carmelo Mario; Rappo, Gaetano; Pepi, Annamaria; Pavan, Andrea; Martino, Davide

2012-01-01

Recent imaging studies have associated Developmental dyscalculia (DD) to structural and functional alterations corresponding Parietal and the Prefrontal cortex (PFC). Since these areas were shown also to be involved in timing abilities, we hypothesized that time processing is abnormal in DD. We compared time processing abilities between 10 children with pure DD (8 years old) and 11 age-matched healthy children. Results show that the DD group underestimated duration of a sub-second scale when asked to perform a time comparison task. The timing abnormality observed in our DD participants is consistent with evidence of a shared fronto-parietal neural network for representing time and quantity.

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (L-CHAD) deficiency in a patient with the Bannayan-Riley-Ruvalcaba syndrome.

PubMed

Fryburg, J S; Pelegano, J P; Bennett, M J; Bebin, E M

1994-08-01

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is an autosomal dominant condition of macrocephaly in combination with lipomas/hemangiomas, hypotonia, developmental delay, and a lipid myopathy. The etiology of the lipid storage myopathy has been unclear. We describe a black boy with findings of BRRS who also has a defect in long-chain fatty acid oxidation expressed in cultured skin fibroblasts as a deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (L-CHAD). He also has an abnormal brain MRI and increased size of both lower limbs. We present this child because of his unusual combination of findings, and postulate that L-CHAD deficiency may be the cause of the lipid myopathy in BRRS.

Molecular analysis of nicotinic receptor expression in autism.

PubMed

Martin-Ruiz, C M; Lee, M; Perry, R H; Baumann, M; Court, J A; Perry, E K

2004-04-07

Autism is a developmental disorder of unknown aetiopathology and lacking any specific pharmacological therapeutic intervention. Neurotransmitters such as serotonin, gamma-aminobutyric acid (GABA) and acetylcholine have been implicated. Abnormalities in nicotinic acetylcholine receptors have been identified including cortical loss of binding to the alpha4/beta2 subtype and increase in cerebellar alpha7 binding. Receptor expression (mRNA) has not so far been systematically examined. This study aims to further explore the role of nicotinic receptors in autism by analysing nicotinic receptor subunit mRNA in conjunction with protein levels and receptor binding in different brain areas. Quantitative RT-PCR for alpha4, alpha7 and beta2 subunit mRNA expression levels; alpha3, alpha4, alpha7 and beta2 subunit protein expression immunochemistry and specific radioligand receptor binding were performed in adult autism and control brain samples from cerebral cortex and cerebellum. Alpha4 and beta2 protein expression and receptor binding density as well as alpha4 mRNA levels were lower in parietal cortex in autism, while alpha7 did not change for any of these parameters. In cerebellum, alpha4 mRNA expression was increased, whereas subunit protein and receptor levels were decreased. Alpha7 receptor binding in cerebellum was increased alongside non-significant elevations in mRNA and protein expression levels. No significant changes were found for beta2 in cerebellum. The data obtained, using complementary measures of receptor expression, indicate that reduced gene expression of the alpha4beta2 nicotinic receptor in the cerebral cortex is a major feature of the neurochemical pathology of autism, whilst post-transcriptional abnormalities of both this and the alpha7 subtype are apparent in the cerebellum. The findings point to dendritic and/or synaptic nicotinic receptor abnormalities that may relate to disruptions in cerebral circuitry development.

[Ocular coloboma and results of brain MRI: preliminary results].

PubMed

Denis, D; Girard, N; Levy-Mozziconacci, A; Berbis, J; Matonti, F

2013-03-01

Congenital ocular colobomas are the result of a failure in closure of the embryonal fissure. We present a prospective study (2007-2011) in which we report brain MRI findings in children with ocular coloboma. Thirty-five children (54 eyes) were included; 15 boys, 20 girls with a median age of 24.0 months (1.0-96.0) at first presentation. Within 2 to 3 months following complete ophthalmologic examination, brain MRI was performed. Colobomas were bilateral in 19 cases and unilateral in 16 cases. Eleven different types of coloboma were identified. Of 54 eyes, 74% demonstrated optic nerve coloboma, of which 28 were severe. Of 35 MRI's performed, abnormalities were present in 86%: gyration abnormalities (n=21), lateral ventricular dilatation (n=17), dilatation of the Virchow-Robin and subarachnoid spaces (n=14), signal abnormalities and brain stem malformations (n=14), white matter signal abnormalities (n=11), corpus callosum abnormalities (n=10). Most of these abnormalities were related. Gyration abnormalities were the most frequent. There was no significant association between the severity of the coloboma and the abnormalities found (P=1.0). Likewise, there was no significant association of gyration abnormalities with the severity of coloboma in children (P=1.0). This study shows, for the first time, the existence of frequent cerebral abnormalities on MRI in children with ocular coloboma. The most common abnormality being gyration abnormalities, in 60% of cases. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Transient dysautonomia in an acute phase of encephalopathy with biphasic seizures and late reduced diffusion.

PubMed

Ichimiya, Yuko; Kaku, Noriyuki; Sakai, Yasunari; Yamashita, Fumiya; Matsuoka, Wakato; Muraoka, Mamoru; Akamine, Satoshi; Mizuguchi, Soichi; Torio, Michiko; Motomura, Yoshitomo; Hirata, Yuichiro; Ishizaki, Yoshito; Sanefuji, Masafumi; Torisu, Hiroyuki; Takada, Hidetoshi; Maehara, Yoshihiko; Ohga, Shouichi

2017-08-01

Paroxysmal sympathetic hyperactivity (PSH) is a dysautonomic condition that is associated with various types of acquired brain injuries. Traumatic brain lesions have been documented as the leading cause of PSH. However, detailed clinical features of pediatric PSH caused by intrinsic brain lesions remain to be elusive. We present a 3-year-old boy, who had been diagnosed as having cerebral palsy, developmental delay and epilepsy after perinatal hypoxia-induced brain injury. He developed status epilepticus with fever on the third day of respiratory infection. Whereas the seizure was terminated by systemic infusion of midazolam, consciousness remained disturbed for the next 48h. Serial magnetic resonance imaging studies revealed that acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) evolved on 3days after the seizure. Therapeutic hypothermia was immediately introduced, however, the brain lesion extended to the whole subcortical white matters on day 8. The intermittent bilateral dilation of pupils with increased blood pressure and tachycardia were observed until day 12. Real-time monitoring of electroencephalograms ruled out the recurrent attacks of seizures. The abnormal signs of autonomic nervous system gradually ceased and never relapsed after recovery from the hypothermia. PSH or a transient condition of dysautonomia may emerge and persist during the acute phase of AESD. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

A high resolution spatiotemporal atlas of gene expression of the developing mouse brain

PubMed Central

Thompson, Carol L.; Ng, Lydia; Menon, Vilas; Martinez, Salvador; Lee, Chang-Kyu; Glattfelder, Katie; Sunkin, Susan M.; Henry, Alex; Lau, Christopher; Dang, Chinh; Garcia-Lopez, Raquel; Martinez-Ferre, Almudena; Pombero, Ana; Rubenstein, John L.R.; Wakeman, Wayne B.; Hohmann, John; Dee, Nick; Sodt, Andrew J.; Young, Rob; Smith, Kimberly; Nguyen, Thuc-Nghi; Kidney, Jolene; Kuan, Leonard; Jeromin, Andreas; Kaykas, Ajamete; Miller, Jeremy; Page, Damon; Orta, Geri; Bernard, Amy; Riley, Zackery; Smith, Simon; Wohnoutka, Paul; Hawrylycz, Mike; Puelles, Luis; Jones, Allan R.

2015-01-01

SUMMARY To provide a temporal framework for the genoarchitecture of brain development, in situ hybridization data were generated for embryonic and postnatal mouse brain at 7 developmental stages for ~2100 genes, processed with an automated informatics pipeline and manually annotated. This resource comprises 434,946 images, 7 reference atlases, an ontogenetic ontology, and tools to explore co-expression of genes across neurodevelopment. Gene sets coinciding with developmental phenomena were identified. A temporal shift in the principles governing the molecular organization of the brain was detected, with transient neuromeric, plate-based organization of the brain present at E11.5 and E13.5. Finally, these data provided a transcription factor code that discriminates brain structures and identifies the developmental age of a tissue, providing a foundation for eventual genetic manipulation or tracking of specific brain structures over development. The resource is available as the Allen Developing Mouse Brain Atlas (developingmouse.brain-map.org). PMID:24952961

Fetal magnetic resonance imaging (MRI): a tool for a better understanding of normal and abnormal brain development.

PubMed

Saleem, Sahar N

2013-07-01

Knowledge of the anatomy of the developing fetal brain is essential to detect abnormalities and understand their pathogenesis. Capability of magnetic resonance imaging (MRI) to visualize the brain in utero and to differentiate between its various tissues makes fetal MRI a potential diagnostic and research tool for the developing brain. This article provides an approach to understand the normal and abnormal brain development through schematic interpretation of fetal brain MR images. MRI is a potential screening tool in the second trimester of pregnancies in fetuses at risk for brain anomalies and helps in describing new brain syndromes with in utero presentation. Accurate interpretation of fetal MRI can provide valuable information that helps genetic counseling, facilitates management decisions, and guides therapy. Fetal MRI can help in better understanding the pathogenesis of fetal brain malformations and can support research that could lead to disease-specific interventions.

USING THE MEDAKA EMBRYO ASSAY TO INVESTIGATE DEVELOPMENTAL ETHANOL TOXICITY.

EPA Science Inventory

Ethanol (EtOH) is a well-known developmental toxicant that produces a range of abnormal phenotypes. While the toxic potential of developmental EtOH exposure is well characterized, the effect of the timing of exposure on the extent of toxicity remains unknown. Fish models such as ...

[Phocomelia in Africa: thoughts about a case report].

PubMed

Mouafo Tambo, Faustin Félicien; Andze, Ondobo Gervais

2010-01-01

Phocomelia is a developmental abnormality which occurs during pregnancy and results in congenital ectromelia (developmental arrest of one or more limbs), with characteristically atrophied limbs that look as if they were directly implanted on the trunk, that is, like seal (phocid) flippers. The authors report the case of a Cameroonian neonate. Abnormalities were limited to the upper limbs. The lack of useful causal information and especially the difficulties in therapeutic management in this context are highlighted.

Growth and development of children prenatally exposed to telbivudine administered for the treatment of chronic hepatitis B in their mothers.

PubMed

Zeng, Huihui; Cai, Haodong; Wang, Ying; Shen, Ying

2015-04-01

We studied the growth and development of children prenatally exposed to telbivudine used to treat chronic hepatitis B virus (HBV) infection in their mothers. Maternal abnormalities during pregnancy and delivery and infant congenital anomalies, physical development status, developmental quotient (DQ), HBV vertical transmission status, and HBV vaccination outcomes of 54 infants were evaluated (2010-2013). No fetal abnormalities were observed during pregnancy or delivery. Postpartum, three infants (5.56%) had abnormalities: ankyloglossia, cutaneous hemangioma, and vaginal canal leak. Height and weight were within the normal range at birth and at 6 weeks, but were higher than the reference at 12 months (p<0.05). Body mass index increased gradually with age (p<0.05). DQ scores were normal (84.81%, 229/270) in 37 children (68.52%), abnormal or suspicious for a developmental delay (15.19%, 41/270) in 17 children (31.48%), and indicated a developmental delay (4.07%, 11/270) in seven children (12.96%). There were no significant differences in developmental delay between children prenatally exposed to telbivudine and controls (p>0.05). HBV vertical transmission was successfully blocked in all infants. The effective HBV vaccination rate was 98.15% (53/54). The growth and development of children prenatally exposed to telbivudine was normal, indicating that telbivudine treatment during pregnancy is safe and effective. Copyright © 2015. Published by Elsevier Ltd.

RADIATION MALFORMATIONS BELONGING TO THE CYCLOPIA-ARRHINENCEPHALIA- OTECEPHALIA GROUP IN THE MOUSE FETUS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marakami, U.; Kameyana, Y.; Majima, A.

1962-03-01

Pregnant mice on the 8.5th day of gestation were subjected to 200-r whole-body irradiation and the fetuses were examined on the l3th to l9th day of gestation. Incidence of fetal death (23.0%) was much higher than in the controls (8.2%1, and malformations of the nose, eyes, and ears cecurred in 32%. These malformations included alterations leading to a beaklike snout (19%), a univentricular telencephalon with cyclopia (6%), and forms transitional between these two (6%). These malformations were specific for irradiation on the 8.5th day of gestation; in previous studies they were not prominent when irradiation was carried out on themore » 8th, lOth, or llth day. During this most sensitive developmental stsge at 8.5 days, 3 to 5 brain vesicles are formed and the anterior neuropore is closed, which may account for the greater effect of teratogenic agents on the central nervous system at this time. Other abnormalities included exencephalia 12%), hydrocephalus (4%), microcephalia 10.7%), abnormally shaped head (5%), spinal cord anomalies (6%), eye anomalies (29%1, harelip and cleft palate (12%), tail abnormalities (6%), and thoraco- abdominal hernia (5%). (H.H.D.)« less

RADIATION MALFORMATIONS BELONGING TO THE CYCLOPIA-ARRHINECEPHALIA- OCTOCEPHALIA GROUP IN THE MOUSE FETUS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murakami, U.; Kameyama, Y.; Majima, A.

1962-03-01

Pregnant mice on the 8 1/2th day of gestation were subjected to 200 r whole-body irradiation and the fetuses were examined on the l3th to l9th day of gestation. Incidence of fetal death (23.0%) was much higher than in the controls (8.2%), and malformations of the nose, eyes, and ears occurred in 32%. These malformations included alterations leading to a beaklike snout (19%), a univentricular telencephalon with cyclopia (6%), and fomas transitional between these two (6%). These malformations were specific for irradiation on the 8 1/2th day of gestation. In previous studies they were not prominent when irradiation was carriedmore » out on the 8th, l0th, or llth day. During this most sensitive developmental stage at 8 1/2 days, 3 to 5 brain vesicles are formed and the anterior neuropore is closed, which may account for the greater effect of teratogenic agents on the central nervous system at this time. Other abnormalities included exencephalia (2%), hydrocephalus (4%), microcephalia (0.7%), abnormally shaped head (5%), spinal cord anomalies (6%), eye anomalies (29%), harelip and cleft palate (l2%), tail abnormalities (6%), and thoraco- abdominal hennia (5%). (H.H.D.)« less

Brain ultrasound findings in neonates treated with intrauterine transfusion for fetal anaemia.

PubMed

Leijser, Lara M; Vos, Nikki; Walther, Frans J; van Wezel-Meijler, Gerda

2012-09-01

The main causes of severe fetal anaemia are red-cell allo-immunization, parvo B19 virus infection and feto-maternal haemorrhage. Treatment consists of intrauterine transfusion (IUT). Neuro-imaging studies in surviving neonates treated with IUT are scarce. To assess if neonates treated with IUT for fetal anaemia are at risk for cerebral injury, report the incidence and severity of brain ultrasound (US) abnormalities and explore the relation between brain US findings and perinatal parameters and neurological outcome. Brain US scans of neonates born alive between 2001 and 2008 with at least one IUT were retrospectively reviewed and classified as normal, mildly or moderately/severely abnormal. Incidences of abnormalities were calculated for full-term and preterm neonates. Presence and severity of abnormalities were related to clinical and IUT related parameters and to neurological outcome around 2 years of age (adverse: moderate or severe disability; favourable: normal or mild disability). A total of 127 neonates (82 born preterm) were included. Median number of IUTs was 3 (range 1-6) and of brain US 2 (1-6). Median gestational age and weight at birth were 36.6 (26.0-41.1) weeks and 2870 (1040-3950)g. In 72/127 (57%) neonates ≥1 abnormality was seen on brain US, classified as moderate/severe in 30/127 (24%). Neurological outcome was adverse in 5 infants. Presence of brain US abnormalities was not significantly related to any of the perinatal parameters or to neurological outcome. Neonates undergoing IUT for fetal anaemia are at high risk of brain injury. Copyright © 2012 Elsevier Ltd. All rights reserved.

The intersection of stress, drug abuse and development.

PubMed

Thadani, Pushpa V

2002-01-01

Use or abuse of licit and illicit substances is often associated with environmental stress. Current clinical evidence clearly demonstrates neurobehavioral, somatic growth and developmental deficits in children born to drug-using mothers. However, the effects of environmental stress and its interaction with prenatal drug exposure on a child's development is unknown. Studies in pregnant animals under controlled conditions show drug-induced long-term alterations in brain structures and functions of the offspring. These cytoarchitecture alterations in the brain are often associated with perturbations in neurotransmitter systems that are intimately involved in the regulation of the stress responses. Similar abnormalities have been observed in the brains of animals exposed to other adverse exogenous (e.g., environmental stress) and/or endogenous (e.g., glucocorticoids) experiences during early life. The goal of this article is to: (1) provide evidence and a perspective that common neural systems are influenced during development both by perinatal drug exposure and early stress exposure; and (2) identify gaps and encourage new research examining the effects of early stress and perinatal drug exposure, in animal models, that would elucidate how stress- and drug-induced perturbations in neural systems influence later vulnerability to abused drugs in adult offspring.

Neurotoxicants are in the air: convergence of human, animal, and in vitro studies on the effects of air pollution on the brain.

PubMed

Costa, Lucio G; Cole, Toby B; Coburn, Jacki; Chang, Yu-Chi; Dao, Khoi; Roque, Pamela

2014-01-01

In addition to increased morbidity and mortality caused by respiratory and cardiovascular diseases, air pollution may also negatively affect the brain and contribute to central nervous system diseases. Air pollution is a mixture comprised of several components, of which ultrafine particulate matter (UFPM; <100 nm) is of much concern, as these particles can enter the circulation and distribute to most organs, including the brain. A major constituent of ambient UFPM is represented by traffic-related air pollution, mostly ascribed to diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution may lead to neurotoxicity. In addition to a variety of behavioral abnormalities, two prominent effects caused by air pollution are oxidative stress and neuroinflammation, which are seen in both humans and animals and are confirmed by in vitro studies. Among factors which can affect neurotoxic outcomes, age is considered the most relevant. Human and animal studies suggest that air pollution (and DE) may cause developmental neurotoxicity and may contribute to the etiology of neurodevelopmental disorders, including autistic spectrum disorders. In addition, air pollution exposure has been associated with increased expression of markers of neurodegenerative disease pathologies.

Spontaneous Seizures and Altered Gene Expression in GABA Signaling Pathways in a mind bomb Mutant Zebrafish

PubMed Central

Hortopan, Gabriela A.; Dinday, Matthew T.; Baraban, Scott C.

2010-01-01

Disruption of E3 ubiquitin ligase activity in immature zebrafish mind bomb mutants, leads to a failure in Notch signaling, excessive numbers of neurons, and depletion of neural progenitor cells. This neurogenic phenotype is associated with defects in neural patterning and brain development. Because developmental brain abnormalities are recognized as an important feature of childhood neurological disorders such as epilepsy and autism, we determined whether zebrafish mutants with grossly abnormal brain structure exhibit spontaneous electrical activity that resembles the long-duration, high-amplitude multi-spike discharges reported in immature zebrafish exposed to convulsant drugs. Electrophysiological recordings from agar immobilized mind bomb mutants at three days postfertilization (dpf) confirmed the occurrence of electrographic seizure activity; seizure-like behaviors were also noted during locomotion video tracking of freely behaving mutants. To identify genes differentially expressed in the mind bomb mutant and provide insight into molecular pathways that may mediate these epileptic phenotypes, a transcriptome analysis was performed using microarray. Interesting candidate genes were further analyzed using conventional reverse transcriptasepolymerase chain reaction (RT-PCR) and real-time quantitative PCR (qPCR), as well as whole-mount in situ hybridization. Approximately 150 genes, some implicated in development, transcription, cell metabolism and signal transduction, are differentially regulated including down-regulation of several genes necessary for GABA-mediated signaling. These findings identify a collection of gene transcripts that may be responsible for the abnormal electrical discharge and epileptic activities observed in a mind bomb zebrafish mutant. This work may have important implications for neurological and neurodevelopmental disorders associated with mutations in ubiquitin ligase activity. Notch is an essential component of an evolutionarily conserved signal transduction cascade mediating development. In neuroectoderm, where cells have the potential to become neurons, activated Notch inhibits proneural gene expression in a process referred to as lateral inhibition. In the absence of Notch-mediated lateral inhibition, too many early-born cells differentiate into neurons (Chitnis et al., 1995; de la Pompa et al., 1997). Recent studies identified several E3 ligases that modulate Notch signaling through ubiquitin-dependent protein degradation and endocytosis (Lai, 2002). Ubiquitination, which occurs when an E3 ligase enzyme binds to both substrate and an E2 thioesterified protein (Deshaies and Joazeiro, 2009), is a key mechanism regulating many cellular processes. Mutation or small deletions within the ubiquitin E3A ligase gene in humans has been linked to autism spectrum disorders (Glessner et al., 2009) and Angelman syndrome, a neurogenetic disorder characterized by developmental delay, severe intellectual disability, absent speech, exuberant behavior, motor impairment, and epilepsy (Clayton-Smith and Laan, 2003). PMID:20943912

A role for cerebellum in the hereditary dystonia DYT1

PubMed Central

Fremont, Rachel; Tewari, Ambika; Angueyra, Chantal; Khodakhah, Kamran

2017-01-01

DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential developmental compensation between rodents and humans. To address this issue, torsinA was acutely knocked down in select brain regions of adult mice using shRNAs. TorsinA knockdown in the cerebellum, but not in the basal ganglia, was sufficient to induce dystonia. In agreement with a potential developmental compensation for loss of torsinA in rodents, torsinA knockdown in the immature cerebellum failed to produce dystonia. Abnormal motor symptoms in knockdown animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. These data identify the cerebellum as the main site of dysfunction in DYT1, and offer new therapeutic targets. DOI: http://dx.doi.org/10.7554/eLife.22775.001 PMID:28198698

Infantile Autism and Computerized Tomography Brain-Scan Findings: Specific versus Nonspecific Abnormalities.

ERIC Educational Resources Information Center

Balottin, Umberto; And Others

1989-01-01

The study of computerized tomography brain-scan findings with 45 autistic and 19 control subjects concluded that autism is nonspecifically associated with brain-scan abnormalities, and that other nonorganic, as well as organic, factors should be taken into account. (Author/DB)

Developmental amnesia: a new pattern of dissociation with intact episodic memory.

PubMed

Temple, Christine M; Richardson, Paul

2004-01-01

A case of developmental amnesia is reported for a child, CL, of normal intelligence, who has intact episodic memory but impaired semantic memory for both semantic knowledge of facts and semantic knowledge of words, including general world knowledge, knowledge of word meanings and superordinate knowledge of words. In contrast to the deficits in semantic memory, there are no impairments in episodic memory for verbal or visual material, assessed by recall or recognition. Lexical decision was also intact, indicating impairment in semantic knowledge of vocabulary rather than absence of lexical representations. The case forms a double dissociation to the cases of Vargha-Khadem et al. [Science 277 (1997) 376; Episodic memory: new directions in research (2002) 153]; Gadian et al. [Brain 123 (2000) 499] for whom semantic memory was intact but episodic memory was impaired. This double dissociation suggests that semantic memory and episodic memory have the capacity to develop separately and supports models of modularity within memory development and a functional architecture for the developmental disorders within which there is residual normality rather than pervasive abnormality. Knowledge of arithmetical facts is also spared for CL, consistent with adult studies arguing for numeracy knowledge distinct from other semantics. Reading was characterised by difficulty with irregular words and homophones but intact reading of nonwords. CL has surface dyslexia with poor lexico-semantic reading skills but good phonological reading skills. The case was identified following screening from a population of normal schoolchildren suggesting that developmental amnesias may be more pervasive than has been recognised previously.

Rapid Morphological Brain Abnormalities during Acute Methamphetamine Intoxication in the Rat. An Experimental study using Light and Electron Microscopy

PubMed Central

Sharma, Hari S.; Kiyatkin, Eugene A.

2009-01-01

This study describes morphological abnormalities of brain cells during acute methamphetamine (METH) intoxication in the rat and demonstrates the role of hyperthermia, disruption of the blood-brain barrier (BBB) and edema in their development. Rats with chronically implanted brain, muscle and skin temperature probes and an intravenous (iv) catheter were exposed to METH (9 mg/kg) at standard (23°C) and warm (29°C) ambient temperatures, allowing for the observation of hyperthermia ranging from mild to pathological levels (38–42°C). When brain temperature peaked or reached a level suggestive of possible lethality (>41.5°C), rats were injected with Evans blue (EB), rapidly anesthetized, perfused, and their brains were taken for further analyses. Four brain areas (cortex, hippocampus, thalamus and hypothalamus) were analyzed for EB extravasation, water and electrolyte (Na+, K+, Cl−) contents, immunostained for albumin and glial fibrillary acidic protein, and examined for neuronal, glial and axonal alterations using standard light and electron microscopy. These examinations revealed profound abnormalities in neuronal, glial, and endothelial cells, which were stronger with METH administered at 29°C than 23°C and tightly correlated with brain and body hyperthermia. These changes had some structural specificity, but in each structure they tightly correlated with increases in EB levels, the numbers of albumin-positive cells, and water and ion contents, suggesting leakage of the BBB, acutely developing brain edema, and serious shifts in brain ion homeostasis as leading factors underlying brain abnormalities. While most of these acute structural and functional abnormalities appear to be reversible, they could trigger subsequent cellular alterations in the brain and accelerate neurodegeneration—the most dangerous complication of chronic amphetamine-like drug abuse. PMID:18773954

Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice.

PubMed

Martinez-Garay, Isabel; Guidi, Luiz G; Holloway, Zoe G; Bailey, Melissa A G; Lyngholm, Daniel; Schneider, Tomasz; Donnison, Timothy; Butt, Simon J B; Monaco, Anthony P; Molnár, Zoltán; Velayos-Baeza, Antonio

2017-04-01

Developmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319.

Neurogenetics of developmental dyslexia: from genes to behavior through brain neuroimaging and cognitive and sensorial mechanisms

PubMed Central

Mascheretti, S; De Luca, A; Trezzi, V; Peruzzo, D; Nordio, A; Marino, C; Arrigoni, F

2017-01-01

Developmental dyslexia (DD) is a complex neurodevelopmental deficit characterized by impaired reading acquisition, in spite of adequate neurological and sensorial conditions, educational opportunities and normal intelligence. Despite the successful characterization of DD-susceptibility genes, we are far from understanding the molecular etiological pathways underlying the development of reading (dis)ability. By focusing mainly on clinical phenotypes, the molecular genetics approach has yielded mixed results. More optimally reduced measures of functioning, that is, intermediate phenotypes (IPs), represent a target for researching disease-associated genetic variants and for elucidating the underlying mechanisms. Imaging data provide a viable IP for complex neurobehavioral disorders and have been extensively used to investigate both morphological, structural and functional brain abnormalities in DD. Performing joint genetic and neuroimaging studies in humans is an emerging strategy to link DD-candidate genes to the brain structure and function. A limited number of studies has already pursued the imaging–genetics integration in DD. However, the results are still not sufficient to unravel the complexity of the reading circuit due to heterogeneous study design and data processing. Here, we propose an interdisciplinary, multilevel, imaging–genetic approach to disentangle the pathways from genes to behavior. As the presence of putative functional genetic variants has been provided and as genetic associations with specific cognitive/sensorial mechanisms have been reported, new hypothesis-driven imaging–genetic studies must gain momentum. This approach would lead to the optimization of diagnostic criteria and to the early identification of ‘biologically at-risk’ children, supporting the definition of adequate and well-timed prevention strategies and the implementation of novel, specific remediation approach. PMID:28045463

Hippocampal Shape Abnormalities of Patients with Childhood-Onset Schizophrenia and Their Unaffected Siblings

ERIC Educational Resources Information Center

Johnson, Sarah L. M.; Wang, Lei; Alpert, Kathryn I.; Greenstein, Deanna; Clasen, Liv; Lalonde, Francois; Miller, Rachel; Rapoport, Judith; Gogtay, Nitin

2013-01-01

Objective: The hippocampus has been implicated in the pathogenesis of schizophrenia, and hippocampal volume deficits have been a consistently reported abnormality, but the subregional specificity of the deficits remains unknown. The authors explored the nature and developmental trajectory of subregional shape abnormalities of the hippocampus in…

Congenital Zika Virus Infection: Beyond Neonatal Microcephaly.

PubMed

Melo, Adriana Suely de Oliveira; Aguiar, Renato Santana; Amorim, Melania Maria Ramos; Arruda, Monica B; Melo, Fabiana de Oliveira; Ribeiro, Suelem Taís Clementino; Batista, Alba Gean Medeiros; Ferreira, Thales; Dos Santos, Mayra Pereira; Sampaio, Virgínia Vilar; Moura, Sarah Rogéria Martins; Rabello, Luciana Portela; Gonzaga, Clarissa Emanuelle; Malinger, Gustavo; Ximenes, Renato; de Oliveira-Szejnfeld, Patricia Soares; Tovar-Moll, Fernanda; Chimelli, Leila; Silveira, Paola Paz; Delvechio, Rodrigo; Higa, Luiza; Campanati, Loraine; Nogueira, Rita M R; Filippis, Ana Maria Bispo; Szejnfeld, Jacob; Voloch, Carolina Moreira; Ferreira, Orlando C; Brindeiro, Rodrigo M; Tanuri, Amilcar

2016-12-01

Recent studies have reported an increase in the number of fetuses and neonates with microcephaly whose mothers were infected with the Zika virus (ZIKV) during pregnancy. To our knowledge, most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects. To describe the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurological damage associated with ZIKV infection in Brazil. We observed 11 infants with congenital ZIKV infection from gestation to 6 months in the state of Paraíba, Brazil. Ten of 11 women included in this study presented with symptoms of ZIKV infection during the first half of pregnancy, and all 11 had laboratory evidence of the infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by magnetic resonance imaging. Histopathological analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis. Description of the major lesions caused by ZIKV congenital infection. Of the 11 infants, 7 (63.6%) were female, and the median (SD) maternal age at delivery was 25 (6) years. Three of 11 neonates died, giving a perinatal mortality rate of 27.3%. The median (SD) cephalic perimeter at birth was 31 (3) cm, a value lower than the limit to consider a microcephaly case. In all patients, neurological impairments were identified, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence (ie, arthrogryposis). Results of limited testing for other causes of microcephaly, such as genetic disorders and viral and bacterial infections, were negative, and the ZIKV genome was found in both maternal and neonatal tissues (eg, amniotic fluid, cord blood, placenta, and brain). Phylogenetic analyses showed an intrahost virus variation with some polymorphisms in envelope genes associated with different tissues. Combined findings from clinical, laboratory, imaging, and pathological examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported. The term congenital Zika syndrome is preferable to refer to these cases, as microcephaly is just one of the clinical signs of this congenital malformation disorder.

Haloperidol normalized prenatal vitamin D depletion-induced reduction of hippocampal cell proliferation in adult rats.

PubMed

Keilhoff, Gerburg; Grecksch, Gisela; Becker, Axel

2010-05-31

Considering the fact that schizophrenia is a highly complex disorder of the human brain, different models are needed to test specific causative or mechanistic hypotheses. The pathogenesis of schizophrenia is also characterized by abnormal neuronal development. It was found that schizophrenia as well as antipsychotic treatment are accompanied by alterations in neuronal proliferation. Recently we reported on increased neurogenesis and their controllability by neuroleptics in a pharmacological (ketamine) model of schizophrenia. To complete our understanding, here we studied neurogenesis and its sensitivity to the classical neuroleptic haloperidol in a developmental model of schizophrenia (maternal vitamin D deficiency). It was found that maternal vitamin D deficiency resulted in decreased neurogenesis. This effect was ameliorated by subchronic treatment with haloperidol. Thus, the results complete previous findings concerning the ability of haloperidol to ameliorate behavioral abnormalities induced by prenatal vitamin D deficiency and introduce the possibility to explain the curative effects of haloperidol, at least in part, due to re-establishment of disturbed cell proliferation. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Preliminary evidence for obesity and elevations in fasting insulin mediating associations between cortisol awakening response and hippocampal volumes and frontal atrophy.

PubMed

Ursache, Alexandra; Wedin, William; Tirsi, Aziz; Convit, Antonio

2012-08-01

Recent studies have demonstrated alterations in the cortisol awakening response (CAR) and brain abnormalities in adults with obesity and type 2 diabetes mellitus (T2DM). While adolescents with T2DM exhibit similar brain abnormalities, less is known about whether brain impairments and hypothalamic-pituitary-adrenal (HPA) axis abnormalities are already present in adolescents with pre-diabetic conditions such as insulin resistance (IR). This study included 33 adolescents with IR and 20 without IR. Adolescents with IR had a blunted CAR, smaller hippocampal volumes, and greater frontal lobe atrophy compared to controls. Mediation analyses indicated pathways whereby a smaller CAR was associated with higher BMI which was in turn associated with fasting insulin levels, which in turn was related to smaller hippocampal volume and greater frontal lobe atrophy. While we had hypothesized that HPA dysregulation may result from brain abnormalities, our findings suggest that HPA dysregulation may also impact brain structures through associations with metabolic abnormalities. Copyright © 2012 Elsevier Ltd. All rights reserved.

Frequency of brain MRI abnormalities in neuromyelitis optica spectrum disorder at presentation: A cohort of Latin American patients.

PubMed

Carnero Contentti, Edgar; Daccach Marques, Vanessa; Soto de Castillo, Ibis; Tkachuk, Veronica; Antunes Barreira, Amilton; Armas, Elizabeth; Chiganer, Edson; de Aquino Cruz, Camila; Di Pace, José Luis; Hryb, Javier Pablo; Lavigne Moreira, Carolina; Lessa, Carmen; Molina, Omaira; Perassolo, Monica; Soto, Arnoldo; Caride, Alejandro

2018-01-01

Brain magnetic resonance imaging (BMRI) lesions were classically not reported in neuromyelitis optica (NMO). However, BMRI lesions are not uncommon in NMO spectrum disorder (NMOSD) patients. To report BMRI characteristic abnormalities (location and configuration) in NMOSD patients at presentation. Medical records and BMRI characteristics of 79 patients with NMOSD (during the first documented attack) in Argentina, Brazil and Venezuela were reviewed retrospectively. BMRI abnormalities were observed in 81.02% of NMOSD patients at presentation. Forty-two patients (53.1%) showed typical-NMOSD abnormalities. We found BMRI abnormalities at presentation in the brainstem/cerebellum (n = 26; 32.9%), optic chiasm (n = 16; 20.2%), area postrema (n = 13; 16.4%), thalamus/hypothalamus (n = 11; 13.9%), corpus callosum (n = 11; 13.9%), periependymal-third ventricle (n = 9; 11.3%), corticospinal tract (n = 7; 8.8%), hemispheric white matter (n = 1; 1.2%) and nonspecific areas (n = 49; 62.03%). Asymptomatic BMRI lesions were more common. The frequency of brain MRI abnormalities did not differ between patients who were positive and negative for aquaporin 4 antibodies at presentation. Typical brain MRI abnormalities are frequent in NMOSD at disease onset. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of brain-wide connectivity architecture in awake rats.

PubMed

Ma, Zilu; Ma, Yuncong; Zhang, Nanyin

2018-08-01

Childhood and adolescence are both critical developmental periods, evidenced by complex neurophysiological changes the brain undergoes and high occurrence rates of neuropsychiatric disorders during these periods. Despite substantial progress in elucidating the developmental trajectories of individual neural circuits, our knowledge of developmental changes of whole-brain connectivity architecture in animals is sparse. To fill this gap, here we longitudinally acquired rsfMRI data in awake rats during five developmental stages from juvenile to adulthood. We found that the maturation timelines of brain circuits were heterogeneous and system specific. Functional connectivity (FC) tended to decrease in subcortical circuits, but increase in cortical circuits during development. In addition, the developing brain exhibited hemispheric functional specialization, evidenced by reduced inter-hemispheric FC between homotopic regions, and lower similarity of region-to-region FC patterns between the two hemispheres. Finally, we showed that whole-brain network development was characterized by reduced clustering (i.e. local communication) but increased integration (distant communication). Taken together, the present study has systematically characterized the development of brain-wide connectivity architecture from juvenile to adulthood in awake rats. It also serves as a critical reference point for understanding circuit- and network-level changes in animal models of brain development-related disorders. Furthermore, FC data during brain development in awake rodents contain high translational value and can shed light onto comparative neuroanatomy. Copyright © 2018 Elsevier Inc. All rights reserved.

Prediction complements explanation in understanding the developing brain.

PubMed

Rosenberg, Monica D; Casey, B J; Holmes, Avram J

2018-02-21

A central aim of human neuroscience is understanding the neurobiology of cognition and behavior. Although we have made significant progress towards this goal, reliance on group-level studies of the developed adult brain has limited our ability to explain population variability and developmental changes in neural circuitry and behavior. In this review, we suggest that predictive modeling, a method for predicting individual differences in behavior from brain features, can complement descriptive approaches and provide new ways to account for this variability. Highlighting the outsized scientific and clinical benefits of prediction in developmental populations including adolescence, we show that predictive brain-based models are already providing new insights on adolescent-specific risk-related behaviors. Together with large-scale developmental neuroimaging datasets and complementary analytic approaches, predictive modeling affords us the opportunity and obligation to identify novel treatment targets and individually tailor the course of interventions for developmental psychopathologies that impact so many young people today.

Development of the brain's functional network architecture.

PubMed

Vogel, Alecia C; Power, Jonathan D; Petersen, Steven E; Schlaggar, Bradley L

2010-12-01

A full understanding of the development of the brain's functional network architecture requires not only an understanding of developmental changes in neural processing in individual brain regions but also an understanding of changes in inter-regional interactions. Resting state functional connectivity MRI (rs-fcMRI) is increasingly being used to study functional interactions between brain regions in both adults and children. We briefly review methods used to study functional interactions and networks with rs-fcMRI and how these methods have been used to define developmental changes in network functional connectivity. The developmental rs-fcMRI studies to date have found two general properties. First, regional interactions change from being predominately anatomically local in children to interactions spanning longer cortical distances in young adults. Second, this developmental change in functional connectivity occurs, in general, via mechanisms of segregation of local regions and integration of distant regions into disparate subnetworks.

Development of the Brain's Functional Network Architecture

PubMed Central

Power, Jonathan D.; Petersen, Steven E.; Schlaggar, Bradley L.

2013-01-01

A full understanding of the development of the brain's functional network architecture requires not only an understanding of developmental changes in neural processing in individual brain regions but also an understanding of changes in inter-regional interactions. Resting state functional connectivity MRI (rs-fcMRI) is increasingly being used to study functional interactions between brain regions in both adults and children. We briefly review methods used to study functional interactions and networks with rs-fcMRI and how these methods have been used to define developmental changes in network functional connectivity. The developmental rs-fcMRI studies to date have found two general properties. First, regional interactions change from being predominately anatomically local in children to interactions spanning longer cortical distances in young adults. Second, this developmental change in functional connectivity occurs, in general, via mechanisms of segregation of local regions and integration of distant regions into disparate subnetworks. PMID:20976563

Joint Prediction of Longitudinal Development of Cortical Surfaces and White Matter Fibers from Neonatal MRI

PubMed Central

Rekik, Islem; Li, Gang; Yap, Pew-Thian; Chen, Geng; Lin, Weili; Shen, Dinggang

2017-01-01

The human brain can be modeled as multiple interrelated shapes (or a multishape), each for characterizing one aspect of the brain, such as the cortex and white matter pathways. Predicting the developing multishape is a very challenging task due to the contrasting nature of the developmental trajectories of the constituent shapes: smooth for the cortical surface and non-smooth for white matter tracts due to changes such as bifurcation. We recently addressed this problem and proposed an approach for predicting the multishape developmental spatiotemporal trajectories of infant brains based only on neonatal MRI data using a set of geometric, dynamic, and fiber-to-surface connectivity features. In this paper, we propose two key innovations to further improve the prediction of multishape evolution. First, for a more accurate cortical surface prediction, instead of simply relying on one neonatal atlas to guide the prediction of the multishape, we propose to use multiple neonatal atlases to build a spatially heterogeneous atlas using the multidirectional varifold representation. This individualizes the atlas by locally maximizing its similarity to the testing baseline cortical shape for each cortical region, thereby better representing the baseline testing cortical surface, which founds the multishape prediction process. Second, for temporally consistent fiber prediction, we propose to reliably estimate spatiotemporal connectivity features using low-rank tensor completion, thereby capturing the variability and richness of the temporal development of fibers. Experimental results confirm that the proposed variants significantly improve the prediction performance of our original multishape prediction framework for both cortical surfaces and fiber tracts shape at 3, 6, and 9 months of age. Our pioneering model will pave the way for learning how to predict the evolution of anatomical shapes with abnormal changes. Ultimately, devising accurate shape evolution prediction models that can help quantify and predict the severity of a brain disorder as it progresses will be of great aid in individualized treatment planning. PMID:28284800

Joint prediction of longitudinal development of cortical surfaces and white matter fibers from neonatal MRI.

PubMed

Rekik, Islem; Li, Gang; Yap, Pew-Thian; Chen, Geng; Lin, Weili; Shen, Dinggang

2017-05-15

The human brain can be modeled as multiple interrelated shapes (or a multishape), each for characterizing one aspect of the brain, such as the cortex and white matter pathways. Predicting the developing multishape is a very challenging task due to the contrasting nature of the developmental trajectories of the constituent shapes: smooth for the cortical surface and non-smooth for white matter tracts due to changes such as bifurcation. We recently addressed this problem and proposed an approach for predicting the multishape developmental spatiotemporal trajectories of infant brains based only on neonatal MRI data using a set of geometric, dynamic, and fiber-to-surface connectivity features. In this paper, we propose two key innovations to further improve the prediction of multishape evolution. First, for a more accurate cortical surface prediction, instead of simply relying on one neonatal atlas to guide the prediction of the multishape, we propose to use multiple neonatal atlases to build a spatially heterogeneous atlas using the multidirectional varifold representation. This individualizes the atlas by locally maximizing its similarity to the testing baseline cortical shape for each cortical region, thereby better representing the baseline testing cortical surface, which founds the multishape prediction process. Second, for temporally consistent fiber prediction, we propose to reliably estimate spatiotemporal connectivity features using low-rank tensor completion, thereby capturing the variability and richness of the temporal development of fibers. Experimental results confirm that the proposed variants significantly improve the prediction performance of our original multishape prediction framework for both cortical surfaces and fiber tracts shape at 3, 6, and 9 months of age. Our pioneering model will pave the way for learning how to predict the evolution of anatomical shapes with abnormal changes. Ultimately, devising accurate shape evolution prediction models that can help quantify and predict the severity of a brain disorder as it progresses will be of great aid in individualized treatment planning. Copyright © 2017 Elsevier Inc. All rights reserved.

Utility of brain MRI in children with sleep-disordered breathing.

PubMed

Selvadurai, Sarah; Al-Saleh, Suhail; Amin, Reshma; Zweerink, Allison; Drake, James; Propst, Evan J; Narang, Indra

2017-02-01

To investigate the utility of a brain magnetic resonance imaging (MRI) in children with sleep-disordered breathing (SDB), classified as isolated obstructive sleep apnea (OSA) in the absence of adenotonsillar hypertrophy, persistent OSA following adenotonsillectomy, isolated central sleep apnea (CSA) of unclear etiology, OSA with coexisting CSA of unclear etiology, or unexplained nocturnal hypoventilation (NH). Retrospective chart review of polysomnography (PSG) and brain MRI data. Children with PSG evidence of SDB, as described above, and who subsequently had their first brain MRI, were included. PSG, MRI data, and subsequent interventions were recorded. A total of 59 of 6,087 (1%) children met inclusion criteria. Of those, 28 of 59 (47%) were nonsyndromic children and 31 of 59 (53%) were syndromic children with an underlying medical disorder. Abnormal brain MRI findings were observed in 19 of 59 (32%) children, where eight of 19 (42%) were nonsyndromic and 11 of 19 (58%) were syndromic. Abnormal brain MRI findings were most common in syndromic children with combined OSA and CSA without adenotonsillar hypertrophy. Isolated OSA was also a common PSG finding associated with an abnormal brain MRI. Of the nonsyndromic children with an abnormal brain MRI, the most common abnormal brain MRI finding was Chiari malformation (CM), observed in 88% of the group. A brainstem tumor was identified in one nonsyndromic child. Interventions following brain MRI included neurosurgery, chemotherapy, and noninvasive positive pressure ventilation (NiPPV). A brain MRI is an important diagnostic tool in syndromic and nonsyndromic children, especially in children with either isolated OSA or combined OSA and CSA without a clear etiology. 4. Laryngoscope, 2016 127:513-519, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Developmental trajectories of abuse--an hypothesis for the effects of early childhood maltreatment on dorsolateral prefrontal cortical development.

PubMed

Burrus, Caley

2013-11-01

The United States has a high rate of child maltreatment, with nearly 12 in 1000 children being victims of abuse or neglect. Child abuse strongly predicts negative life outcomes, especially in areas of emotional and mental health. Abused children are also more likely than their peers to engage in violence and enter the juvenile justice system, as well as to become abusive parents themselves. Research has shown that child abuse and trauma can lead to decreased hippocampal volume, which could be indicative of abnormal hippocampal development. Hippocampal development appears to directly affect the development of the dorsolateral prefrontal cortex, a brain area responsible for emotion regulation, cognitive reappraisal, and general executive function. Therefore, I hypothesize that if child abuse results in abnormal hippocampal development, which leads to abnormal dorsolateral prefrontal cortex development, many of the correlated risk factors of child abuse, such as emotionally-laden parenting and unfavorable cognitive distortions regarding children's behaviors, may be in part caused by underdevelopment or abnormal functioning of the dorsolateral prefrontal cortex, as a function of the individual's own experiences with abuse during childhood. If this hypothesis is supported with future research, more targeted, successful, and cost-effective prevention and treatment protocols could ensue. For instance, programs that have been empirically shown to increase the activity of the dorsolateral prefrontal cortex, such as cognitive behavioral therapy, could be effective in decreasing the incidence of intergenerational transfer of abuse. Copyright © 2013 Elsevier Ltd. All rights reserved.

Functional Brain Network Abnormalities during Verbal Working Memory Performance in Adolescents and Young Adults with Dyslexia

ERIC Educational Resources Information Center

Wolf, Robert Christian; Sambataro, Fabio; Lohr, Christina; Steinbrink, Claudia; Martin, Claudia; Vasic, Nenad

2010-01-01

Behavioral and functional neuroimaging studies indicate deficits in verbal working memory (WM) and frontoparietal dysfunction in individuals with dyslexia. Additionally, structural brain abnormalities in dyslexics suggest a dysconnectivity of brain regions associated with phonological processing. However, little is known about the functional…

78 FR 734 - Medical Imaging Drugs Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-04

..., LLC. The proposed indication (use) for this product is for magnetic resonance imaging in brain...) to detect and visualize areas with disruption of the blood brain barrier (specialized tissues that help protect the brain) and/or abnormal vascularity (abnormal blood circulation). FDA intends to make...

Mid-gestation brain Doppler and head biometry in fetuses with congenital heart disease predict abnormal brain development at birth.

PubMed

Masoller, N; Sanz-CortéS, M; Crispi, F; Gómez, O; Bennasar, M; Egaña-Ugrinovic, G; Bargalló, N; Martínez, J M; Gratacós, E

2016-01-01

Fetuses with congenital heart disease (CHD) show evidence of abnormal brain development before birth, which is thought to contribute to adverse neurodevelopment during childhood. Our aim was to evaluate whether brain development in late pregnancy can be predicted by fetal brain Doppler, head biometry and the clinical form of CHD at the time of diagnosis. This was a prospective cohort study including 58 fetuses with CHD, diagnosed at 20-24 weeks' gestation, and 58 normal control fetuses. At the time of diagnosis, we recorded fetal head circumference (HC), biparietal diameter, middle cerebral artery pulsatility index (MCA-PI), cerebroplacental ratio (CPR) and brain perfusion by fractional moving blood volume. We classified cases into one of two clinical types defined by the expected levels (high or low) of placental (well-oxygenated) blood perfusion, according to the anatomical defect. All fetuses underwent subsequent 3T-magnetic resonance imaging (MRI) at 36-38 weeks' gestation. Abnormal prenatal brain development was defined by a composite score including any of the following findings on MRI: total brain volume <  10(th) centile, parietoccipital or cingulate fissure depth <  10(th) centile or abnormal metabolic profile in the frontal lobe. Logistic regression analysis demonstrated that MCA-PI (odds ratio (OR), 12.7; P = 0.01), CPR (OR, 8.7; P = 0.02) and HC (OR, 6.2; P = 0.02) were independent predictors of abnormal neurodevelopment; however, the clinical type of CHD was not. Fetal brain Doppler and head biometry at the time of CHD diagnosis are independent predictors of abnormal brain development at birth, and could be used in future algorithms to improve counseling and targeted interventions. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

The intellectual capacity of patients with Laron syndrome (LS) differs with various molecular defects of the growth hormone receptor gene. Correlation with CNS abnormalities.

PubMed

Shevah, O; Kornreich, L; Galatzer, A; Laron, Z

2005-12-01

The correlation between the molecular defects of the GH receptor (R), psychosocial development and brain abnormalities were evaluated in 10 patients with Laron syndrome (LS), in whom all data were available. The findings revealed that the intelligence quotient (IQ) and abnormalities in the brain of the patients with LS differ with various molecular defects of the GH-receptor. The most severe mental deficits and brain pathology occurred in patients with 3, 5, 6 exon deletion. Patients with point mutations in exons 2, 4 and 7 presented various degrees of medium to mild CNS abnormalities that correlated with the IQ. Notably, the patient with the E180 splice mutation in exon 6 had a normal IQ, which fits the report on normal IQ in a large Ecuadorian cohort with the same mutation. This is the first report to support a correlation between IQ, brain abnormalities and localization of the molecular defects in the GH-R gene. As all patients with LS are IGF-I-deficient, it must be assumed that other as yet unknown factors related to the molecular defects in the GH-R are the major cause of the differences in intellect and brain abnormalities.

The interaction between maternal immune activation and alpha 7 nicotinic acetylcholine receptor in regulating behaviors in the offspring.

PubMed

Wu, Wei-Li; Adams, Catherine E; Stevens, Karen E; Chow, Ke-Huan; Freedman, Robert; Patterson, Paul H

2015-05-01

Mutation of human chromosome 15q13.3 increases the risk for autism and schizophrenia. One of the noteworthy genes in 15q13.3 is CHRNA7, which encodes the nicotinic acetylcholine receptor alpha 7 subunit (α7nAChR) associated with schizophrenia in clinical studies and rodent models. This study investigates the role of α7nAChR in maternal immune activation (MIA) mice model, a murine model of environmental risk factor for autism and schizophrenia. We provided choline, a selective α7nAChR agonist among its several developmental roles, in the diet of C57BL/6N wild-type dams throughout the gestation and lactation period and induced MIA at mid-gestation. The adult offspring behavior and gene expression profile in the maternal-placental-fetal axis at mid-gestation were investigated. We found that choline supplementation prevented several MIA-induced behavioral abnormalities in the wild-type offspring. Pro-inflammatory cytokine interleukin-6 (Il6) and Chrna7 gene expression in the wild-type fetal brain were elevated by poly(I:C) injection and were suppressed by gestational choline supplementation. We further investigated the gene expression level of Il6 in Chrna7 mutant mice. We found that the basal level of Il6 was higher in Chrna7 mutant fetal brain, which suggests that α7nAChR may serve an anti-inflammatory role in the fetal brain during development. Lastly, we induced MIA in Chrna7(+/-) offspring. The Chrna7(+/-) offspring were more vulnerable to MIA, with increased behavioral abnormalities. Our study shows that α7nAChR modulates inflammatory response affecting the fetal brain and demonstrates its effects on offspring behavior development after MIA. Copyright © 2015 Elsevier Inc. All rights reserved.

A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy

PubMed Central

Shafi, Mouhsin M.; Whitfield-Gabrieli, Susan; Chu, Catherine J.; Pascual-Leone, Alvaro; Chang, Bernard S.

2017-01-01

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases. PMID:27911366

[Revaluation of the concept of developmental abnormality: the importance of faulty perinatal imprinting].

PubMed

Csaba, György

2015-07-12

The classic definition of developmental abnormalities referred to malformations observed at birth. Later the functional teratogenicity was also recognized and accepted, which can be revealed in functional abnormalities caused by harms during the intrauterine development and can be manifested at any time of life. However, the ontogeny is not closed with the birth, because some systems or organs are developing for a long time after it, and can be influenced by different factors. From this aspect the perinatal period is especially important when the mutual adjustment of the receptor-hormone system is taking place and the hormonal imprinting develops. If this is faulty, it influences the hormone binding capacity of receptors that has consequences for life. The faulty hormonal imprinting is functionally teratogen; it provokes a fault up to the level of a malformation and aggravated with its heredity to the progenies. False imprinting is provoked (in animal experiments, proportioning to human doses) by drugs acting at receptor level, as oxytocin, steroid hormone analogues (pregnancy protectors, oral contraceptives, surfactants), vitamin A and D, environmental pollutant endocrine disruptors (benzpyrene, bisphenol A, pesticides, herbicides) and certain soybean components, etc. From this aspect these are functional teratogens, and their evasion in prevention as well as therapy seems to be vital. This means that the concept of developmental abnormality must be broadened, as developmental abnormalities: 1.) can originate not only in the intrauterine period, but also perinatally or even later, 2.) it can be manifested at any time of life, 3.) it can be present in a latent form which can be activated by inner or outer environmental factors, 4.) the faulty hormonal imprinting is a teratogen factor.

Mutational Analysis of Cell Types in TSC

DTIC Science & Technology

2008-01-01

disability, and autism . TSC1/TSC2 gene mutations lead to developmental alterations in brain structure known as tubers in over 80% of TSC patients. Loss of...that is associated with epilepsy, cognitive disability, and autism . TSC1/TSC2 gene mutations lead to developmental alterations in brain structure...2000). Comorbid neuropsychological disorders such as autism , mental retardation (MR), pervasive developmental disorder, attention deficit disorder (ADD

Developmental nicotine exposure affects larval brain size and the adult dopaminergic system of Drosophila melanogaster.

PubMed

Morris, Melanie; Shaw, Ariel; Lambert, Madison; Perry, Haley Halperin; Lowenstein, Eve; Valenzuela, David; Velazquez-Ulloa, Norma Andrea

2018-06-14

Pregnant women may be exposed to nicotine if they smoke or use tobacco products, nicotine replacement therapy, or via e-cigarettes. Prenatal nicotine exposure has been shown to have deleterious effects on the nervous system in mammals including changes in brain size and in the dopaminergic system. The genetic and molecular mechanisms for these changes are not well understood. A Drosophila melanogaster model for these effects of nicotine exposure could contribute to faster identification of genes and molecular pathways underlying these effects. The purpose of this study was to determine if developmental nicotine exposure affects the nervous system of Drosophila melanogaster, focusing on changes to brain size and the dopaminergic system at two developmental stages. We reared flies on control or nicotine food from egg to 3rd instar larvae or from egg to adult and determined effectiveness of the nicotine treatment. We used immunohistochemistry to visualize the whole brain and dopaminergic neurons, using tyrosine hydroxylase as the marker. We measured brain area, tyrosine hydroxylase fluorescence, and counted the number of dopaminergic neurons in brain clusters. We detected an increase in larval brain hemisphere area, a decrease in tyrosine hydroxylase fluorescence in adult central brains, and a decrease in the number of neurons in the PPM3 adult dopaminergic cluster. We tested involvement of Dα7, one of the nicotinic acetylcholine receptor subunits, and found it was involved in eclosion, as previously described, but not involved in brain size. We conclude that developmental nicotine exposure in Drosophila melanogaster affects brain size and the dopaminergic system. Prenatal nicotine exposure in mammals has also been shown to have effects on brain size and in the dopaminergic system. This study further establishes Drosophila melanogaster as model organism to study the effects of developmental nicotine exposure. The genetic and molecular tools available for Drosophila research will allow elucidation of the mechanisms underlying the effects of nicotine exposure during development.

Abnormal functional lateralization and activity of language brain areas in typical specific language impairment (developmental dysphasia)

PubMed Central

De Guibert, Clément; Maumet, Camille; Jannin, Pierre; Ferré, Jean-Christophe; Tréguier, Catherine; Barillot, Christian; Le Rumeur, Elisabeth; Allaire, Catherine; Biraben, Arnaud

2011-01-01

Atypical functional lateralization and specialization for language have been proposed to account for developmental language disorders, yet results from functional neuroimaging studies are sparse and inconsistent. This functional magnetic resonance imaging study compared children with a specific subtype of specific language impairment affecting structural language (n=21), to a matched group of typically-developing children using a panel of four language tasks neither requiring reading nor metalinguistic skills, including two auditory lexico-semantic tasks (category fluency and responsive naming) and two visual phonological tasks based on picture naming. Data processing involved normalizing the data with respect to a matched pairs pediatric template, groups and between-groups analysis, and laterality indexes assessment within regions of interest using single and combined task analysis. Children with specific language impairment exhibited a significant lack of left lateralization in all core language regions (inferior frontal gyrus-opercularis, inferior frontal gyrus-triangularis, supramarginal gyrus, superior temporal gyrus), across single or combined task analysis, but no difference of lateralization for the rest of the brain. Between-group comparisons revealed a left hypoactivation of Wernicke’s area at the posterior superior temporal/supramarginal junction during the responsive naming task, and a right hyperactivation encompassing the anterior insula with adjacent inferior frontal gyrus and the head of the caudate nucleus during the first phonological task. This study thus provides evidence that this specific subtype of specific language impairment is associated with atypical lateralization and functioning of core language areas. PMID:21719430

Is early adulthood a critical developmental stage for psychosis proneness? A survey of delusional ideation in normal subjects.

PubMed

Verdoux, H; van Os, J; Maurice-Tison, S; Gay, B; Salamon, R; Bourgeois, M

1998-02-09

It has been hypothesized that late adolescence and early adulthood might be a brain developmental stage favoring the clinical expression of psychotic symptoms in psychiatric or neurological diseases. The aim of the present survey was to examine the relationship between age and delusional ideation in a sample of subjects with no psychiatric disorder. The survey was carried out with the Aquitaine Sentinel Network of general practitioners. Consecutive practice attenders were invited to complete the PDI-21 (Peters Delusional Inventory 21 items), a self-report questionnaire designed to measure delusional ideation in the normal population. The study concerned 444 patients who had no lifetime history of psychiatric disorder and who completed the PDI-21. A principal component analysis of the PDI-21 items was performed in order to identify delusional dimensions. An age-related decrease in the likelihood to report delusional ideas was found, younger subjects scoring higher on most dimensions of delusional ideation, such as 'persecution', 'thought disturbance', 'grandiosity' and 'paranormal beliefs'. 'Religiosity' was the only dimension positively associated with age. The results suggest that there may be a physiological neurodevelopmental stage favouring the expression of psychosis proneness in normal subjects, and support the hypothesis that the association between age and positive psychotic symptoms in functional and organic psychoses may be linked to the interaction between normal brain maturational processes and cerebral abnormalities involved in the aetiology of functional and organic psychoses.

Developmental amnesia: effect of age at injury.

PubMed

Vargha-Khadem, F; Salmond, C H; Watkins, K E; Friston, K J; Gadian, D G; Mishkin, M

2003-08-19

Hypoxic-ischemic events sustained within the first year of life can result in developmental amnesia, a disorder characterized by markedly impaired episodic memory and relatively preserved semantic memory, in association with medial temporal pathology that appears to be restricted to the hippocampus. Here we compared children who had hypoxic-ischemic events before 1 year of age (early group, n = 6) with others who showed memory problems after suffering hypoxic-ischemic events between the ages of 6 and 14 years (late group, n = 5). Morphometric analyses of the whole brain revealed that, compared with age-matched controls, both groups had bilateral abnormalities in the hippocampus, putamen, and posterior thalamus, as well as in the right retrosplenial cortex. The two groups also showed similar reductions (approximately 40%) in hippocampal volumes. Neuropsychologically, the only significant differences between the two were on a few tests of immediate memory, where the early group surpassed the late group. The latter measures provided the only clear indication that very early injury can lead to greater functional sparing than injury acquired later in childhood, due perhaps to the greater plasticity of the infant brain. On measures of long-term memory, by contrast, the two groups had highly similar profiles, both showing roughly equivalent preservation of semantic memory combined with marked impairment in episodic memory. It thus appears that, if this selective memory disorder is a special syndrome related to the early occurrence of hypoxia-induced damage, then the effective age at injury for this syndrome extends from birth to puberty.

Temporal lobe developmental malformations and epilepsy: dual pathology and bilateral hippocampal abnormalities.

PubMed

Ho, S S; Kuzniecky, R I; Gilliam, F; Faught, E; Morawetz, R

1998-03-01

Temporal lobe developmental malformations (TLDM) with focal cortical dysplasia and balloon cells may coexist with mesial temporal sclerosis. The true incidence of this dual pathology is unknown. Our aim was to assess the frequency of amygdala (AM)-hippocampal abnormality in a homogeneous population with this specific developmental malformation. MRI-based volumetry of the AM and hippocampal formation (HF) in 30 patients with unilateral TLDM and intractable partial epilepsy was performed. A volume normalization process defined a normal range of HF and AM volumes in control subjects, and enabled the detection of bilateral volume loss. Normalized volumes detected HF atrophy in 26 patients (nine unilateral and 17 bilateral) and AM atrophy in 18 patients (three unilateral and 15 bilateral). Visual analysis detected unilateral HF abnormality in 21 patients and bilateral abnormality in two. When compared with a group of patients with temporal lobe epilepsy and pure hippocampal sclerosis (N = 92), where volumetry revealed bilateral HF atrophy in 18%, a significant difference in the frequency of bilateral HF atrophy was found (p < 0.0001). Dual pathology is frequent in patients with TLDM (87%), and the AM-HF abnormality is often bilateral (57%). Our data suggest that more widespread and potentially epileptogenic lesions coexist with visibly detectable unilateral TLDM. This has implications for the selection of patients for temporal lobe surgery and may influence surgical strategies.

Concerted and mosaic evolution of functional modules in songbird brains

PubMed Central

DeVoogd, Timothy J.

2017-01-01

Vertebrate brains differ in overall size, composition and functional capacities, but the evolutionary processes linking these traits are unclear. Two leading models offer opposing views: the concerted model ascribes major dimensions of covariation in brain structures to developmental events, whereas the mosaic model relates divergent structures to functional capabilities. The models are often cast as incompatible, but they must be unified to explain how adaptive changes in brain structure arise from pre-existing architectures and developmental mechanisms. Here we show that variation in the sizes of discrete neural systems in songbirds, a species-rich group exhibiting diverse behavioural and ecological specializations, supports major elements of both models. In accordance with the concerted model, most variation in nucleus volumes is shared across functional domains and allometry is related to developmental sequence. Per the mosaic model, residual variation in nucleus volumes is correlated within functional systems and predicts specific behavioural capabilities. These comparisons indicate that oscine brains evolved primarily as a coordinated whole but also experienced significant, independent modifications to dedicated systems from specific selection pressures. Finally, patterns of covariation between species and brain areas hint at underlying developmental mechanisms. PMID:28490627

Evaluating predisposition and training in shaping the musician's brain: the need for a developmental perspective.

PubMed

Zuk, Jennifer; Gaab, Nadine

2018-05-24

The study of music training as a model for structural plasticity has evolved significantly over the past 15 years. Neuroimaging studies have identified characteristic structural brain alterations in musicians compared to nonmusicians in school-age children and adults, using primarily cross-sectional designs. Despite this emerging evidence and advances in pediatric neuroimaging techniques, hardly any studies have examined brain development in early childhood (before age 8) in association with musical training, and longitudinal studies starting in infancy or preschool are particularly scarce. Consequently, it remains unclear whether the characteristic "musician brain" is solely the result of musical training, or whether certain predispositions may have an impact on its development. Moving toward a developmental perspective, the present review considers various factors that may contribute to early brain structure prior to the onset of formal musical training. This review introduces a model for potential neurobiological pathways leading to the characteristic "musician brain," which involves a developmental interaction between predisposition and its temporal dynamics, environmental experience, and training-induced plasticity. This perspective illuminates the importance of studying the brain structure associated with musical training through a developmental lens, and the need for longitudinal studies in early childhood to advance our understanding of music training-induced structural plasticity. © 2018 New York Academy of Sciences.

[Neurotransmission in developmental disorders].

PubMed

Takeuchi, Yoshihiro

2008-11-01

Attention deficit/hyperactivity disorder (AD/HD) is a heterogeneous developmental disorder with an etiology that is not fully understood. AD/HD has been considered to occur due to a disturbance in cathecholaminergic neurotransmission, with particular emphasis on dopamine. The neurotransmission of dopamine in subcortical regions such as the basal ganglia and limbic areas is synaptic; on the other hand, dopamine neurotransmission in the frontal cortex is quite different, because there are very few dopamine transporters (DAT) in the frontal cortex that allow dopamine to diffuse away from the dopamine synapse ("volume transmission"). It is now clear that noradrenergic neurons play a key regulatory role in dopaminergic function in the frontal cortex. Furthermore, serotonergic neurons exert an inhibitory effect on midbrain dopamine cell bodies, and they have an influence on dopamine release in terminal regions. There is accumulating neurobiological evidence pointing toward a role of the serotonin system in AD/HD. The etiology of autism spectrum disorders (ASD) is still unclear, but information from genetics, neuropathology, brain imaging, and basic neuroscience has provided insights into the understanding of this developmental disorder. In addition to abnormal circuitry in specific limbic and neocortical areas of the cerebral cortex, impairments in brainstem, cerebellar, thalamic, and basal ganglia connections have been reported. Numerous studies have pointed to abnormalities in serotonin and glutamate neurotransmission. Three important aspects involved in the pathophysiology of ASD have been proposed. The first is cell migration, the second is unbalanced excitatory-inhibitory networks, and the third is synapse formation and pruning, the key factors being reelin, neurexin, and neuroligin. Serotonin is considered to play an important role in all of these aspects of the pathophysiology of ASD. Finally, I would like to emphasize that it is crucial in the field of child neurology medical examination and treatment should be based on the basic neuroscience, always taking "neurons" into consideration.

Developmental Hypothyroidism Alters Brain-Derived Neurotrophic Factor (BDNF) Expression in Adulthood.

EPA Science Inventory

Severe developmental thyroid hormone (TH) insufficiency results in alterations in brain structure/function and lasting behavioral impairments. Environmental toxicants reduce circulating levels of TH, but the disruption is modest and the doseresponse relationships of TH and neuro...

Developmental changes in organization of structural brain networks.

PubMed

Khundrakpam, Budhachandra S; Reid, Andrew; Brauer, Jens; Carbonell, Felix; Lewis, John; Ameis, Stephanie; Karama, Sherif; Lee, Junki; Chen, Zhang; Das, Samir; Evans, Alan C

2013-09-01

Recent findings from developmental neuroimaging studies suggest that the enhancement of cognitive processes during development may be the result of a fine-tuning of the structural and functional organization of brain with maturation. However, the details regarding the developmental trajectory of large-scale structural brain networks are not yet understood. Here, we used graph theory to examine developmental changes in the organization of structural brain networks in 203 normally growing children and adolescents. Structural brain networks were constructed using interregional correlations in cortical thickness for 4 age groups (early childhood: 4.8-8.4 year; late childhood: 8.5-11.3 year; early adolescence: 11.4-14.7 year; late adolescence: 14.8-18.3 year). Late childhood showed prominent changes in topological properties, specifically a significant reduction in local efficiency, modularity, and increased global efficiency, suggesting a shift of topological organization toward a more random configuration. An increase in number and span of distribution of connector hubs was found in this age group. Finally, inter-regional connectivity analysis and graph-theoretic measures indicated early maturation of primary sensorimotor regions and protracted development of higher order association and paralimbic regions. Our finding reveals a time window of plasticity occurring during late childhood which may accommodate crucial changes during puberty and the new developmental tasks that an adolescent faces.

Signs and symptoms of developmental abnormalities of the genitourinary tract.

PubMed

Nogueira, Paulo Cesar Koch; Paz, Isabel de Pádua

2016-01-01

The abnormalities of the genitourinary tract development are the leading cause of chronic kidney disease (CKD) in children. The diagnosis of this disease in Brazil is late and incomplete, which results in increased morbidity and mortality in this age group. Early diagnosis of this condition is the prerogative of generalist pediatricians, and the aim of this study was to review the clinical signs and symptoms associated with developmental abnormalities of the genitourinary tract. Based on the description of a symbolic clinical case, the authors conducted a non-systematic review of medical literature. The results suggest that the following data should be used as a warning for early diagnosis of affected children: (a) combined urinary tract abnormalities (chromosomal abnormalities; sequence of malformations [VACTERLand Prune-Belly]; and musculoskeletal, digestive tract, heart, and nervous system malformations); (b) previous history (congenital anomalies of the kidney and urinary tract [CAKUT] in the family, low birth weight, and oligoamnios); (c) clinical signs (polyuria/nocturia, urinary tract infection, systemic arterial hypertension, failure to thrive, weak urinary stream, difficulty to start urination, distended bladder, non-monosymptomatic enuresis, urinary/urge incontinence, and bowel and bladder dysfunction); and (d) pre- and postnatal ultrasonographic alterations (increased anteroposterior diameter of the renal pelvis, mainly in the third trimester of pregnancy; single kidney; hydronephrosis associated with other abnormalities; and hydronephrosis with parenchymal involvement in the post-neonatal assessment). The suggestions shown here can help the pediatrician to establish clinical hypotheses for the early diagnosis of developmental abnormalities of the genitourinary tract without resorting to expensive and invasive procedures. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Relationship between brain function (aEEG) and brain structure (MRI) and their predictive value for neurodevelopmental outcome of preterm infants.

PubMed

Hüning, Britta; Storbeck, Tobias; Bruns, Nora; Dransfeld, Frauke; Hobrecht, Julia; Karpienski, Julia; Sirin, Selma; Schweiger, Bernd; Weiss, Christel; Felderhoff-Müser, Ursula; Müller, Hanna

2018-05-22

To improve the prediction of neurodevelopmental outcome in very preterm infants, this study used the combination of amplitude-integrated electroencephalography (aEEG) within the first 72 h of life and cranial magnetic resonance imaging (MRI) at term equivalent age. A single-center cohort of 38 infants born before 32 weeks of gestation was subjected to both investigations. Structural measurements were performed on MRI. Multiple regression analysis was used to identify independent factors including functional and structural brain measurements associated with outcome at a corrected age of 24 months. aEEG parameters significantly correlated with MRI measurements. Reduced deep gray matter volume was associated with low Burdjalov Score on day 3 (p < 0.0001) and day 1-3 (p = 0.0012). The biparietal width and the transcerebellar diameter were related to Burdjalov Score on day 1 (p = 0.0111; p = 0.0002). The final multiple regression analysis revealed independent predictors of neurodevelopmental outcome: intraventricular hemorrhage (p = 0.0060) and interhemispheric distance (p = 0.0052) for mental developmental index; Burdjalov Score day 1 (p = 0.0201) and interhemispheric distance (p = 0.0142) for psychomotor developmental index. Functional aEEG parameters were associated with altered brain maturation on MRI. The combination of aEEG and MRI contributes to the prediction of outcome at 24 months. What is Known: • Prematurity remains a risk factor for impaired neurodevelopment. • aEEG is used to measure brain activity in preterm infants and cranial MRI is performed to identify structural gray and white matter abnormalities with impact on neurodevelopmental outcome. What is New: • aEEG parameters observed within the first 72 h of life were associated with altered deep gray matter volumes, biparietal width, and transcerebellar diameter at term equivalent age. • The combination of aEEG and MRI contributes to the prediction of neurodevelopmental outcome at 2 years of corrected age in very preterm infants.

Term-equivalent functional brain maturational measures predict neurodevelopmental outcomes in premature infants.

PubMed

El Ters, Nathalie M; Vesoulis, Zachary A; Liao, Steve M; Smyser, Christopher D; Mathur, Amit M

2018-04-01

Term equivalent age (TEA) brain MRI identifies preterm infants at risk for adverse neurodevelopmental outcomes. But some infants may experience neurodevelopmental impairments even in the absence of neuroimaging abnormalities. Evaluate the association of TEA amplitude-integrated EEG (aEEG) measures with neurodevelopmental outcomes at 24-36 months corrected age. We performed aEEG recordings and brain MRI at TEA (mean post-menstrual age of 39 (±2) weeks in a cohort of 60 preterm infants born at a mean gestational age of 26 (±2) weeks. Forty-four infants underwent Bayley Scales of Infant Development, 3rd Edition (BSID-III) testing at 24-36 months corrected age. Developmental delay was defined by a score greater than one standard deviation below the mean (<85) in any domain. An ROC curve was constructed and a value of SEF 90  < 9.2, yielded the highest sensitivity and specificity for moderate/severe brain injury on MRI. The association between aEEG measures and neurodevelopmental outcomes was assessed using odds ratio, then adjusted for confounding variables using logistic regression. Infants with developmental delay in any domain had significantly lower values of SEF 90 . Absent cyclicity was more prevalent in infants with cognitive and motor delay. Both left and right SEF 90  < 9.2 were associated with motor delay (OR left: 4.7(1.2-18.3), p = 0.02, OR right: 7.9 (1.8-34.5), p < 0.01). Left SEF 90 and right SEF 90 were associated with cognitive delay and language delay respectively. Absent cyclicity was associated with motor and cognitive delay (OR for motor delay: 5.8 (1.3-25.1), p = 0.01; OR for cognitive delay: 16.8 (3.1-91.8), p < 0.01). These associations remained significant after correcting for social risk index score and confounding variables. aEEG may be used at TEA as a new tool for risk stratification of infants at higher risk of poor neurodevelopmental outcomes. Therefore, a larger study is needed to validate these results in premature infants at low and high risk of brain injury. Copyright © 2018. Published by Elsevier B.V.

Global gene expression profiles in brain regions reflecting abnormal neuronal and glial functions targeting myelin sheaths after 28-day exposure to cuprizone in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abe, Hajime

Both developmental and postpubertal cuprizone (CPZ) exposure impairs hippocampal neurogenesis in rats. We previously found that developmental CPZ exposure alters the expression of genes related to neurogenesis, myelination, and synaptic transmission in specific brain regions of offspring. Here, we examined neuronal and glial toxicity profiles in response to postpubertal CPZ exposure by using expression microarray analysis in the hippocampal dentate gyrus, corpus callosum, cerebral cortex, and cerebellar vermis of 5-week-old male rats exposed to 0, 120, and 600 mg/kg CPZ for 28 days. Genes showing transcript upregulation were subjected to immunohistochemical analysis. We found transcript expression alterations at 600 mg/kgmore » for genes related to synaptic transmission, Ache and Prima1, and cell cycle regulation, Tfap4 and Cdkn1a, in the dentate gyrus, which showed aberrant neurogenesis in the subgranular zone. This dose downregulated myelination-related genes in multiple brain regions, whereas KLOTHO{sup +} oligodendrocyte density was decreased only in the corpus callosum. The corpus callosum showed an increase in transcript levels for inflammatory response-related genes and in the number of CD68{sup +} microglia, MT{sup +} astrocytes, and TUNEL{sup +} apoptotic cells. These results suggest that postpubertal CPZ exposure targets synaptic transmission and cell cycle regulation to affect neurogenesis in the dentate gyrus. CPZ suppressed myelination in multiple brain regions and KLOTHO-mediated oligodendrocyte maturation only in the corpus callosum. The increased number of CD68{sup +} microglia, MT{sup +} astrocytes, and TUNEL{sup +} apoptotic cells in the corpus callosum may be involved in the induction of KLOTHO{sup +} oligodendrocyte death and be a protective mechanism against myelin damage following CPZ exposure. - Highlights: • Target gene expression profiles were examined in rats after 28-day CPZ exposure. • Multiple brain region-specific global gene expression profiling was performed. • CPZ affected synaptic function and cell cycling in the hippocampal dentate gyrus. • CPZ suppressed KLOTHO-mediated oligodendrocyte maturation in the corpus callosum. • CPZ increased metallothionein-mediated protective mechanism against myelin damage.« less

Folding, But Not Surface Area Expansion, Is Associated with Cellular Morphological Maturation in the Fetal Cerebral Cortex

PubMed Central

Studholme, Colin; Frias, Antonio E.

2017-01-01

Altered macroscopic anatomical characteristics of the cerebral cortex have been identified in individuals affected by various neurodevelopmental disorders. However, the cellular developmental mechanisms that give rise to these abnormalities are not understood. Previously, advances in image reconstruction of diffusion magnetic resonance imaging (MRI) have made possible high-resolution in utero measurements of water diffusion anisotropy in the fetal brain. Here, diffusion anisotropy within the developing fetal cerebral cortex is longitudinally characterized in the rhesus macaque, focusing on gestation day (G85) through G135 of the 165 d term. Additionally, for subsets of animals characterized at G90 and G135, immunohistochemical staining was performed, and 3D structure tensor analyses were used to identify the cellular processes that most closely parallel changes in water diffusion anisotropy with cerebral cortical maturation. Strong correlations were found between maturation of dendritic arbors on the cellular level and the loss of diffusion anisotropy with cortical development. In turn, diffusion anisotropy changes were strongly associated both regionally and temporally with cortical folding. Notably, the regional and temporal dependence of diffusion anisotropy and folding were distinct from the patterns observed for cerebral cortical surface area expansion. These findings strengthen the link proposed in previous studies between cellular-level changes in dendrite morphology and noninvasive diffusion MRI measurements of the developing cerebral cortex and support the possibility that, in gyroencephalic species, structural differentiation within the cortex is coupled to the formation of gyri and sulci. SIGNIFICANCE STATEMENT Abnormal brain morphology has been found in populations with neurodevelopmental disorders. However, the mechanisms linking cellular level and macroscopic maturation are poorly understood, even in normal brains. This study contributes new understanding to this subject using serial in utero MRI measurements of rhesus macaque fetuses, from which macroscopic and cellular information can be derived. We found that morphological differentiation of dendrites was strongly associated both regionally and temporally with folding of the cerebral cortex. Interestingly, parallel associations were not observed with cortical surface area expansion. These findings support the possibility that perturbed morphological differentiation of cells within the cortex may underlie abnormal macroscopic characteristics of individuals affected by neurodevelopmental disorders. PMID:28069920

Divergent structural brain abnormalities between different genetic subtypes of children with Prader-Willi syndrome.

PubMed

Lukoshe, Akvile; White, Tonya; Schmidt, Marcus N; van der Lugt, Aad; Hokken-Koelega, Anita C

2013-10-22

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim was to investigate global brain morphology in children with PWS, including the comparison between different genetic subtypes of PWS. In addition, we performed exploratory cortical and subcortical focal analyses. High resolution structural magnetic resonance images were acquired in 20 children with genetically confirmed PWS (11 children carrying a deletion (DEL), 9 children with maternal uniparental disomy (mUPD)), and compared with 11 age- and gender-matched typically developing siblings as controls. Brain morphology measures were obtained using the FreeSurfer software suite. Both children with DEL and mUPD showed smaller brainstem volume, and a trend towards smaller cortical surface area and white matter volume. Children with mUPD had enlarged lateral ventricles and larger cortical cerebrospinal fluid (CSF) volume. Further, a trend towards increased cortical thickness was found in children with mUPD. Children with DEL had a smaller cerebellum, and smaller cortical and subcortical grey matter volumes. Focal analyses revealed smaller white matter volumes in left superior and bilateral inferior frontal gyri, right cingulate cortex, and bilateral precuneus areas associated with the default mode network (DMN) in children with mUPD. Children with PWS show signs of impaired brain growth. Those with mUPD show signs of early brain atrophy. In contrast, children with DEL show signs of fundamentally arrested, although not deviant brain development and presented few signs of cortical atrophy. Our results of global brain measurements suggest divergent neurodevelopmental patterns in children with DEL and mUPD.

Divergent structural brain abnormalities between different genetic subtypes of children with Prader–Willi syndrome

PubMed Central

2013-01-01

Background Prader–Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim was to investigate global brain morphology in children with PWS, including the comparison between different genetic subtypes of PWS. In addition, we performed exploratory cortical and subcortical focal analyses. Methods High resolution structural magnetic resonance images were acquired in 20 children with genetically confirmed PWS (11 children carrying a deletion (DEL), 9 children with maternal uniparental disomy (mUPD)), and compared with 11 age- and gender-matched typically developing siblings as controls. Brain morphology measures were obtained using the FreeSurfer software suite. Results Both children with DEL and mUPD showed smaller brainstem volume, and a trend towards smaller cortical surface area and white matter volume. Children with mUPD had enlarged lateral ventricles and larger cortical cerebrospinal fluid (CSF) volume. Further, a trend towards increased cortical thickness was found in children with mUPD. Children with DEL had a smaller cerebellum, and smaller cortical and subcortical grey matter volumes. Focal analyses revealed smaller white matter volumes in left superior and bilateral inferior frontal gyri, right cingulate cortex, and bilateral precuneus areas associated with the default mode network (DMN) in children with mUPD. Conclusions Children with PWS show signs of impaired brain growth. Those with mUPD show signs of early brain atrophy. In contrast, children with DEL show signs of fundamentally arrested, although not deviant brain development and presented few signs of cortical atrophy. Our results of global brain measurements suggest divergent neurodevelopmental patterns in children with DEL and mUPD. PMID:24144356

Genetic and expression analyses reveal elevated expression of syntaxin 1A ( STX1A) in high functioning autism.

PubMed

Nakamura, Kazuhiko; Anitha, Ayyappan; Yamada, Kazuo; Tsujii, Masatsugu; Iwayama, Yoshimi; Hattori, Eiji; Toyota, Tomoko; Suda, Shiro; Takei, Noriyoshi; Iwata, Yasuhide; Suzuki, Katsuaki; Matsuzaki, Hideo; Kawai, Masayoshi; Sekine, Yoshimoto; Tsuchiya, Kenji J; Sugihara, Gen-Ichi; Ouchi, Yasuomi; Sugiyama, Toshiro; Yoshikawa, Takeo; Mori, Norio

2008-12-01

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from 249 AGRE trios with autistic probands. Only male probands were selected, since autism is more prevalent among males. The probands of 102 trios had IQ>70, and were considered as high functioning autism (HFA). In transmission disequilibrium test (TDT) analysis, rs2293485 (p=0.034) and rs4717806 (p=0.033) showed nominal associations with HFA; modest haplotype association was also observed. The SNPs that showed associations were related to early developmental abnormalities (ADI-R_D). We further compared STX1A mRNA expression in the lymphocytes of drug-naive HFA patients (n=12) and age- and sex-matched controls (n=13). STX1A expression in the HFA group was significantly higher (p=0.001) than that of controls. Thus, we suggest a possible role of STX1A in the pathogenesis of HFA. During early childhood, there is a period of high brain serotonin synthesis that is disrupted in autistic children; STX1A might influence the serotonergic system during this stage of neurodevelopment, as implied by the association with ADI-R_D.

A hierarchical model of the evolution of human brain specializations

PubMed Central

Barrett, H. Clark

2012-01-01

The study of information-processing adaptations in the brain is controversial, in part because of disputes about the form such adaptations might take. Many psychologists assume that adaptations come in two kinds, specialized and general-purpose. Specialized mechanisms are typically thought of as innate, domain-specific, and isolated from other brain systems, whereas generalized mechanisms are developmentally plastic, domain-general, and interactive. However, if brain mechanisms evolve through processes of descent with modification, they are likely to be heterogeneous, rather than coming in just two kinds. They are likely to be hierarchically organized, with some design features widely shared across brain systems and others specific to particular processes. Also, they are likely to be largely developmentally plastic and interactive with other brain systems, rather than canalized and isolated. This article presents a hierarchical model of brain specialization, reviewing evidence for the model from evolutionary developmental biology, genetics, brain mapping, and comparative studies. Implications for the search for uniquely human traits are discussed, along with ways in which conventional views of modularity in psychology may need to be revised. PMID:22723350

Erythropoietin attenuates loss of potassium chloride co-transporters following prenatal brain injury.

PubMed

Jantzie, L L; Getsy, P M; Firl, D J; Wilson, C G; Miller, R H; Robinson, S

2014-07-01

Therapeutic agents that restore the inhibitory actions of γ-amino butyric acid (GABA) by modulating intracellular chloride concentrations will provide novel avenues to treat stroke, chronic pain, epilepsy, autism, and neurodegenerative and cognitive disorders. During development, upregulation of the potassium-chloride co-transporter KCC2, and the resultant switch from excitatory to inhibitory responses to GABA guide the formation of essential inhibitory circuits. Importantly, maturation of inhibitory mechanisms is also central to the development of excitatory circuits and proper balance between excitatory and inhibitory networks in the developing brain. Loss of KCC2 expression occurs in postmortem samples from human preterm infant brains with white matter lesions. Here we show that late gestation brain injury in a rat model of extreme prematurity impairs the developmental upregulation of potassium chloride co-transporters during a critical postnatal period of circuit maturation in CA3 hippocampus by inducing a sustained loss of oligomeric KCC2 via a calpain-dependent mechanism. Further, administration of erythropoietin (EPO) in a clinically relevant postnatal dosing regimen following the prenatal injury protects the developing brain by reducing calpain activity, restoring oligomeric KCC2 expression and attenuating KCC2 fragmentation, thus providing the first report of a safe therapy to address deficits in KCC2 expression. Together, these data indicate it is possible to reverse abnormalities in KCC2 expression during the postnatal period, and potentially reverse deficits in inhibitory circuit formation central to cognitive impairment and epileptogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

The ELGAN study of the brain and related disorders in extremely low gestational age newborns.

PubMed

O'Shea, T M; Allred, E N; Dammann, O; Hirtz, D; Kuban, K C K; Paneth, N; Leviton, A

2009-11-01

Extremely low gestational age newborns (ELGANs) are at increased risk for structural and functional brain abnormalities. To identify factors that contribute to brain damage in ELGANs. Multi-center cohort study. We enrolled 1506 ELGANs born before 28 weeks gestation at 14 sites; 1201 (80%) survived to 2 years corrected age. Information about exposures and characteristics was collected by maternal interview, from chart review, microbiologic and histological examination of placentas, and measurement of proteins in umbilical cord and early postnatal blood spots. Indicators of white matter damage, i.e. ventriculomegaly and echolucent lesions, on protocol cranial ultrasound scans; head circumference and developmental outcomes at 24 months adjusted age, i.e., cerebral palsy, mental and motor scales of the Bayley Scales of Infant Development, and a screen for autism spectrum disorders. ELGAN Study publications thus far provide evidence that the following are associated with ultrasongraphically detected white matter damage, cerebral palsy, or both: preterm delivery attributed to preterm labor, prelabor premature rupture of membranes, or cervical insufficiency; recovery of microorganisms in the placenta parenchyma, including species categorized as human skin microflora; histological evidence of placental inflammation; lower gestational age at delivery; greater neonatal illness severity; severe chronic lung disease; neonatal bacteremia; and necrotizing enterocolitis. In addition to supporting a potential role for many previously identified antecedents of brain damage in ELGANs, our study is the first to provide strong evidence that brain damage in extremely preterm infants is associated with microorganisms in placenta parenchyma.

Structural Connectivity Relates to Perinatal Factors and Functional Impairment at 7 Years in Children Born Very Preterm

PubMed Central

Thompson, Deanne K.; Chen, Jian; Beare, Richard; Adamson, Christopher L.; Ellis, Rachel; Ahmadzai, Zohra M.; Kelly, Claire E.; Lee, Katherine J.; Zalesky, Andrew; Yang, Joseph Y.M.; Hunt, Rodney W.; Cheong, Jeanie L.Y.; Inder, Terrie E.; Doyle, Lex W.; Seal, Marc L.; Anderson, Peter J.

2016-01-01

Objective To use structural connectivity to (1) compare brain networks between typically and atypically developing (very preterm) children, (2) explore associations between potential perinatal developmental disturbances and brain networks, and (3) describe associations between brain networks and functional impairments in very preterm children. Methods 26 full-term and 107 very preterm 7-year-old children (born <30 weeks’ gestational age and/or <1250 g) underwent T1- and diffusion-weighted imaging. Global white matter fiber networks were produced using 80 cortical and subcortical nodes, and edges created using constrained spherical deconvolution-based tractography. Global graph theory metrics were analysed, and regional networks were identified using network-based statistics. Cognitive and motor function were assessed at 7 years of age. Results Compared with full-term children, very preterm children had reduced density, lower global efficiency and higher local efficiency. Those with lower gestational age at birth, infection or higher neonatal brain abnormality score had reduced connectivity. Reduced connectivity within a widespread network was predictive of impaired IQ, while reduced connectivity within the right parietal and temporal lobes was associated with motor impairment in very preterm children. Conclusions This study utilized an innovative structural connectivity pipeline to reveal that children born very preterm have less connected and less complex brain networks compared with typically developing term-born children. Adverse perinatal factors led to disturbances in white matter connectivity, which in turn are associated with impaired functional outcomes, highlighting novel structure-function relationships. PMID:27046108

White Matter Volume Predicts Language Development in Congenital Heart Disease

PubMed Central

Rollins, Caitlin K.; Asaro, Lisa A.; Akhondi-Asl, Alireza; Kussman, Barry D.; Rivkin, Michael J.; Bellinger, David C.; Warfield, Simon K.; Wypij, David; Newburger, Jane W.; Soul, Janet S.

2016-01-01

Objective To determine whether brain volume is reduced at one year and whether these volumes are associated with neurodevelopment in biventricular congenital heart disease (CHD) repaired in infancy. Study design Infants with biventricular CHD (n = 48) underwent brain magnetic resonance imaging (MRI) and neurodevelopmental testing with the Bayley Scales of Infant Development-II (BSID-II) and the MacArthur-Bates Communicative Development Inventories (CDI) at one year. A multi-template based probabilistic segmentation algorithm was applied to volumetric MRI data. We compared volumes with those of 13 healthy control infants of comparable ages. In the CHD group, we measured Spearman correlations between neurodevelopmental outcomes and the residuals from linear regression of the volumes on corrected chronological age at MRI and sex. Results Compared with controls, CHD infant had reductions of 54 mL in total brain (P = 0.009), 40 mL in cerebral white matter (P < 0.001), and 1.2 mL in brainstem (P = 0.003) volumes. Within the CHD group, brain volumes were not correlated with BSID-II scores but did correlate positively with CDI language development. Conclusion Infants with biventricular CHD show total brain volume reductions at one year of age, driven by differences in cerebral white matter. White matter volume correlates with language development, but not broader developmental indices. These findings suggest that abnormalities in white matter development detected months after corrective heart surgery may contribute to language impairment. Trial registration ClinicalTrials.gov: NCT00006183 PMID:27837950

Metabolic alterations in developing brain after injury – knowns and unknowns

PubMed Central

McKenna, Mary C.; Scafidi, Susanna; Robertson, Courtney L.

2016-01-01

Brain development is a highly orchestrated complex process. The developing brain utilizes many substrates including glucose, ketone bodies, lactate, fatty acids and amino acids for energy, cell division and the biosynthesis of nucleotides, proteins and lipids. Metabolism is crucial to provide energy for all cellular processes required for brain development and function including ATP formation, synaptogenesis, synthesis, release and uptake of neurotransmitters, maintaining ionic gradients and redox status, and myelination. The rapidly growing population of infants and children with neurodevelopmental and cognitive impairments and life-long disability resulting from developmental brain injury is a significant public health concern. Brain injury in infants and children can have devastating effects because the injury is superimposed on the high metabolic demands of the developing brain. Acute injury in the pediatric brain can derail, halt or lead to dysregulation of the complex and highly regulated normal developmental processes. This paper provides a brief review of metabolism in developing brain and alterations found clinically and in animal models of developmental brain injury. The metabolic changes observed in three major categories of injury that can result in life-long cognitive and neurological disabilities, including neonatal hypoxia-ischemia, pediatric traumatic brain injury, and brain injury secondary to prematurity are reviewed. PMID:26148530

MRI Findings in 77 Children with Non-Syndromic Autistic Disorder

PubMed Central

Boddaert, Nathalie; Zilbovicius, Mônica; Philipe, Anne; Robel, Laurence; Bourgeois, Marie; Barthélemy, Catherine; Seidenwurm, David; Meresse, Isabelle; Laurier, Laurence; Desguerre, Isabelle; Bahi-Buisson, Nadia; Brunelle, Francis; Munnich, Arnold; Samson, Yves; Mouren, Marie-Christine; Chabane, Nadia

2009-01-01

Background The clinical relevance of MR scanning in children with autism is still an open question and must be considered in light of the evolution of this technology. MRI was judged to be of insufficient value to be included in the standard clinical evaluation of autism according to the guidelines of the American Academy of Neurology and Child Neurology Society in 2000 [1]. However, this statement was based on results obtained from small samples of patients and, more importantly, included mostly insufficient MRI sequences. Our main objective was to evaluate the prevalence of brain abnormalities in a large group of children with a non-syndromic autistic disorder (AD) using T1, T2 and FLAIR MRI sequences. Methodology MRI inspection of 77 children and adolescents with non-syndromic AD (mean age 7.4±3.6) was performed. All met the DSM-IV and ADI –R criteria for autism. Based on recommended clinical and biological screenings, we excluded patients with infectious, metabolic or genetic diseases, seizures or any other neurological symptoms. Identical MRI inspections of 77 children (mean age 7.0±4.2) without AD, developmental or neurological disorders were also performed. All MRIs were acquired with a 1.5-T Signa GE (3-D T1-FSPGR, T2, FLAIR coronal and axial sequences). Two neuroradiologists independently inspected cortical and sub-cortical regions. MRIs were reported to be normal, abnormal or uninterpretable. Principal Findings MRIs were judged as uninterpretable in 10% (8/77) of the cases. In 48% of the children (33/69 patients), abnormalities were reported. Three predominant abnormalities were observed, including white matter signal abnormalities (19/69), major dilated Virchow–Robin spaces (12/69) and temporal lobe abnormalities (20/69). In all, 52% of the MRIs were interpreted as normal (36/69 patients). Conclusions An unexpectedly high rate of MRI abnormalities was found in the first large series of clinical MRI investigations in non-syndromic autism. These results could contribute to further etiopathogenetic research into autism. PMID:19204795

Multiscale Entropy of Electroencephalogram as a Potential Predictor for the Prognosis of Neonatal Seizures.

PubMed

Lu, Wen-Yu; Chen, Jyun-Yu; Chang, Chi-Feng; Weng, Wen-Chin; Lee, Wang-Tso; Shieh, Jiann-Shing

2015-01-01

Increasing animal studies supported the harmful effects of prolonged or frequent neonatal seizures in developing brain, including increased risk of later epilepsy. Various nonlinear analytic measures had been applied to investigate the change of brain complexity with age. This study focuses on clarifying the relationship between later epilepsy and the changes of electroencephalogram (EEG) complexity in neonatal seizures. EEG signals from 19 channels of the whole brain from 32 neonates below 2 months old were acquired. The neonates were classified into 3 groups: 9 were normal controls, 9 were neonatal seizures without later epilepsy, and 14 were neonatal seizures with later epilepsy. Sample entropy (SamEn), multiscale entropy (MSE) and complexity index (CI) were analyzed. Although there was no significant change in SamEn, the CI values showed significantly decreased over Channels C3, C4, and Cz in patients with neonatal seizures and later epilepsy compared with control group. More multifocal epileptiform discharges in EEG, more abnormal neuroimaging findings, and higher incidence of future developmental delay were noted in the group with later epilepsy. Decreased MSE and CI values in patients with neonatal seizures and later epilepsy may reflect the mixed effects of acute insults, underlying brain immaturity, and prolonged seizures-related injuries. The analysis of MSE and CI can therefore provide a quantifiable and accurate way to decrypt the mystery of neonatal seizures, and could be a promising predictor.

Cyclin A2 promotes DNA repair in the brain during both development and aging.

PubMed

Gygli, Patrick E; Chang, Joshua C; Gokozan, Hamza N; Catacutan, Fay P; Schmidt, Theresa A; Kaya, Behiye; Goksel, Mustafa; Baig, Faisal S; Chen, Shannon; Griveau, Amelie; Michowski, Wojciech; Wong, Michael; Palanichamy, Kamalakannan; Sicinski, Piotr; Nelson, Randy J; Czeisler, Catherine; Otero, José J

2016-07-01

Various stem cell niches of the brain have differential requirements for Cyclin A2. Cyclin A2 loss results in marked cerebellar dysmorphia, whereas forebrain growth is retarded during early embryonic development yet achieves normal size at birth. To understand the differential requirements of distinct brain regions for Cyclin A2, we utilized neuroanatomical, transgenic mouse, and mathematical modeling techniques to generate testable hypotheses that provide insight into how Cyclin A2 loss results in compensatory forebrain growth during late embryonic development. Using unbiased measurements of the forebrain stem cell niche, we parameterized a mathematical model whereby logistic growth instructs progenitor cells as to the cell-types of their progeny. Our data was consistent with prior findings that progenitors proliferate along an auto-inhibitory growth curve. The growth retardation inCCNA2-null brains corresponded to cell cycle lengthening, imposing a developmental delay. We hypothesized that Cyclin A2 regulates DNA repair and that CCNA2-null progenitors thus experienced lengthened cell cycle. We demonstrate that CCNA2-null progenitors suffer abnormal DNA repair, and implicate Cyclin A2 in double-strand break repair. Cyclin A2's DNA repair functions are conserved among cell lines, neural progenitors, and hippocampal neurons. We further demonstrate that neuronal CCNA2 ablation results in learning and memory deficits in aged mice.

Developmental neurotoxicity of traffic-related air pollution: focus on autism

PubMed Central

Costa, Lucio G.; Chang, Yu-Chi; Cole, Toby B.

2018-01-01

Purpose of Review Epidemiological and animal studies suggest that air pollution may negatively affect the central nervous system (CNS) and contribute to CNS diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component. Recent findings Several studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity, and that perinatal exposure may cause or contribute to developmental disabilities and behavioral abnormalities. In particular, a number of recent studies have found associations between exposures to traffic-related air pollution and autism spectrum disorders (ASD), which are characterized by impairment in socialization and in communication, and by the presence of repetitive and unusual behaviors. The cause(s) of ASD are unknown, and while it may have a hereditary component, environmental factors are increasingly suspected as playing a pivotal role in its etiology, particularly in genetically susceptible individuals. Summary Autistic children present higher levels of neuroinflammation and systemic inflammation, which are also hallmarks of exposure to traffic-related air pollution. Gene-environment interactions may play a relevant role in determining individual susceptibility to air pollution developmental neurotoxicity. Given the worldwide presence of elevated air pollution, studies on its effects and mechanisms on the developing brain, genetic susceptibility, role in neurodevelopmental disorders, and possible therapeutic interventions, are certainly warranted. PMID:28417440

The Cerebellum and Neurodevelopmental Disorders.

PubMed

Stoodley, Catherine J

2016-02-01

Cerebellar dysfunction is evident in several developmental disorders, including autism, attention deficit-hyperactivity disorder (ADHD), and developmental dyslexia, and damage to the cerebellum early in development can have long-term effects on movement, cognition, and affective regulation. Early cerebellar damage is often associated with poorer outcomes than cerebellar damage in adulthood, suggesting that the cerebellum is particularly important during development. Differences in cerebellar development and/or early cerebellar damage could impact a wide range of behaviors via the closed-loop circuits connecting the cerebellum with multiple cerebral cortical regions. Based on these anatomical circuits, behavioral outcomes should depend on which cerebro-cerebellar circuits are affected. Here, we briefly review cerebellar structural and functional differences in autism, ADHD, and developmental dyslexia, and discuss clinical outcomes following pediatric cerebellar damage. These data confirm the prediction that abnormalities in different cerebellar subregions produce behavioral symptoms related to the functional disruption of specific cerebro-cerebellar circuits. These circuits might also be crucial to structural brain development, as peri-natal cerebellar lesions have been associated with impaired growth of the contralateral cerebral cortex. The specific contribution of the cerebellum to typical development may therefore involve the optimization of both the structure and function of cerebro-cerebellar circuits underlying skill acquisition in multiple domains; when this process is disrupted, particularly in early development, there could be long-term alterations of these neural circuits, with significant impacts on behavior.

The cerebellum and neurodevelopmental disorders

PubMed Central

Stoodley, Catherine J.

2015-01-01

Cerebellar dysfunction is evident in several developmental disorders, including autism, attention deficit hyperactivity disorder (ADHD), and developmental dyslexia, and damage to the cerebellum early in development can have long-term effects on movement, cognition, and affective regulation. Early cerebellar damage is often associated with poorer outcomes than cerebellar damage in adulthood, suggesting that the cerebellum is particularly important during development. Differences in cerebellar development and/or early cerebellar damage could impact a wide range of behaviors via the closed-loop circuits connecting the cerebellum with multiple cerebral cortical regions. Based on these anatomical circuits, behavioral outcomes should depend on which cerebro-cerebellar circuits are affected. Here, we briefly review cerebellar structural and functional differences in autism, ADHD, and developmental dyslexia, and discuss clinical outcomes following pediatric cerebellar damage. These data confirm the prediction that abnormalities in different cerebellar subregions produce behavioral symptoms related to the functional disruption of specific cerebro-cerebellar circuits. These circuits might also be crucial to structural brain development, as peri-natal cerebellar lesions have been associated with impaired growth of the contralateral cerebral cortex. The specific contribution of the cerebellum to typical development may therefore involve the optimization of both the structure and function of cerebro-cerebellar circuits underlying skill acquisition in multiple domains; when this process is disrupted, particularly in early development, there could be long-term alterations of these neural circuits, with significant impacts on behavior. PMID:26298473

Childhood visual impairment: normal and abnormal visual function in the context of developmental disability.

PubMed

Nyong'o, Omondi L; Del Monte, Monte A

2008-12-01

Abnormal or failed development of vision in children may give rise to varying degrees of visual impairment and disability. Disease and organ-specific mechanisms by which visual impairments arise are presented. The presentation of these mechanisms, along with an explanation of established pathologic processes and correlative up-to-date clinical and social research in the field of pediatrics, ophthalmology, and rehabilitation medicine are discussed. The goal of this article is to enhance the practitioner's recognition and care for children with developmental disability associated with visual impairment.

Fluorine magnetic resonance spectroscopy measurement of brain fluvoxamine and fluoxetine in pediatric patients treated for pervasive developmental disorders.

PubMed

Strauss, Wayne L; Unis, Alan S; Cowan, Charles; Dawson, Geraldine; Dager, Stephen R

2002-05-01

Pediatric populations, including those with autistic disorder or other pervasive developmental disorders, increasingly are being prescribed selective serotonin reuptake inhibitors (SSRIs). Little is known about the age-related brain pharmacokinetics of SSRIs; there is a lack of data regarding optimal dosing of medications for children. The authors used fluorine magnetic resonance spectroscopy ((19)F MRS) to evaluate age effects on whole-brain concentrations of fluvoxamine and fluoxetine in children taking SSRIs. Twenty-one pediatric subjects with diagnoses of autistic disorder or other pervasive developmental disorders, 6-15 years old and stabilized with a consistent dose of fluvoxamine or fluoxetine, were recruited for the study; 16 successfully completed the imaging protocol. Whole-brain drug levels in this group were compared to similarly acquired data from 28 adults. A significant relationship between dose and brain drug concentration was observed for both drugs across the age range studied. Brain fluvoxamine concentration in the children was lower, consistent with a lower dose/body mass drug prescription; when brain concentration was adjusted for dose/mass, age effects were no longer significant. Brain fluoxetine concentration was similar between age groups; no significant age effects on brain fluoxetine drug levels remained after adjustment for dose/mass. Observations of brain fluoxetine bioavailability and elimination half-life also were similar between age groups. These findings suggest that fluvoxamine or fluoxetine prescriptions adjusted for dose/mass are an acceptable treatment approach for medicating children with autistic disorder or other pervasive developmental disorders. It must be determined whether these findings can be generalized to other pediatric populations.

On Expression Patterns and Developmental Origin of Human Brain Regions.

PubMed

Kirsch, Lior; Chechik, Gal

2016-08-01

Anatomical substructures of the human brain have characteristic cell-types, connectivity and local circuitry, which are reflected in area-specific transcriptome signatures, but the principles governing area-specific transcription and their relation to brain development are still being studied. In adult rodents, areal transcriptome patterns agree with the embryonic origin of brain regions, but the processes and genes that preserve an embryonic signature in regional expression profiles were not quantified. Furthermore, it is not clear how embryonic-origin signatures of adult-brain expression interplay with changes in expression patterns during development. Here we first quantify which genes have regional expression-patterns related to the developmental origin of brain regions, using genome-wide mRNA expression from post-mortem adult human brains. We find that almost all human genes (92%) exhibit an expression pattern that agrees with developmental brain-region ontology, but that this agreement changes at multiple phases during development. Agreement is particularly strong in neuron-specific genes, but also in genes that are not spatially correlated with neuron-specific or glia-specific markers. Surprisingly, agreement is also stronger in early-evolved genes. We further find that pairs of similar genes having high agreement to developmental region ontology tend to be more strongly correlated or anti-correlated, and that the strength of spatial correlation changes more strongly in gene pairs with stronger embryonic signatures. These results suggest that transcription regulation of most genes in the adult human brain is spatially tuned in a way that changes through life, but in agreement with development-determined brain regions.

On Expression Patterns and Developmental Origin of Human Brain Regions

PubMed Central

Kirsch, Lior; Chechik, Gal

2016-01-01

Anatomical substructures of the human brain have characteristic cell-types, connectivity and local circuitry, which are reflected in area-specific transcriptome signatures, but the principles governing area-specific transcription and their relation to brain development are still being studied. In adult rodents, areal transcriptome patterns agree with the embryonic origin of brain regions, but the processes and genes that preserve an embryonic signature in regional expression profiles were not quantified. Furthermore, it is not clear how embryonic-origin signatures of adult-brain expression interplay with changes in expression patterns during development. Here we first quantify which genes have regional expression-patterns related to the developmental origin of brain regions, using genome-wide mRNA expression from post-mortem adult human brains. We find that almost all human genes (92%) exhibit an expression pattern that agrees with developmental brain-region ontology, but that this agreement changes at multiple phases during development. Agreement is particularly strong in neuron-specific genes, but also in genes that are not spatially correlated with neuron-specific or glia-specific markers. Surprisingly, agreement is also stronger in early-evolved genes. We further find that pairs of similar genes having high agreement to developmental region ontology tend to be more strongly correlated or anti-correlated, and that the strength of spatial correlation changes more strongly in gene pairs with stronger embryonic signatures. These results suggest that transcription regulation of most genes in the adult human brain is spatially tuned in a way that changes through life, but in agreement with development-determined brain regions. PMID:27564987

The development of functional network organization in early childhood and early adolescence: A resting-state fNIRS study.

PubMed

Cai, Lin; Dong, Qi; Niu, Haijing

2018-04-01

Early childhood (7-8 years old) and early adolescence (11-12 years old) constitute two landmark developmental stages that comprise considerable changes in neural cognition. However, very limited information from functional neuroimaging studies exists on the functional topological configuration of the human brain during specific developmental periods. In the present study, we utilized continuous resting-state functional near-infrared spectroscopy (rs-fNIRS) imaging data to examine topological changes in network organization during development from early childhood and early adolescence to adulthood. Our results showed that the properties of small-worldness and modularity were not significantly different across development, demonstrating the developmental maturity of important functional brain organization in early childhood. Intriguingly, young children had a significantly lower global efficiency than early adolescents and adults, which revealed that the integration of the distributed networks strengthens across the developmental stages underlying cognitive development. Moreover, local efficiency of young children and adolescents was significantly lower than that of adults, while there was no difference between these two younger groups. This finding demonstrated that functional segregation remained relatively steady from early childhood to early adolescence, and the brain in these developmental periods possesses no optimal network configuration. Furthermore, we found heterogeneous developmental patterns in the regional nodal properties in various brain regions, such as linear increased nodal properties in the frontal cortex, indicating increasing cognitive capacity over development. Collectively, our results demonstrated that significant topological changes in functional network organization occurred during these two critical developmental stages, and provided a novel insight into elucidating subtle changes in brain functional networks across development. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

PubMed

Croll, S D; Suri, C; Compton, D L; Simmons, M V; Yancopoulos, G D; Lindsay, R M; Wiegand, S J; Rudge, J S; Scharfman, H E

1999-01-01

Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

Brain abnormalities in murderers indicated by positron emission tomography.

PubMed

Raine, A; Buchsbaum, M; LaCasse, L

1997-09-15

Murderers pleading not guilty by reason of insanity (NGRI) are thought to have brain dysfunction, but there have been no previous studies reporting direct measures of both cortical and subcortical brain functioning in this specific group. Positron emission tomography brain imaging using a continuous performance challenge task was conducted on 41 murderers pleading not guilty by reason of insanity and 41 age- and sex-matched controls. Murderers were characterized by reduced glucose metabolism in the prefrontal cortex, superior parietal gyrus, left angular gyrus, and the corpus callosum, while abnormal asymmetries of activity (left hemisphere lower than right) were also found in the amygdala, thalamus, and medial temporal lobe. These preliminary findings provide initial indications of a network of abnormal cortical and subcortical brain processes that may predispose to violence in murderers pleading NGRI.

Deficits in Neurite Density Underlie White Matter Structure Abnormalities in First-Episode Psychosis.

PubMed

Rae, Charlotte L; Davies, Geoff; Garfinkel, Sarah N; Gabel, Matt C; Dowell, Nicholas G; Cercignani, Mara; Seth, Anil K; Greenwood, Kathryn E; Medford, Nick; Critchley, Hugo D

2017-11-15

Structural abnormalities across multiple white matter tracts are recognized in people with early psychosis, consistent with dysconnectivity as a neuropathological account of symptom expression. We applied advanced neuroimaging techniques to characterize microstructural white matter abnormalities for a deeper understanding of the developmental etiology of psychosis. Thirty-five first-episode psychosis patients, and 19 healthy controls, participated in a quantitative neuroimaging study using neurite orientation dispersion and density imaging, a multishell diffusion-weighted magnetic resonance imaging technique that distinguishes white matter fiber arrangement and geometry from changes in neurite density. Fractional anisotropy (FA) and mean diffusivity images were also derived. Tract-based spatial statistics compared white matter structure between patients and control subjects and tested associations with age, symptom severity, and medication. Patients with first-episode psychosis had lower regional FA in multiple commissural, corticospinal, and association tracts. These abnormalities predominantly colocalized with regions of reduced neurite density, rather than aberrant fiber bundle arrangement (orientation dispersion index). There was no direct relationship with active symptoms. FA decreased and orientation dispersion index increased with age in patients, but not control subjects, suggesting accelerated effects of white matter geometry change. Deficits in neurite density appear fundamental to abnormalities in white matter integrity in early psychosis. In the first application of neurite orientation dispersion and density imaging in psychosis, we found that processes compromising axonal fiber number, density, and myelination, rather than processes leading to spatial disruption of fiber organization, are implicated in the etiology of psychosis. This accords with a neurodevelopmental origin of aberrant brain-wide structural connectivity predisposing individuals to psychosis. Copyright © 2017 Society of Biological Psychiatry. All rights reserved.

Neurocognitive profile of a young adolescent with DK phocomelia/von Voss phocomelia/von Voss Cherstvoy syndrome.

PubMed

Antonini, Tanya N; Van Horn Kerne, Valerie; Axelrad, Marni E; Karaviti, Lefkothea P; Schwartz, David D

2015-07-01

DK phocomelia/von Voss Cherstvoy syndrome is a rare condition characterized by upper limb and urogenital abnormalities and various brain anomalies. Previously reported cases have noted significant developmental delays, although no formal testing of cognitive abilities has been reported. In this paper we describe results from a comprehensive neuropsychological evaluation of a 12-year-old male with DK phocomelia syndrome. Test findings indicated mild impairment in intellectual functioning, with more significant impairment in adaptive skills and academic achievement. The neuropsychological profile converged with neurological findings, showing a distinct pattern of strengths and weaknesses that suggests functional compromise of posterior brain regions with relatively well-preserved functioning of more anterior regions. Specifically, impairments were evident in perceptual reasoning, visual perception, and visuomotor integration, whereas normal or near normal functioning was evident in memory, receptive language, social cognition, attention, and most aspects of executive functioning. To our knowledge this is the first report to describe the neurocognitive profile of an individual with DK phocomelia syndrome. © 2015 Wiley Periodicals, Inc.

DEVELOPMENTAL NEUROTOXICITY FOLLOWING NEONATAL EXPOSURE TO 3,3'-IMINODIPROPIONITRILE IN THE RAT

EPA Science Inventory

Adult exposure to the neurotoxicant 3,3'-iminodipropionitrile (IDPN) induces a hyperkinetic syndrome consisting of spontaneous head movements, abnormal circling, backwards locomotion, and sensory disruption. e report here the behavioral effects of developmental exposure to IDPN i...

Developmental Toxicity of Louisiana Crude Oiled Sediment to Zebrafish - Abstract

EPA Science Inventory

Polycyclic aromatic hydrocarbons (PAHs) cause a number of developmental abnormalities in developing fish embryos, which has been primarily demonstrated through water-accommodated fractions. PAH-bound sediment is a more ecologically relevant route of exposure to many developing fi...

Associations between prenatal, childhood, and adolescent stress and variations in white-matter properties in young men.

PubMed

Jensen, Sarah K G; Pangelinan, Melissa; Björnholm, Lassi; Klasnja, Anja; Leemans, Alexander; Drakesmith, Mark; Evans, C J; Barker, Edward D; Paus, Tomáš

2017-10-21

Previous studies have shown that both pre- and post-natal adversities, the latter including exposures to stress during childhood and adolescence, explain variation in structural properties of white matter (WM) in the brain. While previous studies have examined effects of independent stress exposures within one developmental period, such as childhood, we examine effects of stress across development using data from a prospective longitudinal study. More specifically, we ask how stressful events during prenatal development, childhood, and adolescence relate to variation in WM properties in early adulthood in young men recruited from a birth cohort. Using data from 393 mother-son pairs from a community-based birth cohort from England (Avon Longitudinal Study of Parents and Children), we examined how stressful life events relate to variation in different structural properties of WM in the corpus callosum and across the whole brain in early adulthood in men aged 18-21 years. We distinguish between stress occurring during three developmental periods: a) prenatal maternal stress, b) postnatal stress within the first four years of life, c) stress during adolescence (age 12-16 years). To obtain a comprehensive quantification of variation in WM, we assess structural properties of WM using four different measures, namely fractional anisotropy (FA), mean diffusivity (MD), magnetization transfer ratio (MTR) and myelin water fraction (MWF). The developmental model shows that prenatal stress is associated with lower MTR and MWF in the genu and/or splenium of the corpus callosum, and with lower MTR in global (lobar) WM. Stress during early childhood is associated with higher MTR in the splenium, and stress during adolescence is associated with higher MTR in the genu and lower MD in the splenium. We see no associations between postnatal stress and variation in global (lobar) WM. The current study found evidence for independent effects of stress on WM properties during distinct neurodevelopmental periods. We speculate that these independent effects are due to differences in the developmental processes unfolding at different developmental time points. We suggest that associations between prenatal stress and WM properties may relate to abnormalities in neurogenesis, affecting the number and density of axons, while postnatal stress may interfere with processes related to myelination or radial growth of axons. Potential consequences of prenatal glucocorticoid exposure should be considered in obstetric care. Copyright © 2017 Elsevier Inc. All rights reserved.

Fluctuating asymmetry as risk marker for stress and structural defects in a toxicologic experiment.

PubMed

Breno, Matteo; Bots, Jessica; De Schaepdrijver, Luc; Van Dongen, Stefan

2013-08-01

Fluctuating asymmetry (the directionally random asymmetry of bilateral structures, FA) is commonly used as a measure of developmental instability, and may increase with stress. As several studies reported a relation between FA and developmental abnormalities, we investigate whether FA could be an additional perhaps more sensitive marker of developmental toxicity. The aim of this work is analyzing patterns of FA in multiple traits in a large dataset of rabbit fetuses, which were prenatally exposed to a toxic compound and sacrificed just before natural delivery. Gravid females were exposed to three doses of this compound, inducing abnormalities in the fetuses at the high dose only. The average FA, however, was already higher than control in rabbit fetuses of the low-dose group but did not further increase with higher concentrations. Moreover, the increase in FA differed between traits, with the hindlimbs showing the strongest response. In addition, we did not find any association between FA and the presence of fetal abnormalities at the individual level. Although these results suggest that FA may act as "an early warning system," we did not find a dose-response relationship with increasing stress and effects were trait-specific. Further testing is needed before FA may be considered as a sensitive marker in developmental toxicity studies. © 2013 Wiley Periodicals, Inc.

Microstructural Abnormalities Were Found in Brain Gray Matter from Patients with Chronic Myofascial Pain

PubMed Central

Xie, Peng; Qin, Bangyong; Song, Ganjun; Zhang, Yi; Cao, Song; Yu, Jin; Wu, Jianjiang; Wang, Jiang; Zhang, Tijiang; Zhang, Xiaoming; Yu, Tian; Zheng, Hong

2016-01-01

Myofascial pain, presented as myofascial trigger points (MTrPs)-related pain, is a common, chronic disease involving skeletal muscle, but its underlying mechanisms have been poorly understood. Previous studies have revealed that chronic pain can induce microstructural abnormalities in the cerebral gray matter. However, it remains unclear whether the brain gray matters of patients with chronic MTrPs-related pain undergo alteration. In this study, we employed the Diffusion Kurtosis Imaging (DKI) technique, which is particularly sensitive to brain microstructural perturbation, to monitor the MTrPs-related microstructural alterations in brain gray matter of patients with chronic pain. Our results revealed that, in comparison with the healthy controls, patients with chronic myofascial pain exhibited microstructural abnormalities in the cerebral gray matter and these lesions were mainly distributed in the limbic system and the brain areas involved in the pain matrix. In addition, we showed that microstructural abnormalities in the right anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) had a significant negative correlation with the course of disease and pain intensity. The results of this study demonstrated for the first time that there are microstructural abnormalities in the brain gray matter of patients with MTrPs-related chronic pain. Our findings may provide new insights into the future development of appropriate therapeutic strategies to this disease. PMID:28066193

CDC Kerala 7: Effect of early language intervention among children 0-3 y with speech and language delay.

PubMed

Nair, M K C; Mini, A O; Leena, M L; George, Babu; Harikumaran Nair, G S; Bhaskaran, Deepa; Russell, Paul Swamidhas Sudhakar

2014-12-01

To assess the effect of systematic clinic and home based early language intervention program in children reporting to the early language intervention clinic with full partnership of specially trained developmental therapist and the parents. All babies between 0 and 3 y referred to Child Development Centre (CDC) Kerala for suspected speech/language delay were assessed and those without hearing impairment were screened first using Language Evaluation Scale Trivandrum (LEST) and assessed in detail using Receptive Expressive Emergent Language Scale (REELS). Those having language delay are enrolled into the early language intervention program for a period of 6 mo, 1 h at the CDC clinic once every month followed by home stimulation for rest of the month by the mother trained at CDC. Out of the total 455 children between 0 and 3 y, who successfully completed 6 mo intervention, the mean pre and post intervention language quotient (LQ) were 60.79 and 70.62 respectively and the observed 9.83 increase was statistically significant. The developmental diagnosis included developmental delay (62.4%), global developmental delay (18.5%), Trisomy and other chromosomal abnormalities (10.5%), microcephaly and other brain problems (9.9%), misarticulation (8.4%), autistic features (5.3%) and cleft palate and lip (3.3%) in the descending order. In the present study among 455 children between 0 and 3 y without hearing impairment, who successfully completed 6 mo early language intervention, the mean pre and post intervention LQ were 60.79 and 70.62 respectively and the observed 9.83 increase was statistically significant.

The Puzzle of Visual Development: Behavior and Neural Limits.

PubMed

Kiorpes, Lynne

2016-11-09

The development of visual function takes place over many months or years in primate infants. Visual sensitivity is very poor near birth and improves over different times courses for different visual functions. The neural mechanisms that underlie these processes are not well understood despite many decades of research. The puzzle arises because research into the factors that limit visual function in infants has found surprisingly mature neural organization and adult-like receptive field properties in very young infants. The high degree of visual plasticity that has been documented during the sensitive period in young children and animals leaves the brain vulnerable to abnormal visual experience. Abnormal visual experience during the sensitive period can lead to amblyopia, a developmental disorder of vision affecting ∼3% of children. This review provides a historical perspective on research into visual development and the disorder amblyopia. The mismatch between the status of the primary visual cortex and visual behavior, both during visual development and in amblyopia, is discussed, and several potential resolutions are considered. It seems likely that extrastriate visual areas further along the visual pathways may set important limits on visual function and show greater vulnerability to abnormal visual experience. Analyses based on multiunit, population activity may provide useful representations of the information being fed forward from primary visual cortex to extrastriate processing areas and to the motor output. Copyright © 2016 the authors 0270-6474/16/3611384-10$15.00/0.

Abolition of lemniscal barrellette patterning in Prrxl1 knockout mice: Effects upon ingestive behavior.

PubMed

Bakalar, Dana; Tamaiev, Jonathan; Zeigler, H Philip; Feinstein, Paul

2015-01-01

Ingestive behaviors in mice are dependent on orosensory cues transmitted via the trigeminal nerve, as confirmed by transection studies. However, these studies cannot differentiate between deficits caused by the loss of the lemniscal pathway vs. the parallel paralemniscal pathway. The paired-like homeodomain protein Prrxl1 is expressed widely in the brain and spinal cord, including the trigeminal system. A knockout of Prrxl1 abolishes somatotopic barrellette patterning in the lemniscal brainstem nucleus, but not in the parallel paralemniscal nucleus. Null animals are significantly smaller than littermates by postnatal day 5, but reach developmental landmarks at appropriate times, and survive to adulthood on liquid diet. A careful analysis of infant and adult ingestive behavior reveals subtle impairments in suckling, increases in time spent feeding and the duration of feeding bouts, feeding during inappropriate times of the day, and difficulties in the mechanics of feeding. During liquid diet feeding, null mice display abnormal behaviors including extensive use of the paws to move food into the mouth, submerging the snout in the diet, changes in licking, and also have difficulty consuming solid chow pellets. We suggest that our Prrxl1(-/-) animal is a valuable model system for examining the genetic assembly and functional role of trigeminal lemniscal circuits in the normal control of eating in mammals and for understanding feeding abnormalities in humans resulting from the abnormal development of these circuits.

If the skull fits: magnetic resonance imaging and microcomputed tomography for combined analysis of brain and skull phenotypes in the mouse

PubMed Central

Blank, Marissa C.; Roman, Brian B.; Henkelman, R. Mark; Millen, Kathleen J.

2012-01-01

The mammalian brain and skull develop concurrently in a coordinated manner, consistently producing a brain and skull that fit tightly together. It is common that abnormalities in one are associated with related abnormalities in the other. However, this is not always the case. A complete characterization of the relationship between brain and skull phenotypes is necessary to understand the mechanisms that cause them to be coordinated or divergent and to provide perspective on the potential diagnostic or prognostic significance of brain and skull phenotypes. We demonstrate the combined use of magnetic resonance imaging and microcomputed tomography for analysis of brain and skull phenotypes in the mouse. Co-registration of brain and skull images allows comparison of the relationship between phenotypes in the brain and those in the skull. We observe a close fit between the brain and skull of two genetic mouse models that both show abnormal brain and skull phenotypes. Application of these three-dimensional image analyses in a broader range of mouse mutants will provide a map of the relationships between brain and skull phenotypes generally and allow characterization of patterns of similarities and differences. PMID:22947655

Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.

PubMed

Wakefield, A J; Murch, S H; Anthony, A; Linnell, J; Casson, D M; Malik, M; Berelowitz, M; Dhillon, A P; Thomson, M A; Harvey, P; Valentine, A; Davies, S E; Walker-Smith, J A

1998-02-28

We investigated a consecutive series of children with chronic enterocolitis and regressive developmental disorder. 12 children (mean age 6 years [range 3-10], 11 boys) were referred to a paediatric gastroenterology unit with a history of normal development followed by loss of acquired skills, including language, together with diarrhoea and abdominal pain. Children underwent gastroenterological, neurological, and developmental assessment and review of developmental records. Ileocolonoscopy and biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were done under sedation. Barium follow-through radiography was done where possible. Biochemical, haematological, and immunological profiles were examined. Onset of behavioural symptoms was associated, by the parents, with measles, mumps, and rubella vaccination in eight of the 12 children, with measles infection in one child, and otitis media in another. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Histology showed patchy chronic inflammation in the colon in 11 children and reactive ileal lymphoid hyperplasia in seven, but no granulomas. Behavioural disorders included autism (nine), disintegrative psychosis (one), and possible postviral or vaccinal encephalitis (two). There were no focal neurological abnormalities and MRI and EEG tests were normal. Abnormal laboratory results were significantly raised urinary methylmalonic acid compared with age-matched controls (p=0.003), low haemoglobin in four children, and a low serum IgA in four children. We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers.

Denver Developmental Test Findings and their Relationship with Sociodemographic Variables in a Large Community Sample of 0-4-Year-Old Children.

PubMed

Çelikkiran, Seyhan; Bozkurt, Hasan; Coşkun, Murat

2015-06-01

The aim of this study was to investigate the prevalence of developmental problems and relationship with sociodemographic variables in a community sample of young children. Participants included 1000 children (558 males, 442 females, age range 1-48 months, mean 18.4 months, SD 7.8 months). Children were referred generally by their parents for developmental evaluation and consultation in response to a public announcement in a district area in Istanbul, Turkey. An interview form and the Denver Developmental Screening Test II (DDST) were used for sociodemographic data and developmental evaluation. The χ 2 test and Pearson's correlation test were used for data analysis. Seven hundred forty-one out of 1000 children (74.1%) had normal, 140 (14%) had risky, and 119 (11.9%) had abnormal findings on the DDST results. The probability of abnormal findings on the DDST results was significantly higher in males (p=0.003), the 2-4-year-old group (p<0.05), families with more than one child (p=0.001), consanguineous marriages (p<0.01), low parental educational levels and low household income (p<0.01), and in children without a history of breastfeeding (p=0.000). Immigration status and delivery mode did not have a significant effect on the probability of abnormal findings on the DDST results (p>0.05). Sociodemographic factors have a noteworthy impact on development. Determining these factors is important especially during the first years of life.

Neonatal Brain Abnormalities and Memory and Learning Outcomes at 7 Years in Children Born Very Preterm

PubMed Central

Omizzolo, Cristina; Scratch, Shannon E; Stargatt, Robyn; Kidokoro, Hiroyuki; Thompson, Deanne K; Lee, Katherine J; Cheong, Jeanie; Neil, Jeffrey; Inder, Terrie E; Doyle, Lex W; Anderson, Peter J

2014-01-01

Using prospective longitudinal data from 198 very preterm and 70 full term children, this study characterised the memory and learning abilities of very preterm children at 7 years of age in both verbal and visual domains. The relationship between the extent of brain abnormalities on neonatal magnetic resonance imaging (MRI) and memory and learning outcomes at 7 years of age in very preterm children was also investigated. Neonatal MRI scans were qualitatively assessed for global, white-matter, cortical grey-matter, deep grey-matter, and cerebellar abnormalities. Very preterm children performed less well on measures of immediate memory, working memory, long-term memory, and learning compared with term born controls. Neonatal brain abnormalities, and in particular deep grey matter abnormality, were associated with poorer memory and learning performance at 7 years in very preterm children, especially global, white-matter, grey-matter and cerebellar abnormalities. Findings support the importance of cerebral neonatal pathology for predicting later memory and learning function. PMID:23805915

HUPO BPP pilot study: a proteomics analysis of the mouse brain of different developmental stages.

PubMed

Wang, Jing; Gu, Yong; Wang, Lihong; Hang, Xingyi; Gao, Yan; Wang, Hangyan; Zhang, Chenggang

2007-11-01

This study is a part of the HUPO Brain Proteome Project (BPP) pilot study, which aims at obtaining a reliable database of mouse brain proteome, at the comparison of techniques, laboratories, and approaches as well as at preparing subsequent proteome studies of neurologic diseases. The C57/Bl6 mouse brains of three developmental stages at embryonic day 16 (E16), postnatal day 7 (P7), and 8 wk (P56) (n = 5 in each group) were provided by the HUPO BPP executive committee. The whole brain proteins of each animal were individually prepared using 2-DE coupled with PDQuest software analysis. The protein spots representing developmentally related or stably expressed proteins were then prepared with in-gel digestion followed with MALDI-TOF/TOF MS/MS and analyzed using the MASCOT search engines to search the Swiss-Prot or NCBInr database. The 2-DE gel maps of the mouse brains of all of the developmental stages were obtained and submitted to the Data Collection Centre (DCC). The proteins alpha-enolase, stathmin, actin, C14orf166 homolog, 28,000 kDa heat- and acid-stable phosphoprotein, 3-mercaptopyruvate sulfurtransferase and 40 S ribosomal protein S3a were successfully identified. A further Western blotting analysis demonstrated that enolase is a protein up-regulated in the mouse brain from embryonic stage to adult stage. These data are helpful for understanding the proteome changes in the development of the mouse brain.

Structural brain imaging correlates of ASD and ADHD across the lifespan: a hypothesis-generating review on developmental ASD-ADHD subtypes.

PubMed

Rommelse, Nanda; Buitelaar, Jan K; Hartman, Catharina A

2017-02-01

We hypothesize that it is plausible that biologically distinct developmental ASD-ADHD subtypes are present, each characterized by a distinct time of onset of symptoms, progression and combination of symptoms. The aim of the present narrative review was to explore if structural brain imaging studies may shed light on key brain areas that are linked to both ASD and ADHD symptoms and undergo significant changes during development. These findings may possibly pinpoint to brain mechanisms underlying differential developmental ASD-ADHD subtypes. To this end we brought together the literature on ASD and ADHD structural brain imaging symptoms and particularly highlight the adolescent years and beyond. Findings indicate that the vast majority of existing MRI studies has been cross-sectional and conducted in children, and sometimes did include adolescents as well, but without explicitly documenting on this age group. MRI studies documenting on age effects in adults with ASD and/or ADHD are rare, and if age is taken into account, only linear effects are examined. Data from various studies suggest that a crucial distinctive feature underlying different developmental ASD-ADHD subtypes may be the differential developmental thinning patterns of the anterior cingulate cortex and related connections towards other prefrontal regions. These regions are crucial for the development of cognitive/effortful control and socio-emotional functioning, with impairments in these features as key to both ASD and ADHD.

Developmental Changes in Organization of Structural Brain Networks

PubMed Central

Khundrakpam, Budhachandra S.; Reid, Andrew; Brauer, Jens; Carbonell, Felix; Lewis, John; Ameis, Stephanie; Karama, Sherif; Lee, Junki; Chen, Zhang; Das, Samir; Evans, Alan C.; Ball, William S.; Byars, Anna Weber; Schapiro, Mark; Bommer, Wendy; Carr, April; German, April; Dunn, Scott; Rivkin, Michael J.; Waber, Deborah; Mulkern, Robert; Vajapeyam, Sridhar; Chiverton, Abigail; Davis, Peter; Koo, Julie; Marmor, Jacki; Mrakotsky, Christine; Robertson, Richard; McAnulty, Gloria; Brandt, Michael E.; Fletcher, Jack M.; Kramer, Larry A.; Yang, Grace; McCormack, Cara; Hebert, Kathleen M.; Volero, Hilda; Botteron, Kelly; McKinstry, Robert C.; Warren, William; Nishino, Tomoyuki; Robert Almli, C.; Todd, Richard; Constantino, John; McCracken, James T.; Levitt, Jennifer; Alger, Jeffrey; O'Neil, Joseph; Toga, Arthur; Asarnow, Robert; Fadale, David; Heinichen, Laura; Ireland, Cedric; Wang, Dah-Jyuu; Moss, Edward; Zimmerman, Robert A.; Bintliff, Brooke; Bradford, Ruth; Newman, Janice; Evans, Alan C.; Arnaoutelis, Rozalia; Bruce Pike, G.; Louis Collins, D.; Leonard, Gabriel; Paus, Tomas; Zijdenbos, Alex; Das, Samir; Fonov, Vladimir; Fu, Luke; Harlap, Jonathan; Leppert, Ilana; Milovan, Denise; Vins, Dario; Zeffiro, Thomas; Van Meter, John; Lange, Nicholas; Froimowitz, Michael P.; Botteron, Kelly; Robert Almli, C.; Rainey, Cheryl; Henderson, Stan; Nishino, Tomoyuki; Warren, William; Edwards, Jennifer L.; Dubois, Diane; Smith, Karla; Singer, Tish; Wilber, Aaron A.; Pierpaoli, Carlo; Basser, Peter J.; Chang, Lin-Ching; Koay, Chen Guan; Walker, Lindsay; Freund, Lisa; Rumsey, Judith; Baskir, Lauren; Stanford, Laurence; Sirocco, Karen; Gwinn-Hardy, Katrina; Spinella, Giovanna; McCracken, James T.; Alger, Jeffry R.; Levitt, Jennifer; O'Neill, Joseph

2013-01-01

Recent findings from developmental neuroimaging studies suggest that the enhancement of cognitive processes during development may be the result of a fine-tuning of the structural and functional organization of brain with maturation. However, the details regarding the developmental trajectory of large-scale structural brain networks are not yet understood. Here, we used graph theory to examine developmental changes in the organization of structural brain networks in 203 normally growing children and adolescents. Structural brain networks were constructed using interregional correlations in cortical thickness for 4 age groups (early childhood: 4.8–8.4 year; late childhood: 8.5–11.3 year; early adolescence: 11.4–14.7 year; late adolescence: 14.8–18.3 year). Late childhood showed prominent changes in topological properties, specifically a significant reduction in local efficiency, modularity, and increased global efficiency, suggesting a shift of topological organization toward a more random configuration. An increase in number and span of distribution of connector hubs was found in this age group. Finally, inter-regional connectivity analysis and graph-theoretic measures indicated early maturation of primary sensorimotor regions and protracted development of higher order association and paralimbic regions. Our finding reveals a time window of plasticity occurring during late childhood which may accommodate crucial changes during puberty and the new developmental tasks that an adolescent faces. PMID:22784607

Developmental implications of children's brain networks and learning.

PubMed

Chan, John S Y; Wang, Yifeng; Yan, Jin H; Chen, Huafu

2016-10-01

The human brain works as a synergistic system where information exchanges between functional neuronal networks. Rudimentary networks are observed in the brain during infancy. In recent years, the question of how functional networks develop and mature in children has been a hotly discussed topic. In this review, we examined the developmental characteristics of functional networks and the impacts of skill training on children's brains. We first focused on the general rules of brain network development and on the typical and atypical development of children's brain networks. After that, we highlighted the essentials of neural plasticity and the effects of learning on brain network development. We also discussed two important theoretical and practical concerns in brain network training. Finally, we concluded by presenting the significance of network training in typically and atypically developed brains.

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities.

PubMed

Teotia, Pooja; Van Hook, Matthew J; Wichman, Christopher S; Allingham, R Rand; Hauser, Michael A; Ahmad, Iqbal

2017-11-01

Glaucoma represents a group of multifactorial diseases with a unifying pathology of progressive retinal ganglion cell (RGC) degeneration, causing irreversible vision loss. To test the hypothesis that RGCs are intrinsically vulnerable in glaucoma, we have developed an in vitro model using the SIX6 risk allele carrying glaucoma patient-specific induced pluripotent stem cells (iPSCs) for generating functional RGCs. Here, we demonstrate that the efficiency of RGC generation by SIX6 risk allele iPSCs is significantly lower than iPSCs-derived from healthy, age- and sex-matched controls. The decrease in the number of RGC generation is accompanied by repressed developmental expression of RGC regulatory genes. The SIX6 risk allele RGCs display short and simple neurites, reduced expression of guidance molecules, and immature electrophysiological signature. In addition, these cells have higher expression of glaucoma-associated genes, CDKN2A and CDKN2B, suggesting an early onset of the disease phenotype. Consistent with the developmental abnormalities, the SIX6 risk allele RGCs display global dysregulation of genes which map on developmentally relevant biological processes for RGC differentiation and signaling pathways such as mammalian target of rapamycin that integrate diverse functions for differentiation, metabolism, and survival. The results suggest that SIX6 influences different stages of RGC differentiation and their survival; therefore, alteration in SIX6 function due to the risk allele may lead to cellular and molecular abnormalities. These abnormalities, if carried into adulthood, may make RGCs vulnerable in glaucoma. Stem Cells 2017;35:2239-2252. © 2017 AlphaMed Press.

Occipitoparietal epilepsy, hippocampal atrophy, and congenital developmental abnormalities.

PubMed

Lawn, N; Londono, A; Sawrie, S; Morawetz, R; Martin, R; Gilliam, F; Faught, E; Kuzniecky, R

2000-12-01

Diagnostic uncertainty may arise in patients with occipitoparietal epilepsy when there is neuroimaging evidence of a posterior quadrant lesion and coexistent hippocampal abnormalities ("dual pathology"). It is not known whether hippocampal atrophy (HA) in these patients results from seizure propagation to temporolimbic structures or whether it is part of the pathological process underlying the occipitoparietal epilepsy. Clarification of this issue may have a significant bearing on the management of these patients. We studied 20 patients with occipitoparietal epilepsy and neuroimaging or pathologic evidence of a congenital developmental abnormality. Normalized hippocampal volumes were obtained in all patients. The medical records and video-EEG recordings were analyzed to correlate the MRI findings with clinical data, seizure semiology, and EEG findings. HA was found in seven patients (35%). Neuroimaging abnormalities concordant with the side of HA were seen in all cases. There was clinical or EEG evidence of temporal spread in 12 patients. There was no correlation between the presence of HA and temporal lobe spread. The only clinical factor associated with HA in this series was a younger age of seizure onset. HA in patients with occipitoparietal epilepsy due to congenital developmental abnormalities is most likely to be a marker of a more widespread process related to a common pathogenesis during prenatal or perinatal development. HA in these patients is unlikely to be the result of secondary spread from an extrahippocampal focus. Surgical treatment should be tailored toward the primary epileptogenic zone rather the site of seizure spread.

Dissociation of functional and anatomical brain abnormalities in unaffected siblings of schizophrenia patients.

PubMed

Guo, Wenbin; Song, Yan; Liu, Feng; Zhang, Zhikun; Zhang, Jian; Yu, Miaoyu; Liu, Jianrong; Xiao, Changqing; Liu, Guiying; Zhao, Jingping

2015-05-01

Schizophrenia patients and their unaffected siblings share similar brain functional and structural abnormalities. However, no study is engaged to investigate whether and how functional abnormalities are related to structural abnormalities in unaffected siblings. This study was undertaken to examine the association between functional and anatomical abnormalities in unaffected siblings. Forty-six unaffected siblings of schizophrenia patients and 46 age-, sex-, and education-matched healthy controls underwent structural and resting-state functional magnetic resonance imaging scanning. Voxel-based morphometry (VBM), amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) were utilized to analyze imaging data. The VBM analysis showed gray matter volume decreases in the fronto-temporal regions (the left middle temporal gyrus and right inferior frontal gyrus, orbital part) and increases in basal ganglia system (the left putamen). Functional abnormalities measured by ALFF and fALFF mainly involved in the fronto-limbic-sensorimotor circuit (decreased ALFF in bilateral middle frontal gyrus and the right middle cingulate gyrus, and decreased fALFF in the right inferior frontal gyrus, orbital part; and increased ALFF in the left fusiform gyrus and left lingual gyrus, and increased fALFF in bilateral calcarine cortex). No significant correlation was found between functional and anatomical abnormalities in the sibling group. A dissociation pattern of brain regions with functional and anatomical abnormalities is observed in unaffected siblings. Our findings suggest that brain functional and anatomical abnormalities might be present independently in unaffected siblings of schizophrenia patients. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Adolescent TBI-induced hypopituitarism causes sexual dysfunction in adult male rats.

PubMed

Greco, Tiffany; Hovda, David A; Prins, Mayumi L

2015-02-01

Adolescents are at greatest risk for traumatic brain injury (TBI) and repeat TBI (RTBI). TBI-induced hypopituitarism has been documented in both adults and juveniles and despite the necessity of pituitary function for normal physical and brain development, it is still unrecognized and untreated in adolescents following TBI. TBI induced hormonal dysfunction during a critical developmental window has the potential to cause long-term cognitive and behavioral deficits and the topic currently remains unaddressed. The purpose of this study was to determine if four mild TBIs delivered to adolescent male rats disrupts testosterone production and adult behavioral outcomes. Plasma testosterone was quantified from 72 hrs preinjury to 3 months postinjury and pubertal onset, reproductive organ growth, erectile function and reproductive behaviors were assessed at 1 and 2 months postinjury. RTBI resulted in both acute and chronic decreases in testosterone production and delayed onset of puberty. Significant deficits were observed in reproductive organ growth, erectile function and reproductive behaviors in adult rats at both 1 and 2 months postinjury. These data suggest adolescent RTBI-induced hypopituitarism underlies abnormal behavioral changes observed during adulthood. The impact of undiagnosed hypopituitarism following RTBI in adolescence has significance not only for growth and puberty, but also for brain development and neurobehavioral function as adults. © 2014 Wiley Periodicals, Inc.

Methylphenidate and the Juvenile Brain: Enhancement of Attention at the Expense of Cortical Plasticity?

PubMed Central

Urban, Kimberly R.; Gao, Wen-Jun

2013-01-01

Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug for juveniles and adolescents. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, it has been regarded as a relatively safe medication for the past several decades. However, a thorough review of the literature reveals that the age-dependent activities of the drug, as well as potential developmental effects, are largely ignored. In addition, the diagnosis of ADHD is subjective, leaving open the possibility of misdiagnosis and excessive prescription of the drug. Recent studies have suggested that early life exposure of healthy rodent models to methylphenidate resulted in altered sleep/wake cycle, heightened stress reactivity, and, in fact, a dosage previously thought of as therapeutic depressed neuronal function in juvenile rats. Furthermore, juvenile rats exposed to low-dose methylphenidate displayed alterations in neural markers of plasticity, indicating that the drug might alter the basic properties of prefrontal cortical circuits. In this review of the current literature, we propose that juvenile exposure to methylphenidate may cause abnormal prefrontal function and impaired plasticity in the healthy brain, strengthening the case for developing a more thorough understanding of methylphenidate’s actions on the developing, juvenile brain, as well as better diagnostic measures for ADHD. PMID:24095262

Neurotoxicants Are in the Air: Convergence of Human, Animal, and In Vitro Studies on the Effects of Air Pollution on the Brain

PubMed Central

Costa, Lucio G.; Cole, Toby B.; Coburn, Jacki; Chang, Yu-Chi; Dao, Khoi; Roque, Pamela

2014-01-01

In addition to increased morbidity and mortality caused by respiratory and cardiovascular diseases, air pollution may also negatively affect the brain and contribute to central nervous system diseases. Air pollution is a mixture comprised of several components, of which ultrafine particulate matter (UFPM; <100 nm) is of much concern, as these particles can enter the circulation and distribute to most organs, including the brain. A major constituent of ambient UFPM is represented by traffic-related air pollution, mostly ascribed to diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution may lead to neurotoxicity. In addition to a variety of behavioral abnormalities, two prominent effects caused by air pollution are oxidative stress and neuroinflammation, which are seen in both humans and animals and are confirmed by in vitro studies. Among factors which can affect neurotoxic outcomes, age is considered the most relevant. Human and animal studies suggest that air pollution (and DE) may cause developmental neurotoxicity and may contribute to the etiology of neurodevelopmental disorders, including autistic spectrum disorders. In addition, air pollution exposure has been associated with increased expression of markers of neurodegenerative disease pathologies. PMID:24524086

Neonatal brain abnormalities and memory and learning outcomes at 7 years in children born very preterm.

PubMed

Omizzolo, Cristina; Scratch, Shannon E; Stargatt, Robyn; Kidokoro, Hiroyuki; Thompson, Deanne K; Lee, Katherine J; Cheong, Jeanie; Neil, Jeffrey; Inder, Terrie E; Doyle, Lex W; Anderson, Peter J

2014-01-01

Using prospective longitudinal data from 198 very preterm and 70 full term children, this study characterised the memory and learning abilities of very preterm children at 7 years of age in both verbal and visual domains. The relationship between the extent of brain abnormalities on neonatal magnetic resonance imaging (MRI) and memory and learning outcomes at 7 years of age in very preterm children was also investigated. Neonatal MRI scans were qualitatively assessed for global, white-matter, cortical grey-matter, deep grey-matter, and cerebellar abnormalities. Very preterm children performed less well on measures of immediate memory, working memory, long-term memory, and learning compared with term-born controls. Neonatal brain abnormalities, and in particular deep grey-matter abnormality, were associated with poorer memory and learning performance at 7 years in very preterm children. Findings support the importance of cerebral neonatal pathology for predicting later memory and learning function.

Childcare Workers' Knowledge about the Brain and Developmentally Appropriate Practice

ERIC Educational Resources Information Center

Zambo, Debby

2008-01-01

Advances in neuroscience are providing information about the brain and its development. Some researchers propose that childcare workers need to understand this information because it confirms their importance and their use of developmentally appropriate practice (DAP). Given the fact that childcare workers could benefit from this insight, it seems…

Developmental Hypothyroidism Reduces the Expression of Activity-Dependent Plasticity Genes in Denate Gyrus of the Adult Following Long Term Potentiation

EPA Science Inventory

Disruption of thyroid hormone (TH) is a known effect of environmental contaminants. Neurotrophins including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have been implicated in brain dysfunction resulting from severe developmental TH insufficiency. Neuro...

MRI or not to MRI! Should brain MRI be a routine investigation in children with autistic spectrum disorders?

PubMed

Zeglam, Adel M; Al-Ogab, Marwa F; Al-Shaftery, Thouraya

2015-09-01

To evaluate the routine usage of Magnetic Resonance Imaging (MRI) of brain and estimate the prevalence of brain abnormalities in children presenting to the Neurodevelopment Clinic of Al-Khadra Hospital (NDC-KH), Tripoli, Libya with autistic spectrum disorders (ASD). The records of all children with ASD presented to NDC-KH over 4-year period (from January 2009 to December 2012) were reviewed. All MRIs were acquired with a 1.5-T Philips (3-D T1, T2, FLAIR coronal and axial sequences). MRIs were reported to be normal, abnormal or no significant abnormalities by a consultant neuroradiologist. One thousand and seventy-five children were included in the study. Seven hundred and eighty-two children (72.7 %) had an MRI brain of whom 555 (71 %) were boys. 26 children (24 males and 2 females) (3.3 %) demonstrated MRI abnormalities (8 leukodystrophic changes, 4 periventricular leukomalacia, 3 brain atrophy, 2 tuberous sclerosis, 2 vascular changes, 1 pineoblastoma, 1 cerebellar angioma, 1 cerebellar hypoplasia, 3 agenesis of corpus callosum, 1 neuro-epithelial cyst). An unexpectedly high rate of MRI abnormalities was found in the first large series of clinical MRI investigations in children with autism. These results could contribute to further research into the pathogenesis of autistic spectrum disorder.

Genetically induced abnormal cranial development in human trisomy 18 with holoprosencephaly: comparisons with the normal tempo of osteogenic-neural development.

PubMed

Reid, Shaina N; Ziermann, Janine M; Gondré-Lewis, Marjorie C

2015-07-01

Craniofacial malformations are common congenital defects caused by failed midline inductive signals. These midline defects are associated with exposure of the fetus to exogenous teratogens and with inborn genetic errors such as those found in Down, Patau, Edwards' and Smith-Lemli-Opitz syndromes. Yet, there are no studies that analyze contributions of synchronous neurocranial and neural development in these disorders. Here we present the first in-depth analysis of malformations of the basicranium of a holoprosencephalic (HPE) trisomy 18 (T18; Edwards' syndrome) fetus with synophthalmic cyclopia and alobar HPE. With a combination of traditional gross dissection and state-of-the-art computed tomography, we demonstrate the deleterious effects of T18 caused by a translocation at 18p11.31. Bony features included a single developmentally unseparated frontal bone, and complete dual absence of the anterior cranial fossa and ethmoid bone. From a superior view with the calvarium plates removed, there was direct visual access to the orbital foramen and hard palate. Both the eyes and the pituitary gland, normally protected by bony structures, were exposed in the cranial cavity and in direct contact with the brain. The middle cranial fossa was shifted anteriorly, and foramina were either missing or displaced to an abnormal location due to the absence or misplacement of its respective cranial nerve (CN). When CN development was conserved in its induction and placement, the respective foramen developed in its normal location albeit with abnormal gross anatomical features, as seen in the facial nerve (CNVII) and the internal acoustic meatus. More anteriorly localized CNs and their foramina were absent or heavily disrupted compared with posterior ones. The severe malformations exhibited in the cranial fossae, orbital region, pituitary gland and sella turcica highlight the crucial involvement of transcription factors such as TGIF, which is located on chromosome 18 and contributes to neural patterning, in the proper development of neural and cranial structures. Our study of a T18 specimen emphasizes the intricate interplay between bone and brain development in midline craniofacial abnormalities in general. © 2015 Anatomical Society.

Thyroid Hormone Acts Locally to Increase Neurogenesis, Neuronal Differentiation, and Dendritic Arbor Elaboration in the Tadpole Visual System

PubMed Central

Thompson, Christopher K.

2016-01-01

Thyroid hormone (TH) regulates many cellular events underlying perinatal brain development in vertebrates. Whether and how TH regulates brain development when neural circuits are first forming is less clear. Furthermore, although the molecular mechanisms that impose spatiotemporal constraints on TH action in the brain have been described, the effects of local TH signaling are poorly understood. We determined the effects of manipulating TH signaling on development of the optic tectum in stage 46–49 Xenopus laevis tadpoles. Global TH treatment caused large-scale morphological effects in tadpoles, including changes in brain morphology and increased tectal cell proliferation. Either increasing or decreasing endogenous TH signaling in tectum, by combining targeted DIO3 knockdown and methimazole, led to corresponding changes in tectal cell proliferation. Local increases in TH, accomplished by injecting suspensions of tri-iodothyronine (T3) in coconut oil into the midbrain ventricle or into the eye, selectively increased tectal or retinal cell proliferation, respectively. In vivo time-lapse imaging demonstrated that local TH first increased tectal progenitor cell proliferation, expanding the progenitor pool, and subsequently increased neuronal differentiation. Local T3 also dramatically increased dendritic arbor growth in neurons that had already reached a growth plateau. The time-lapse data indicate that the same cells are differentially sensitive to T3 at different time points. Finally, TH increased expression of genes pertaining to proliferation and neuronal differentiation. These experiments indicate that endogenous TH locally regulates neurogenesis at developmental stages relevant to circuit assembly by affecting cell proliferation and differentiation and by acting on neurons to increase dendritic arbor elaboration. SIGNIFICANCE STATEMENT Thyroid hormone (TH) is a critical regulator of perinatal brain development in vertebrates. Abnormal TH signaling in early pregnancy is associated with significant cognitive deficits in humans; however, it is difficult to probe the function of TH in early brain development in mammals because of the inaccessibility of the fetal brain in the uterine environment and the challenge of disambiguating maternal versus fetal contributions of TH. The external development of tadpoles allows manipulation and direct observation of the molecular and cellular mechanisms underlying TH's effects on brain development in ways not possible in mammals. We find that endogenous TH locally regulates neurogenesis at developmental stages relevant to circuit assembly by affecting neural progenitor cell proliferation and differentiation and by acting on neurons to enhance dendritic arbor elaboration. PMID:27707971

Brain microstructural development at near-term age in very-low-birth-weight preterm infants: An atlas-based diffusion imaging study

PubMed Central

Rose, Jessica; Vassar, Rachel; Cahill-Rowley, Katelyn; Guzman, Ximena Stecher; Stevenson, David K.; Barnea-Goraly, Naama

2014-01-01

At near-term age the brain undergoes rapid growth and development. Abnormalities identified during this period have been recognized as potential predictors of neurodevelopment in children born preterm. This study used diffusion tensor imaging (DTI) to examine white matter (WM) microstructure in very-low-birth-weight (VLBW) preterm infants to better understand regional WM developmental trajectories at near-term age. DTI scans were analyzed in a cross-sectional sample of 45 VLBW preterm infants (BW ≤ 1500 g, GA ≤ 32 weeks) within a cohort of 102 neonates admitted to the NICU and recruited to participate prior to standard-of-care MRI, from 2010 to 2011, 66/102 also had DTI. For inclusion in this analysis, 45 infants had DTI, no evidence of brain abnormality on MRI, and were scanned at PMA ≤40 weeks (34.7–38.6). White matter microstructure was analyzed in 19 subcortical regions defined by DiffeoMap neonatal brain atlas, using threshold values of trace b0.006 mm2 s−1 and FA >0.15. Regional fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and temporal–spatial trajectories of development were examined in relation to PMA and brain region location. Posterior regions within the corona radiata (CR), corpus callosum (CC), and internal capsule (IC) demonstrated significantly higher mean FA values compared to anterior regions. Posterior regions of the CR and IC demonstrated significantly lower RD values compared to anterior regions. Centrally located projection fibers demonstrated higher mean FA and lower RD values than peripheral regions including the posterior limb of the internal capsule (PLIC), cerebral peduncle, retrolenticular part of the IC, posterior thalamic radiation, and sagittal stratum. Centrally located association fibers of the external capsule had higher FA and lower RD than the more peripherally-located superior longitudinal fasciculus (SLF). A significant relationship between PMA-at-scan and FA, MD, and RD was demonstrated by a majority of regions, the strongest correlations were observed in the anterior limb of the internal capsule, a region undergoing early stages of myelination at near-term age, in which FA increased (r = .433, p = .003) and MD (r = –.545, p = .000) and RD (r = –.540, p = .000) decreased with PMA-at-scan. No correlation with PMA-at-scan was observed in the CC or SLF, regions that myelinate later in infancy. Regional patterns of higher FA and lower RD were observed at this near-term age, suggestive of more advanced microstructural development in posterior compared to anterior regions within the CR, CC, and IC and in central compared to peripheral WM structures. Evidence of region-specific rates of microstructural development was observed. Temporal–spatial patterns of WM microstructure development at near-term age have important implications for interpretation of near-term DTI and for identification of aberrations in typical developmental trajectories that may signal future impairment. PMID:24091089

Brain microstructural development at near-term age in very-low-birth-weight preterm infants: an atlas-based diffusion imaging study.

PubMed

Rose, Jessica; Vassar, Rachel; Cahill-Rowley, Katelyn; Guzman, Ximena Stecher; Stevenson, David K; Barnea-Goraly, Naama

2014-02-01

At near-term age the brain undergoes rapid growth and development. Abnormalities identified during this period have been recognized as potential predictors of neurodevelopment in children born preterm. This study used diffusion tensor imaging (DTI) to examine white matter (WM) microstructure in very-low-birth-weight (VLBW) preterm infants to better understand regional WM developmental trajectories at near-term age. DTI scans were analyzed in a cross-sectional sample of 45 VLBW preterm infants (BW≤1500g, GA≤32weeks) within a cohort of 102 neonates admitted to the NICU and recruited to participate prior to standard-of-care MRI, from 2010 to 2011, 66/102 also had DTI. For inclusion in this analysis, 45 infants had DTI, no evidence of brain abnormality on MRI, and were scanned at PMA ≤40weeks (34.7-38.6). White matter microstructure was analyzed in 19 subcortical regions defined by DiffeoMap neonatal brain atlas, using threshold values of trace <0.006mm(2)s(-1) and FA >0.15. Regional fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and temporal-spatial trajectories of development were examined in relation to PMA and brain region location. Posterior regions within the corona radiata (CR), corpus callosum (CC), and internal capsule (IC) demonstrated significantly higher mean FA values compared to anterior regions. Posterior regions of the CR and IC demonstrated significantly lower RD values compared to anterior regions. Centrally located projection fibers demonstrated higher mean FA and lower RD values than peripheral regions including the posterior limb of the internal capsule (PLIC), cerebral peduncle, retrolenticular part of the IC, posterior thalamic radiation, and sagittal stratum. Centrally located association fibers of the external capsule had higher FA and lower RD than the more peripherally-located superior longitudinal fasciculus (SLF). A significant relationship between PMA-at-scan and FA, MD, and RD was demonstrated by a majority of regions, the strongest correlations were observed in the anterior limb of the internal capsule, a region undergoing early stages of myelination at near-term age, in which FA increased (r=.433, p=.003) and MD (r=-.545, p=.000) and RD (r=-.540, p=.000) decreased with PMA-at-scan. No correlation with PMA-at-scan was observed in the CC or SLF, regions that myelinate later in infancy. Regional patterns of higher FA and lower RD were observed at this near-term age, suggestive of more advanced microstructural development in posterior compared to anterior regions within the CR, CC, and IC and in central compared to peripheral WM structures. Evidence of region-specific rates of microstructural development was observed. Temporal-spatial patterns of WM microstructure development at near-term age have important implications for interpretation of near-term DTI and for identification of aberrations in typical developmental trajectories that may signal future impairment. © 2013.

A dysmorphology score system for assessing embryo abnormalities in rat whole embryo culture.

PubMed

Zhang, Cindy X; Danberry, Tracy; Jacobs, Mary Ann; Augustine-Rauch, Karen

2010-12-01

The rodent whole embryo culture (WEC) system is a well-established model for characterizing developmental toxicity of test compounds and conducting mechanistic studies. Laboratories have taken various approaches in describing type and severity of developmental findings of organogenesis-stage rodent embryos, but the Brown and Fabro morphological score system is commonly used as a quantitative approach. The associated score criteria is based upon developmental stage and growth parameters, where a series of embryonic structures are assessed and assigned respective scores relative to their gestational stage, with a Total Morphological Score (TMS) assigned to the embryo. This score system is beneficial because it assesses a series of stage-specific anatomical landmarks, facilitating harmonized evaluation across laboratories. Although the TMS provides a quantitative approach to assess growth and determine developmental delay, it is limited to its ability to identify and/or delineate subtle or structure-specific abnormalities. Because of this, the TMS may not be sufficiently sensitive for identifying compounds that induce structure or organ-selective effects. This study describes a distinct morphological score system called the "Dysmorphology Score System (DMS system)" that has been developed for assessing gestation day 11 (approximately 20-26 somite stage) rat embryos using numerical scores to differentiate normal from abnormal morphology and define the respective severity of dysmorphology of specific embryonic structures and organ systems. This method can also be used in scoring mouse embryos of the equivalent developmental stage. The DMS system enhances capabilities to rank-order compounds based upon teratogenic potency, conduct structure- relationships of chemicals, and develop statistical prediction models to support abbreviated developmental toxicity screens. © 2010 Wiley-Liss, Inc.

Morphological and Glucose Metabolism Abnormalities in Alcoholic Korsakoff's Syndrome: Group Comparisons and Individual Analyses

PubMed Central

Pitel, Anne-Lise; Aupée, Anne-Marie; Chételat, Gaël; Mézenge, Florence; Beaunieux, Hélène; de la Sayette, Vincent; Viader, Fausto; Baron, Jean-Claude; Eustache, Francis; Desgranges, Béatrice

2009-01-01

Background Gray matter volume studies have been limited to few brain regions of interest, and white matter and glucose metabolism have received limited research attention in Korsakoff's syndrome (KS). Because of the lack of brain biomarkers, KS was found to be underdiagnosed in postmortem studies. Methodology/Principal Findings Nine consecutively selected patients with KS and 22 matched controls underwent both structural magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography examinations. Using a whole-brain analysis, the between-group comparisons of gray matter and white matter density and relative glucose uptake between patients with KS and controls showed the involvement of both the frontocerebellar and the Papez circuits, including morphological abnormalities in their nodes and connection tracts and probably resulting hypometabolism. The direct comparison of the regional distribution and degree of gray matter hypodensity and hypometabolism within the KS group indicated very consistent gray matter distribution of both abnormalities, with a single area of significant difference in the middle cingulate cortex showing greater hypometabolism than hypodensity. Finally, the analysis of the variability in the individual patterns of brain abnormalities within our sample of KS patients revealed that the middle cingulate cortex was the only brain region showing significant GM hypodensity and hypometabolism in each of our 9 KS patients. Conclusions/Significance These results indicate widespread brain abnormalities in KS including both gray and white matter damage mainly involving two brain networks, namely, the fronto-cerebellar circuit and the Papez circuit. Furthermore, our findings suggest that the middle cingulate cortex may play a key role in the pathophysiology of KS and could be considered as a potential in vivo brain biomarker. PMID:19936229

Evolved developmental homeostasis disturbed in LB1 from Flores, Indonesia, denotes Down syndrome and not diagnostic traits of the invalid species Homo floresiensis

NASA Astrophysics Data System (ADS)

Henneberg, Maciej; Eckhardt, Robert B.; Chavanaves, Sakdapong; Hsü, Kenneth J.

2014-08-01

Human skeletons from Liang Bua Cave, Flores, Indonesia, are coeval with only Homo sapiens populations worldwide and no other previously known hominins. We report here for the first time to our knowledge the occipitofrontal circumference of specimen LB1. This datum makes it possible to link the 430-mL endocranial volume of LB1 reported by us previously, later confirmed independently by other investigators, not only with other human skeletal samples past and present but also with a large body of clinical data routinely collected on patients with developmental disorders. Our analyses show that the brain size of LB1 is in the range predicted for an individual with Down syndrome (DS) in a normal small-bodied population from the geographic region that includes Flores. Among additional diagnostic signs of DS and other skeletal dysplasiae are abnormally short femora combined with disproportionate flat feet. Liang Bua Cave femora, known only for LB1, match interlimb proportions for DS. Predictions based on corrected LB1 femur lengths show a stature normal for other H. sapiens populations in the region.

A review of MRI findings in schizophrenia

PubMed Central

Shenton, Martha E.; Dickey, Chandlee C.; Frumin, Melissa; McCarley, Robert W.

2009-01-01

After more than 100 years of research, the neuropathology of schizophrenia remains unknown and this is despite the fact that both Kraepelin (1919/1971: Kraepelin,E., 1919/1971. Dementia praecox. Churchill Livingston Inc., New York) and Bleuler (1911/1950: Bleuler, E., 1911/1950. Dementia praecox or the group of schizophrenias. International Universities Press, New York), who first described ‘dementia praecox’ and the ‘ schizophrenias’, were convinced that schizophrenia would ultimately be linked to an organic brain disorder. Alzheimer (1897: Alzheimer, A., 1897. Beitrage zur pathologischen anatomie der hirnrinde und zur anatomischen grundlage einiger psychosen. Monatsschrift fur Psychiarie und Neurologie. 2, 82–120) was the first to investigate the neuropathology of schizophrenia, though he went on to study more tractable brain diseases. The results of subsequent neuropathological studies were disappointing because of conflicting findings. Research interest thus waned and did not flourish again until 1976, following the pivotal computer assisted tomography (CT) finding of lateral ventricular enlargement in schizophrenia by Johnstone and colleagues. Since that time significant progress has been made in brain imaging, particularly with the advent of magnetic resonance imaging (MRI), beginning with the first MRI study of schizophrenia by Smith and coworkers in 1984 (Smith, R.C., Calderon, M., Ravichandran, G.K., et al. (1984). Nuclear magnetic resonance in schizophrenia: A preliminary study. Psychiatry Res. 12, 137–147). MR in vivo imaging of the brain now confirms brain abnormalities in schizophrenia. The 193 peer reviewed MRI studies reported in the current review span the period from 1988 to August, 2000. This 12 year period has witnessed a burgeoning of MRI studies and has led to more definitive findings of brain abnormalities in schizophrenia than any other time period in the history of schizophrenia research. Such progress in defining the neuropathology of schizophrenia is largely due to advances in in vivo MRI techniques. These advances have now led to the identification of a number of brain abnormalities in schizophrenia. Some of these abnormalities confirm earlier post-mortem findings, and most are small and subtle, rather than large, thus necessitating more advanced and accurate measurement tools. These findings include ventricular enlargement (80% of studies reviewed) and third ventricle enlargement (73% of studies reviewed). There is also preferential involvement of medial temporal lobe structures (74% of studies reviewed), which include the amygdala, hippocampus, and parahippocampal gyrus, and neocortical temporal lobe regions (superior temporal gyrus) (100% of studies reviewed). When gray and white matter of superior temporal gyrus was combined, 67% of studies reported abnormalities. There was also moderate evidence for frontal lobe abnormalities (59% of studies reviewed), particularly prefrontal gray matter and orbitofrontal regions. Similarly, there was moderate evidence for parietal lobe abnormalities (60% of studies reviewed), particularly of the inferior parietal lobule which includes both supramarginal and angular gyri. Additionally, there was strong to moderate evidence for subcortical abnormalities (i.e. cavum septi pellucidi—92% of studies reviewed, basal ganglia—68% of studies reviewed, corpus callosum—63% of studies reviewed, and thalamus—42% of studies reviewed), but more equivocal evidence for cerebellar abnormalities (31% of studies reviewed). The timing of such abnormalities has not yet been determined, although many are evident when a patient first becomes symptomatic. There is, however, also evidence that a subset of brain abnormalities may change over the course of the illness. The most parsimonious explanation is that some brain abnormalities are neurodevelopmental in origin but unfold later in development, thus setting the stage for the development of the symptoms of schizophrenia. Or there may be additional factors, such as stress or neurotoxicity, that occur during adolescence or early adulthood and are necessary for the development of schizophrenia, and may be associated with neurodegenerative changes. Importantly, as several different brain regions are involved in the neuropathology of schizophrenia, new models need to be developed and tested that explain neural circuitry abnormalities effecting brain regions not necessarily structurally proximal to each other but nonetheless functionally interrelated. Future studies will likely benefit from: (1) studying more homogeneous patient groups so that the relationship between MRI findings and clinical symptoms become more meaningful; (2) studying at risk populations such as family members of patients diagnosed with schizophrenia and subjects diagnosed with schizotypal personality disorder in order to define which abnormalities are specific to schizophrenia spectrum disorders, which are the result of epiphenomena such as medication effects and chronic institutionalization, and which are needed for the development of frank psychosis; (3) examining shape differences not detectable from measuring volume alone; (4) applying newer methods such as diffusion tensor imaging to investigate abnormalities in brain connectivity and white matter fiber tracts; and, (5) using methods that analyze brain function (fMRI) and structure simultaneously. PMID:11343862

On the Application of Quantitative EEG for Characterizing Autistic Brain: A Systematic Review

PubMed Central

Billeci, Lucia; Sicca, Federico; Maharatna, Koushik; Apicella, Fabio; Narzisi, Antonio; Campatelli, Giulia; Calderoni, Sara; Pioggia, Giovanni; Muratori, Filippo

2013-01-01

Autism-Spectrum Disorders (ASD) are thought to be associated with abnormalities in neural connectivity at both the global and local levels. Quantitative electroencephalography (QEEG) is a non-invasive technique that allows a highly precise measurement of brain function and connectivity. This review encompasses the key findings of QEEG application in subjects with ASD, in order to assess the relevance of this approach in characterizing brain function and clustering phenotypes. QEEG studies evaluating both the spontaneous brain activity and brain signals under controlled experimental stimuli were examined. Despite conflicting results, literature analysis suggests that QEEG features are sensitive to modification in neuronal regulation dysfunction which characterize autistic brain. QEEG may therefore help in detecting regions of altered brain function and connectivity abnormalities, in linking behavior with brain activity, and subgrouping affected individuals within the wide heterogeneity of ASD. The use of advanced techniques for the increase of the specificity and of spatial localization could allow finding distinctive patterns of QEEG abnormalities in ASD subjects, paving the way for the development of tailored intervention strategies. PMID:23935579

Mixed vascular nevus syndrome: a report of four new cases and a literature review.

PubMed

Ruggieri, Martino; Polizzi, Agata; Strano, Serena; Schepis, Carmelo; Morano, Massimiliano; Belfiore, Giuseppe; Palmucci, Stefano; Foti, Pietro Valerio; Pirrone, Concetta; Sofia, Vito; David, Emanuele; Salpietro, Vincenzo; Mankad, Kshitij; Milone, Pietro

2016-10-01

Mixed vascular nevus (or nevus vascularis mixtus) represents an admixture of cutaneous vascular malformations of the telangiectatic type and angiospastic spots of nevus anemicus. It can occur as an purely cutaneous trait or as a hallmark of a neurocutaneous phenotype (mixed vascular nevus syndrome) characterised by the combination of: (I) paired vascular (telangiectatic and anemic) twin nevi and brain abnormalities of the Dyke-Davidoff-Masson type (i.e., crossed cerebral/cerebellar hemiatrophy with hypoplasia of the ipsilateral cerebral vessels and homolateral hypertrophy of the skull and sinuses (hyperpneumatisation) with contralateral hemispheric hypertrophy); or (II) paired vascular twin nevi and brain malformations of the Dyke-Davidoff-Masson type in association with systemic abnormalities consisting in facial asymmetry, skeletal anomalies (i.e., Legg-Calvé-Perthes-like disease) and disorders of autoimmunity (i.e., diabetes, thyroiditis). In 2014, Happle proposed to name the syndrome with the eponym Ruggieri-Leech syndrome. Review of the existing literature on nevus vascularis mixtus and information on our personal experience on new cases and follow-up of previously reported cases by some of us. The existing literature revealed 4 previous studies including 33 cases with an inferred purely cutaneous trait and 3 cases with a combination of paired vascular twin nevi and brain malformation of the Dyke-Davidoff-Masson type. Our personal experience includes 4 unpublished patients (1 female and 3 males; currently aged 2 to 34 years) seen and followed-up at our Institutions in Italy who had: paired vascular nevi involving either the face (n=2) or the face and parts of the body (n=2); facial asymmetry (n=4); mild to moderate facial dysmorphic features (n=2); developmental delay (n=3); seizures/stroke-like episodes and associated hemiplegia (n=4); muscular hypotrophy (n=2); mild to moderate hemispheric atrophy (n=4); skull osseous hypertrophy (n=4); hyperpneumatisation of the sinuses (n=2); hypoplastic brain vessels (n=4); colpocephaly and malformation of cortical development (n=2). Follow-up data on our previous 2 cases revealed that the vascular abnormalities in the skin and nervous system were stable over years without neurological progression or deterioration. Pathogenically, this complex phenotype suggests that embryonic pairing and somatic recombination of recessive (didymotic) alleles controlling the balance between constriction (i.e., nevus anemicus) and dilatation (i.e., nevus telangiectaticus) of blood vessels could be the primary event causing the phenomena of cutaneous and brain vascular twin spotting and the paired phenomena of skull hyperpneumatisation vs . hypertrophy and brain megalencephaly/colpocephaly vs . cortical dysplasia. This association is likely more frequent than previously thought and should be investigated by means of: (I) brain and spinal cord imaging (combination of CT and MRI studies); (II) skeletal X-ray studies (when dictated by clinical findings); (III) systemic ultrasound studies; (IV) neurophysiologic studies (EEG); (V) psychomotor testing; (VI) and laboratory investigation (including immune-mediated dysfunction).

Mixed vascular nevus syndrome: a report of four new cases and a literature review

PubMed Central

Polizzi, Agata; Strano, Serena; Schepis, Carmelo; Morano, Massimiliano; Belfiore, Giuseppe; Palmucci, Stefano; Foti, Pietro Valerio; Pirrone, Concetta; Sofia, Vito; David, Emanuele; Salpietro, Vincenzo; Mankad, Kshitij; Milone, Pietro

2016-01-01

Background Mixed vascular nevus (or nevus vascularis mixtus) represents an admixture of cutaneous vascular malformations of the telangiectatic type and angiospastic spots of nevus anemicus. It can occur as an purely cutaneous trait or as a hallmark of a neurocutaneous phenotype (mixed vascular nevus syndrome) characterised by the combination of: (I) paired vascular (telangiectatic and anemic) twin nevi and brain abnormalities of the Dyke-Davidoff-Masson type (i.e., crossed cerebral/cerebellar hemiatrophy with hypoplasia of the ipsilateral cerebral vessels and homolateral hypertrophy of the skull and sinuses (hyperpneumatisation) with contralateral hemispheric hypertrophy); or (II) paired vascular twin nevi and brain malformations of the Dyke-Davidoff-Masson type in association with systemic abnormalities consisting in facial asymmetry, skeletal anomalies (i.e., Legg-Calvé-Perthes-like disease) and disorders of autoimmunity (i.e., diabetes, thyroiditis). In 2014, Happle proposed to name the syndrome with the eponym Ruggieri-Leech syndrome. Methods Review of the existing literature on nevus vascularis mixtus and information on our personal experience on new cases and follow-up of previously reported cases by some of us. Results The existing literature revealed 4 previous studies including 33 cases with an inferred purely cutaneous trait and 3 cases with a combination of paired vascular twin nevi and brain malformation of the Dyke-Davidoff-Masson type. Our personal experience includes 4 unpublished patients (1 female and 3 males; currently aged 2 to 34 years) seen and followed-up at our Institutions in Italy who had: paired vascular nevi involving either the face (n=2) or the face and parts of the body (n=2); facial asymmetry (n=4); mild to moderate facial dysmorphic features (n=2); developmental delay (n=3); seizures/stroke-like episodes and associated hemiplegia (n=4); muscular hypotrophy (n=2); mild to moderate hemispheric atrophy (n=4); skull osseous hypertrophy (n=4); hyperpneumatisation of the sinuses (n=2); hypoplastic brain vessels (n=4); colpocephaly and malformation of cortical development (n=2). Follow-up data on our previous 2 cases revealed that the vascular abnormalities in the skin and nervous system were stable over years without neurological progression or deterioration. Conclusions Pathogenically, this complex phenotype suggests that embryonic pairing and somatic recombination of recessive (didymotic) alleles controlling the balance between constriction (i.e., nevus anemicus) and dilatation (i.e., nevus telangiectaticus) of blood vessels could be the primary event causing the phenomena of cutaneous and brain vascular twin spotting and the paired phenomena of skull hyperpneumatisation vs. hypertrophy and brain megalencephaly/colpocephaly vs. cortical dysplasia. This association is likely more frequent than previously thought and should be investigated by means of: (I) brain and spinal cord imaging (combination of CT and MRI studies); (II) skeletal X-ray studies (when dictated by clinical findings); (III) systemic ultrasound studies; (IV) neurophysiologic studies (EEG); (V) psychomotor testing; (VI) and laboratory investigation (including immune-mediated dysfunction). PMID:27942471

Increased Functional Connectivity Between Subcortical and Cortical Resting-State Networks in Autism Spectrum Disorder

PubMed Central

Cerliani, Leonardo; Mennes, Maarten; Thomas, Rajat M.; Di Martino, Adriana; Thioux, Marc; Keysers, Christian

2016-01-01

Importance Individuals with autism spectrum disorder (ASD) exhibit severe difficulties in social interaction, motor coordination, behavioral flexibility, and atypical sensory processing, with considerable interindividual variability. This heterogeneous set of symptoms recently led to investigating the presence of abnormalities in the interaction across large-scale brain networks. To date, studies have focused either on constrained sets of brain regions or whole-brain analysis, rather than focusing on the interaction between brain networks. Objectives To compare the intrinsic functional connectivity between brain networks in a large sample of individuals with ASD and typically developing control subjects and to estimate to what extent group differences would predict autistic traits and reflect different developmental trajectories. Design, Setting, and Participants We studied 166 male individuals (mean age, 17.6 years; age range, 7-50 years) diagnosed as having DSM-IV-TR autism or Asperger syndrome and 193 typical developing male individuals (mean age, 16.9 years; age range, 6.5-39.4 years) using resting-state functional magnetic resonance imaging (MRI). Participants were matched for age, IQ, head motion, and eye status (open or closed) in the MRI scanner. We analyzed data from the Autism Brain Imaging Data Exchange (ABIDE), an aggregated MRI data set from 17 centers, made public in August 2012. Main Outcomes and Measures We estimated correlations between time courses of brain networks extracted using a data-driven method (independent component analysis). Subsequently, we associated estimates of interaction strength between networks with age and autistic traits indexed by the Social Responsiveness Scale. Results Relative to typically developing control participants, individuals with ASD showed increased functional connectivity between primary sensory networks and subcortical networks (thalamus and basal ganglia) (all t ≥ 3.13, P < .001 corrected). The strength of such connections was associated with the severity of autistic traits in the ASD group (all r ≥ 0.21, P < .0067 corrected). In addition, subcortico-cortical interaction decreased with age in the entire sample (all r ≤ −0.09, P < .012 corrected), although this association was significant only in typically developing participants (all r ≤ −0.13, P < .009 corrected). Conclusions and Relevance Our results showing ASD-related impairment in the interaction between primary sensory cortices and subcortical regions suggest that the sensory processes they subserve abnormally influence brain information processing in individuals with ASD. This might contribute to the occurrence of hyposensitivity or hypersensitivity and of difficulties in top-down regulation of behavior. PMID:26061743

Chronic Overeating without Obesity in Children with Developmental Disabilities: Description of a New Syndrome.

ERIC Educational Resources Information Center

Ayoob, Keith-Thomas; And Others

1994-01-01

Thirteen children (ages 3.1 to 5.2 years) referred for developmental delay and excessive eating (without obesity) were evaluated. Commonalities included being in foster care, prenatal drug exposure, and abnormally withdrawn and/or aggressive behavior. (Author/DB)

New insights into the mechanism of phthalate-induced developmental effects.

PubMed

Mu, Xiyan; Huang, Ying; Li, Jia; Yang, Ke; Yang, Wenbo; Shen, Gongming; Li, Xuxing; Lei, Yunlei; Pang, Sen; Wang, Chengju; Li, Xuefeng; Li, Yingren

2018-06-11

To investigate the biological pathways involved in phthalate-induced developmental effects, zebrafish embryos were exposed to different concentrations of di-(2-ethylhexyl) (DEHP) and di-butyl phthalate (DBP) for 96 h. Embryonic exposure to DEHP and DBP induced body length decrease, yolk sac abnormities, and immune responses (up-regulation of immune proteins and genes). The lipidomic results showed that at a concentration of 50 μg/L, DEHP and DBP significantly reduced the levels of fatty acids, triglycerides, diacylglycerol, and cholesterol. These effects are partly explained by biological pathway enrichment based on data from the transcriptional and proteomic profiles. Co-exposure to DBP and ER antagonist did not significantly relieve the toxic symptoms compared with exposure to DBP alone. This indicates that phthalate-induced developmental abnormities in zebrafish might not be mediated by the ER pathway. In conclusion, we identified the possible biological pathways that mediate phthalate-induced developmental effects and found that these effects may not be driven by estrogenic activation. Copyright © 2018 Elsevier Ltd. All rights reserved.

Decorticate posture

MedlinePlus

Abnormal posturing - decorticate posture; Traumatic brain injury - decorticate posture ... Brain problem due to drugs, poisoning, or infection Traumatic brain injury Brain problem due to liver failure Increased pressure ...

Recurrent abnormalities in conifer cones and the evolutionary origins of flower-like structures.

PubMed

Rudall, Paula J; Hilton, Jason; Vergara-Silva, Francisco; Bateman, Richard M

2011-03-01

Conifer cones are reproductive structures that are typically of restricted growth and either exclusively pollen-bearing (male) or exclusively ovule-bearing (female). Here, we review two common spontaneous developmental abnormalities of conifer cones: proliferated cones, in which the apex grows vegetatively, and bisexual cones, which possess both male and female structures. Emerging developmental genetic data, combined with evidence from comparative morphology, ontogeny and palaeobotany, provide new insights into the evolution of both cones and flowers, and prompt novel strategies for understanding seed-plant evolution. Copyright © 2010 Elsevier Ltd. All rights reserved.

The association of antipsychotic medication and lithium with brain measures in patients with bipolar disorder.

PubMed

Abramovic, Lucija; Boks, Marco P M; Vreeker, Annabel; Bouter, Diandra C; Kruiper, Caitlyn; Verkooijen, Sanne; van Bergen, Annet H; Ophoff, Roel A; Kahn, René S; van Haren, Neeltje E M

2016-11-01

There is evidence that brain structure is abnormal in patients with bipolar disorder. Lithium intake appears to ׳normalise׳ global and local brain volumes, but effects of antipsychotic medication on brain volume or cortical thickness are less clear. Here, we aim to disentangle disease-specific brain deviations from those induced by antipsychotic medication and lithium intake using a large homogeneous sample of patients with bipolar disorder type I. Magnetic resonance imaging brain scans were obtained from 266 patients and 171 control subjects. Subcortical volumes and global and focal cortical measures (volume, thickness, and surface area) were compared between patients and controls. In patients, the association between lithium and antipsychotic medication intake and global, subcortical and cortical measures was investigated. Patients showed significantly larger lateral and third ventricles, smaller total brain, caudate nucleus, and pallidum volumes and thinner cortex in some small clusters in frontal, parietal and cingulate regions as compared with controls. Lithium-free patients had significantly smaller total brain, thalamus, putamen, pallidum, hippocampus and accumbens volumes compared to patients on lithium. In patients, use of antipsychotic medication was related to larger third ventricle and smaller hippocampus and supramarginal cortex volume. Patients with bipolar disorder show abnormalities in total brain, subcortical, and ventricle volume, particularly in the nucleus caudate and pallidum. Abnormalities in cortical thickness were scattered and clusters were relatively small. Lithium-free patients showed more pronounced abnormalities as compared with those on lithium. The associations between antipsychotic medication and brain volume are subtle and less pronounced than those of lithium. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study.

PubMed

Grachev, I D; Fredrickson, B E; Apkarian, A V

2000-12-15

The neurobiology of chronic pain, including chronic back pain, is unknown. Structural imaging studies of the spine cannot explain all cases of chronic back pain. Functional brain imaging studies indicate that the brain activation patterns are different between chronic pain patients and normal subjects, and the thalamus, and prefrontal and cingulate cortices are involved in some types of chronic pain. Animal models of chronic pain suggest abnormal spinal cord chemistry. Does chronic pain cause brain chemistry changes? We examined brain chemistry changes in patients with chronic back pain using in vivo single- voxel proton magnetic resonance spectroscopy ((1)H-MRS). In vivo (1)H-MRS was used to measure relative concentrations of N-acetyl aspartate, creatine, choline, glutamate, glutamine, gamma-aminobutyric acid, inositol, glucose and lactate in relation to the concentration of creatine. These measurements were performed in six brain regions of nine chronic low back pain patients and 11 normal volunteers. All chronic back pain subjects underwent clinical evaluation and perceptual measures of pain and anxiety. We show that chronic back pain alters the human brain chemistry. Reductions of N-acetyl aspartate and glucose were demonstrated in the dorsolateral prefrontal cortex. Cingulate, sensorimotor, and other brain regions showed no chemical concentration differences. In chronic back pain, the interrelationship between chemicals within and across brain regions was abnormal, and there was a specific relationship between regional chemicals and perceptual measures of pain and anxiety. These findings provide direct evidence of abnormal brain chemistry in chronic back pain, which may be useful in diagnosis and future development of more effective pharmacological treatments.

KCC3 axonopathy: neuropathological features in the central and peripheral nervous system.

PubMed

Auer, Roland N; Laganière, Janet L; Robitaille, Yves O; Richardson, John; Dion, Patrick A; Rouleau, Guy A; Shekarabi, Masoud

2016-09-01

Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC) is an autosomal recessive disease of the central and peripheral nervous system that presents as early-onset polyneuropathy. Patients are hypotonic and areflexic from birth, with abnormal facial features and atrophic muscles. Progressive peripheral neuropathy eventually confines them to a wheelchair in the second decade of life, and death occurs by the fourth decade. We here define the neuropathologic features of the disease in autopsy tissues from eight cases. Both developmental and neurodegenerative features were found. Hypoplasia or absence of the major telencephalic commissures and a hypoplasia of corticospinal tracts to half the normal size, were the major neurodevelopmental defects we observed. Despite being a neurodegenerative disease, preservation of brain weight and a conspicuous absence of neuronal or glial cell death were signal features of this disease. Small tumor-like overgrowths of axons, termed axonomas, were found in the central and peripheral nervous system, indicating attempted axonal regeneration. We conclude that the neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development, affecting peripheral but also central nervous system axons, all ultimately because of a genetic defect in the axonal cotransporter KCC3.

Therapeutic Role of Hematopoietic Stem Cells in Autism Spectrum Disorder-Related Inflammation

PubMed Central

Siniscalco, Dario; Bradstreet, James Jeffrey; Antonucci, Nicola

2013-01-01

Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neuro-developmental disorders with core symptoms of dysfunctions in social interactions and communication skills, restricted interests, repetitive – stereotypic verbal and non-verbal behaviors. Biomolecular evidence points to complex gene-environmental interactions in ASDs. Several biochemical processes are associated with ASDs: oxidative stress (including endoplasmic reticulum stress), decreased methylation capacity, limited production of glutathione; mitochondrial dysfunction, intestinal dysbiosis, increased toxic metal burden, and various immune abnormalities. The known immunological disorders include: T-lymphocyte populations and function, gene expression changes in monocytes, several autoimmune-related findings, high levels of N-acetylgalactosaminidase (which precludes macrophage activation), and primary immune deficiencies. These immunological observations may result in minicolumn structural changes in the brain, as well as, abnormal immune mediation of synaptic functions. Equally, these immune dysregulations serve as the rationale for immune-directed interventions such as hematopoietic stem cells (HSCs), which are pivotal in controlling chronic inflammation and in the restoration of immunological balance. These properties make them intriguing potential agents for ASD treatments. This prospective review will focus on the current state-of-the-art knowledge and challenges intrinsic in the application of HSCs for ASD-related immunological disorders. PMID:23772227

Altered heavy metals and transketolase found in autistic spectrum disorder.

PubMed

Obrenovich, Mark E; Shamberger, Raymond J; Lonsdale, Derrick

2011-12-01

Autism and autism spectrum disorder (ASD) are developmental brain disorders with complex, obscure, and multifactorial etiology. Our recent clinical survey of patient records from ASD children under the age of 6 years and their age-matched controls revealed evidence of abnormal markers of thiol metabolism, as well as a significant alteration in deposition of several heavy metal species, particularly arsenic, mercury, copper, and iron in hair samples between the groups. Altered thiol metabolism from heavy metal toxicity may be responsible for the biochemical alterations in transketolase, and are mechanisms for oxidative stress production, dysautonomia, and abnormal thiamine homeostasis. It is unknown why the particular metals accumulate, but we suspect that children with ASD may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. Accumulation or altered mercury clearance, as well as concomitant oxidative stress, arising from redox-active metal and arsenic toxicity, offers an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Taken together, these factors may be more important to the etiology of this symptomatically diverse disease spectrum and may offer insights into new treatment approaches and avenues of exploration for this devastating and growing disease.

Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: a review of rodent and human data.

PubMed

Rasier, G; Toppari, J; Parent, A-S; Bourguignon, J-P

2006-07-25

Natural hormones and some synthetic chemicals spread into our surrounding environment share the capacity to interact with hormone action and metabolism. Exposure to such compounds can cause a variety of developmental and reproductive detrimental abnormalities in wildlife species and, potentially, in human. Many experimental and epidemiological data have reported that exposure of the developing fetus or neonate to environmentally relevant concentrations of some among these endocrine disrupters induces morphological, biochemical and/or physiological disorders in brain and reproductive organs, by interfering with the hormone actions. The impact of such exposures on the hypothalamic-pituitary-gonadal axis and subsequent sexual maturation is the subject of the present review. We will highlight epidemiological human studies and the effects of early exposure during gestational, perinatal or postnatal life in female rodents.

Joubert syndrome with autism in two siblings: A rare presentation.

PubMed

Raghavan, D Vijaya; Doshi, V Vimal; Nambi, Shanthi

2016-01-01

Joubert syndrome is a rare autosomal recessive disorder with partial or complete agenesis of cerebellar vermis. This syndrome is identified mainly by the presence of molar tooth sign in magnetic resonance imaging of the brain since it has a varied phenotypic presentation. Of the 200 cases reported so far in the literature, only three reports show the presence of autistic symptoms in siblings suggesting a link between the cerebellar vermis and autistic spectrum disorders. In this case report of two siblings, the female child satisfied the criterion for autistic spectrum disorder in accordance with Diagnostic and Statistical Manual of Mental Disorders Fifth Editon. The boy showed developmental delay with autistic features (not amounting to diagnostic threshold). This report is important in that it adds evidence to the literature that abnormalities of cerebellum are involved in the cognitive development and autistic symptoms.

Neurodevelopmental Theories of Schizophernia : Application to Late-Onset Schizophernia

PubMed Central

Palmer, Barton W.; Jeste, Dilip V.

1996-01-01

A review of literature on the neurodevelopmental origins of schizophemia is presented, with particular attention to neurodevelopmental processes in late-onset schizophemia. Definitions of the term “neurodevelopmental” as used in schizophernia literature are first provided. Next, evidence for the developmental origins of the neuropathology in schizophemia is reviewed. This evidence includes studies of the associations between schizophemia and neurodevelopmental brain aberrations, minor physical anomalies, obstetric complications, prenatal viral exposure, childhood neuromotor abnormalities, and pandysmaturation. A brief discussion of the predominant theories about the neurodevelopmental origins of schizophemia is then provided. The concept and nature of “late-onset schizophenia ”is next defined and discussed. Finally, the neurodevelopmental literature is discussed in relation to the phenomenon of late-onset schizophemia. Based on this review, we conclude that there exists a strong likelihood that late-onset schizophrenia involves neurodevelopmental processes. PMID:21584112

Phenotypic convergence of Menkes and Wilson disease.

PubMed

Bansagi, Boglarka; Lewis-Smith, David; Pal, Endre; Duff, Jennifer; Griffin, Helen; Pyle, Angela; Müller, Juliane S; Rudas, Gabor; Aranyi, Zsuzsanna; Lochmüller, Hanns; Chinnery, Patrick F; Horvath, Rita

2016-12-01

Menkes disease is an X-linked multisystem disorder with epilepsy, kinky hair, and neurodegeneration caused by mutations in the copper transporter ATP7A . Other ATP7A mutations have been linked to juvenile occipital horn syndrome and adult-onset hereditary motor neuropathy. 1,2 About 5%-10% of the patients present with "atypical Menkes disease" characterized by longer survival, cerebellar ataxia, and developmental delay. 2 The intracellular copper transport is regulated by 2 P type ATPase copper transporters ATP7A and ATP7B. These proteins are expressed in the trans-Golgi network that guides copper to intracellular compartments, and in copper excess, it relocates copper to the plasma membrane to pump it out from the cells. 3 ATP7B mutations cause Wilson disease with dystonia, ataxia, tremor, and abnormal copper accumulation in the brain, liver, and other organs. 4 .

White matter changes in an untreated, newly diagnosed case of classical homocystinuria.

PubMed

Brenton, J Nicholas; Matsumoto, Julie A; Rust, Robert S; Wilson, William G

2014-01-01

The authors report the case of a 4-year-old boy who developed progressive unilateral weakness and developmental delays prior to his diagnosis of classical homocystinuria. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse white matter changes, raising the concern for a secondary diagnosis causing leukoencephalopathy, since classical homocystinuria is not typically associated with these changes. Other inborn errors of the transsulfuration pathway have been reported as causing these changes. Once begun on therapy for his homocystinuria, his neurologic deficits resolved and his delays rapidly improved. Repeat MRI performed one year after instating therapy showed resolution of his white matter abnormalities. This case illustrates the need to consider homocystinuria and other amino acidopathies in the differential diagnosis of childhood white matter diseases and lends weight to the hypothesis that hypermethioninemia may induce white matter changes.

Neurocognitive, Social-Behavioral, and Adaptive Functioning in Preschool Children with Mild to Moderate Kidney Disease

PubMed Central

Hooper, Stephen R.; Gerson, Arlene C.; Johnson, Rebecca J.; Mendley, Susan R.; Shinnar, Shlomo; Lande, Marc B.; Matheson, Matthew B.; Gipson, Debbie S.; Morgenstern, Bruce; Warady, Bradley A.; Furth, Susan L.

2016-01-01

Objective The negative impact of End Stage Kidney Disease on cognitive function in children is well established, but no studies have examined the neurocognitive, social-behavioral, and adaptive behavior skills of preschool children with mild to moderate chronic kidney disease (CKD). Methods Participants included 124 preschool children with mild to moderate CKD, ages 12-68 months (median=3.7 years), and an associated mean glomerular filtration rate (GFR) of 50.0 ml/min per 1.73m2. In addition to level of function and percent of participants scoring≥1SD below the test mean, regression models examined the associations between biomarkers of CKD (GFR, anemia, hypertension, seizures, abnormal birth history), and Developmental Level/IQ, attention regulation, and parent ratings of executive functions, social-behavior, and adaptive behaviors. Results Median scores for all measures were in the average range; however, 27% were deemed at-risk for a Developmental Level/IQ<85, 20% were at-risk for attention variability, and parent ratings indicated 30% and 37% to be at-risk for executive dysfunction and adaptive behavior problems, respectively. Approximately 43% were deemed at-risk on two or more measures. None of the disease-related variables were significantly associated with these outcomes, although the presence of hypertension approached significance for attention variability (p<.09). Abnormal birth history and lower maternal education were significantly related to lower Developmental Level/IQ; seizures were related to lower parental ratings of executive function and adaptive behavior; and abnormal birth history was significantly related to lower ratings of adaptive behavior. When predicting risk status, the logistic regression did evidence both higher GFR and the lack of anemia to be associated with more intact Developmental Level/IQ. Conclusions These findings suggest relatively intact functioning for preschool children with mild to moderate CKD, but the need for ongoing developmental surveillance in this population remains warranted, particularly for those with abnormal birth histories, seizures, and heightened disease severity. PMID:26890559

The role of the pediatrician in preventing congenital malformations.

PubMed

Brent, Robert L

2011-10-01

• The development of new knowledge and new diagnostic techniques and technology as well as the sophistication of epidemiology studies and maturation of the fields of clinical genetics and clinical teratology have revolutionized the field of reproductive and developmental biology.• Advances have enabled physicians and scientists to determine the causes of developmental abnormalities and, therefore, discover methods of prevention. The process of evaluation is based on the knowledge base developed over the past 50 years.• Although genetic abnormalities are responsible for a significant proportion of reproductive and developmental deleterious effects, a larger proportion of these effects are due to unknown causes.• Environmental causes are less frequent, although many of the environmental effects as well as many of the genetic effects can be prevented through genetic counseling and preconceptual planning. Effective treatment and amelioration of developmental effects also have improved.• More than 50 environmental drugs, chemicals, maternal diseases, infections, nutritional abnormalities, and physical agents can affect reproduction deleteriously and result in CMs.Theoretically, all these causes are preventable.• Throughout the developing world, the addition of folic acid and iodine could prevent tens of thousands of birth defects and developmental abnormalities.• In the United States, the opportunity for prevention can be introduced at the population level and by addressing individual patients’ clinical problems.• If a mother of a malformed infant had some type of exposure during pregnancy, such as a diagnostic radiologic examination or medication, the consulting physician should not support or suggest the possibility of a causal relationship before performing a complete evaluation. If a pregnant woman who has not yet delivered had some type of exposure during pregnancy, the consulting physician should not support or suggest the possibility that the fetus is at increased risk before performing a complete evaluation. • Every patient deserves a complete, scholarly evaluation that uses the basic principles of teratology and risk analysis.

Influence of History of Brain Disease or Brain Trauma on Psychopathological Abnormality in Young Male in Korea : Analysis of Multiphasic Personal Inventory Test

PubMed Central

Paik, Ho Kyu; Oh, Chang-Hyun; Choi, Kang; Kim, Chul-Eung; Yoon, Seung Hwan

2011-01-01

Objective The purpose of this study is to confirm whether brain disease or brain trauma actually affect psychopathology in young male group in Korea. Methods The authors manually reviewed the result of Korean military multiphasic personal inventory (KMPI) in the examination of conscription in Korea from January 2008 to May 2010. There were total 237 young males in this review. Normal volunteers group (n=150) was composed of those who do not have history of brain disease or brain trauma. Brain disease group (n=33) was consisted of those with history of brain disease. Brain trauma group (n=54) was consisted of those with history of brain trauma. The results of KMPI in each group were compared. Results Abnormal results of KMPI were found in both brain disease and trauma groups. In the brain disease group, higher tendencies of faking bad response, anxiety, depression, somatization, personality disorder, schizophrenic and paranoid psychopathy was observed and compared to the normal volunteers group. In the brain trauma group, higher tendencies of faking-good, depression, somatization and personality disorder was observed and compared to the normal volunteers group. Conclusion Young male with history of brain disease or brain trauma may have higher tendencies to have abnormal results of multiphasic personal inventory test compared to young male without history of brain disease or brain trauma, suggesting that damaged brain may cause psychopathology in young male group in Korea. PMID:22053230

Atypical Brain Torque in Boys With Developmental Stuttering

PubMed Central

Mock, Jeffrey Ryan; Zadina, Janet N.; Corey, David M.; Cohen, Jeremy D.; Lemen, Lisa C.; Foundas, Anne L.

2017-01-01

The counterclockwise brain torque, defined as a larger right prefrontal and left parietal-occipital lobe, is a consistent brain asymmetry. Reduced or reversed lobar asymmetries are markers of atypical cerebral laterality and have been found in adults who stutter. It was hypothesized that atypical brain torque would be more common in children who stutter. MRI-based morphology measures were completed in boys who stutter (n=14) and controls (n=14), ages 8–13. The controls had the expected brain torque configurations whereas the boys who stutter were atypical. These results support the hypothesis that developmental stuttering is associated with atypical prefrontal and parietal-occipital lobe asymmetries. PMID:22799762

Neural Decoding Reveals Impaired Face Configural Processing in the Right Fusiform Face Area of Individuals with Developmental Prosopagnosia

PubMed Central

Zhang, Jiedong; Liu, Jia

2015-01-01

Most of human daily social interactions rely on the ability to successfully recognize faces. Yet ∼2% of the human population suffers from face blindness without any acquired brain damage [this is also known as developmental prosopagnosia (DP) or congenital prosopagnosia]). Despite the presence of severe behavioral face recognition deficits, surprisingly, a majority of DP individuals exhibit normal face selectivity in the right fusiform face area (FFA), a key brain region involved in face configural processing. This finding, together with evidence showing impairments downstream from the right FFA in DP individuals, has led some to argue that perhaps the right FFA is largely intact in DP individuals. Using fMRI multivoxel pattern analysis, here we report the discovery of a neural impairment in the right FFA of DP individuals that may play a critical role in mediating their face-processing deficits. In seven individuals with DP, we discovered that, despite the right FFA's preference for faces and it showing decoding for the different face parts, it exhibited impaired face configural decoding and did not contain distinct neural response patterns for the intact and the scrambled face configurations. This abnormality was not present throughout the ventral visual cortex, as normal neural decoding was found in an adjacent object-processing region. To our knowledge, this is the first direct neural evidence showing impaired face configural processing in the right FFA in individuals with DP. The discovery of this neural impairment provides a new clue to our understanding of the neural basis of DP. PMID:25632131

Long-term reorganization of structural brain networks in a rabbit model of intrauterine growth restriction.

PubMed

Batalle, Dafnis; Muñoz-Moreno, Emma; Arbat-Plana, Ariadna; Illa, Miriam; Figueras, Francesc; Eixarch, Elisenda; Gratacos, Eduard

2014-10-15

Characterization of brain changes produced by intrauterine growth restriction (IUGR) is among the main challenges of modern fetal medicine and pediatrics. This condition affects 5-10% of all pregnancies and is associated with a wide range of neurodevelopmental disorders. Better understanding of the brain reorganization produced by IUGR opens a window of opportunity to find potential imaging biomarkers in order to identify the infants with a high risk of having neurodevelopmental problems and apply therapies to improve their outcomes. Structural brain networks obtained from diffusion magnetic resonance imaging (MRI) is a promising tool to study brain reorganization and to be used as a biomarker of neurodevelopmental alterations. In the present study this technique is applied to a rabbit animal model of IUGR, which presents some advantages including a controlled environment and the possibility to obtain high quality MRI with long acquisition times. Using a Q-Ball diffusion model, and a previously published rabbit brain MRI atlas, structural brain networks of 15 IUGR and 14 control rabbits at 70 days of age (equivalent to pre-adolescence human age) were obtained. The analysis of graph theory features showed a decreased network infrastructure (degree and binary global efficiency) associated with IUGR condition and a set of generalized fractional anisotropy (GFA) weighted measures associated with abnormal neurobehavior. Interestingly, when assessing the brain network organization independently of network infrastructure by means of normalized networks, IUGR showed increased global and local efficiencies. We hypothesize that this effect could reflect a compensatory response to reduced infrastructure in IUGR. These results present new evidence on the long-term persistence of the brain reorganization produced by IUGR that could underlie behavioral and developmental alterations previously described. The described changes in network organization have the potential to be used as biomarkers to monitor brain changes produced by experimental therapies in IUGR animal model. Copyright © 2014 Elsevier Inc. All rights reserved.

DTI-measured white matter abnormalities in adolescents with Conduct Disorder

PubMed Central

Haney-Caron, Emily; Caprihan, Arvind; Stevens, Michael C.

2013-01-01

Emerging research suggests that antisocial behavior in youth is linked to abnormal brain white matter microstructure, but the extent of such anatomical connectivity abnormalities remain largely untested because previous Conduct Disorder (CD) studies typically have selectively focused on specific frontotemporal tracts. This study aimed to replicate and extend previous frontotemporal diffusion tensor imaging (DTI) findings to determine whether noncomorbid CD adolescents have white matter microstructural abnormalities in major white matter tracts across the whole brain. Seventeen CD-diagnosed adolescents recruited from the community were compared to a group of 24 non-CD youth which did not differ in average age (12–18) or gender proportion. Tract-based spatial statistics (TBSS) fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) measurements were compared between groups using FSL nonparametric two-sample t test, clusterwise whole-brain corrected, p<.05. CD FA and AD deficits were widespread, but unrelated to gender, verbal ability, or CD age of onset. CD adolescents had significantly lower FA and AD values in frontal lobe and temporal lobe regions, including frontal lobe anterior/superior corona radiata, and inferior longitudinal and fronto-occpital fasciculi passing through the temporal lobe. The magnitude of several CD FA deficits was associated with number of CD symptoms. Because AD, but not RD, differed between study groups, abnormalities of axonal microstructure in CD rather than myelination are suggested. This study provides evidence that adolescent antisocial disorder is linked to abnormal white matter microstructure in more than just the uncinate fasciulcus as identified in previous DTI studies, or frontotemporal brain structures as suggested by functional neuroimaging studies. Instead, neurobiological risk specific to antisociality in adolescence is linked to microstructural abnormality in numerous long-range white matter connections among many diverse different brain regions. PMID:24139595

How Does Neuroscience Inform the Study of Cognitive Development?

ERIC Educational Resources Information Center

Nelson, Charles A.; Moulson, Margaret C.; Richmond, Jenny

2006-01-01

The fields of developmental psychology and developmental neuroscience have existed independently of one another for many years. This is unfortunate, as knowledge of how the brain develops can inform the study of behavioral development. In this paper, we provide two examples of how knowledge about brain development has improved our understanding of…

The brain adapts to orthography with experience: Evidence from English and Chinese

PubMed Central

Cao, Fan; Brennan, Christine; Booth, James R.

2016-01-01

Using functional magnetic resonance imaging (fMRI), we examined the process of language specialization in the brain by comparing developmental changes in two contrastive orthographies: Chinese and English. In a visual word rhyming judgment task, we found a significant interaction between age and language in left inferior parietal lobule and left superior temporal gyrus, which was due to greater developmental increases in English than in Chinese. Moreover, we found that higher skill only in English children was correlated with greater activation in left inferior parietal lobule. These findings suggest that the regions associated with phonological processing are essential in English reading development. We also found greater developmental increases in English than in Chinese in left inferior temporal gyrus, suggesting refinement of this region for fine-grained word form recognition. In contrast, greater developmental increases in Chinese than in English were found in right middle occipital gyrus, suggesting the importance of holistic visual-orthographic analysis in Chinese reading acquisition. Our results suggest that the brain adapts to the special features of the orthography by engaging relevant brain regions to a greater degree over development. PMID:25444089

Understanding Brain Tumors

MedlinePlus

... to Know About Brain Tumors . What is a Brain Tumor? A brain tumor is an abnormal growth
 ... Tumors” from Frankly Speaking Frankly Speaking About Cancer: Brain Tumors Download the full book Questions to ask ...

Genetic abnormality predicts benefit for a rare brain tumor

Cancer.gov

A clinical trial has shown that addition of chemotherapy to radiation therapy leads to a near doubling of median survival time in patients with a form of brain tumor (oligodendroglioma) that carries a chromosomal abnormality called the 1p19q co-deletion.

Solitary tuberculous brain lesions: 24 new cases and a review of the literature.

PubMed

Psimaras, D; Bonnet, C; Heinzmann, A; Cárdenas, G; Hernández José Luis, S; Tungaria, A; Behari, S; Lacrois, D; Mokhtari, K; Karantoni, E; Sokrab Tag, E; Idris Mohamed, N; Sönmez, G; Caumes, E; Roze, E

2014-01-01

A solitary tuberculous brain lesion (STBL) can be difficult to distinguish from a glioma, metastasis or other infectious disease, especially from a pyogenic brain abscess. We analyzed the clinical characteristics, diagnostic procedures and outcomes of 24 patients with STBL diagnosed in three centers from France, India and Mexico. We also reviewed 92 STBL cases previously reported in the literature. General symptoms were found in 54% of our patients, including enlarged lymph nodes in 20%. Cerebrospinal fluid was typically abnormal, with lymphocytic pleocytosis and a high protein level. The lung CT scan was abnormal in 56% of patients, showing lymphadenopathy or pachipleuritis. Brain MRI or CT was always abnormal, showing contrast-enhanced lesions. Typically, MRI abnormalities were hypointense on T1-weighted sequences, while T2-weighted sequences showed both a peripheral hypersignal and a central hyposignal. The diagnosis was documented microbiologically or supported histologically in 71% of cases. Clinical outcome was good in 83% of cases. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Brain anomalies in velo-cardio-facial syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mitnick, R.J.; Bello, J.A.; Shprintzen, R.J.

Magnetic resonance imaging of the brain in 11 consecutively referred patients with velo-cardio-facial syndrome (VCF) showed anomalies in nine cases including small vermis, cysts adjacent to the frontal horns, and small posterior fossa. Focal signal hyperintensities in the white matter on long TR images were also noted. The nine patients showed a variety of behavioral abnormalities including mild development delay, learning disabilities, and characteristic personality traits typical of this common multiple anomaly syndrome which has been related to a microdeletion at 22q11. Analysis of the behavorial findings showed no specific pattern related to the brain anomalies, and the patients withmore » VCF who did not have detectable brain lesions also had behavioral abnormalities consistent with VCF. The significance of the lesions is not yet known, but the high prevalence of anomalies in this sample suggests that structural brain abnormalities are probably common in VCF. 25 refs.« less

TSPO Expression and Brain Structure in the Psychosis Spectrum.

PubMed

Hafizi, Sina; Guma, Elisa; Koppel, Alex; Da Silva, Tania; Kiang, Michael; Houle, Sylvain; Wilson, Alan A; Rusjan, Pablo M; Chakravarty, M Mallar; Mizrahi, Romina

2018-06-12

Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [ 18 F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [ 18 F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [ 18 F]FEPPA V T (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [ 18 F]FEPPA V T and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis. Copyright © 2018. Published by Elsevier Inc.

Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function.

PubMed

Lenz, Kathryn M; Nelson, Lars H

2018-01-01

Innate immune cells play a well-documented role in the etiology and disease course of many brain-based conditions, including multiple sclerosis, Alzheimer's disease, traumatic brain and spinal cord injury, and brain cancers. In contrast, it is only recently becoming clear that innate immune cells, primarily brain resident macrophages called microglia, are also key regulators of brain development. This review summarizes the current state of knowledge regarding microglia in brain development, with particular emphasis on how microglia during development are distinct from microglia later in life. We also summarize the effects of early life perturbations on microglia function in the developing brain, the role that biological sex plays in microglia function, and the potential role that microglia may play in developmental brain disorders. Finally, given how new the field of developmental neuroimmunology is, we highlight what has yet to be learned about how innate immune cells shape the development of brain and behavior.

Brain Tumors

MedlinePlus

A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

Hitting a Moving Target: Basic Mechanisms of Recovery from Acquired Developmental Brain Injury

PubMed Central

Giza, Christopher C.; Kolb, Bryan; Harris, Neil G.; Asarnow, Robert F.; Prins, Mayumi L.

2009-01-01

Acquired brain injuries represent a major cause of disability in the pediatric population. Understanding responses to developmental acquired brain injuries requires knowledge of the neurobiology of normal development, age-at-injury effects and experience-dependent neuroplasticity. In the developing brain, full recovery cannot be considered as a return to the premorbid baseline, since ongoing maturation means that cerebral functioning in normal individuals will continue to advance. Thus, the recovering immature brain has to ‘hit a moving target’ to achieve full functional recovery, defined as parity with age-matched uninjured peers. This review will discuss the consequences of developmental injuries such as focal lesions, diffuse hypoxia and traumatic brain injury (TBI). Underlying cellular and physiological mechanisms relevant to age-at-injury effects will be described in considerable detail, including but not limited to alterations in neurotransmission, connectivity/network functioning, the extracellular matrix, response to oxidative stress and changes in cerebral metabolism. Finally, mechanisms of experience-dependent plasticity will be reviewed in conjunction with their effects on neural repair and recovery. PMID:19956795

Low glucose utilization and neurodegenerative changes caused by sodium fluoride exposure in rat's developmental brain.

PubMed

Jiang, Chunyang; Zhang, Shun; Liu, Hongliang; Guan, Zhizhong; Zeng, Qiang; Zhang, Cheng; Lei, Rongrong; Xia, Tao; Wang, Zhenglun; Yang, Lu; Chen, Yihu; Wu, Xue; Zhang, Xiaofei; Cui, Yushan; Yu, Linyu; Wang, Aiguo

2014-03-01

Fluorine, a toxic and reactive element, is widely prevalent throughout the environment and can induce toxicity when absorbed into the body. This study was to explore the possible mechanisms of developmental neurotoxicity in rats treated with different levels of sodium fluoride (NaF). The rats' intelligence, as well as changes in neuronal morphology, glucose absorption, and functional gene expression within the brain were determined using the Morris water maze test, transmission electron microscopy, small-animal magnetic resonance imaging and Positron emission tomography and computed tomography, and Western blotting techniques. We found that NaF treatment-impaired learning and memory in these rats. Furthermore, NaF caused neuronal degeneration, decreased brain glucose utilization, decreased the protein expression of glucose transporter 1 and glial fibrillary acidic protein, and increased levels of brain-derived neurotrophic factor in the rat brains. The developmental neurotoxicity of fluoride may be closely associated with low glucose utilization and neurodegenerative changes.

An oscillopathic approach to developmental dyslexia: From genes to speech processing.

PubMed

Jiménez-Bravo, Miguel; Marrero, Victoria; Benítez-Burraco, Antonio

2017-06-30

Developmental dyslexia is a heterogeneous condition entailing problems with reading and spelling. Several genes have been linked or associated to the disease, many of which contribute to the development and function of brain areas important for auditory and phonological processing. Nonetheless, a clear link between genes, the brain, and the symptoms of dyslexia is still pending. The goal of this paper is contributing to bridge this gap. With this aim, we have focused on how the dyslexic brain fails to process speech sounds and reading cues. We have adopted an oscillatory perspective, according to which dyslexia may result from a deficient integration of different brain rhythms during reading/spellings tasks. Moreover, we show that some candidate genes for this condition are related to brain rhythms. This fresh approach is expected to provide a better understanding of the aetiology and the clinical presentation of developmental dyslexia, but also to achieve an earlier and more accurate diagnosis of the disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Optical Coherence Tomography for Brain Imaging and Developmental Biology

PubMed Central

Men, Jing; Huang, Yongyang; Solanki, Jitendra; Zeng, Xianxu; Alex, Aneesh; Jerwick, Jason; Zhang, Zhan; Tanzi, Rudolph E.; Li, Airong; Zhou, Chao

2016-01-01

Optical coherence tomography (OCT) is a promising research tool for brain imaging and developmental biology. Serving as a three-dimensional optical biopsy technique, OCT provides volumetric reconstruction of brain tissues and embryonic structures with micrometer resolution and video rate imaging speed. Functional OCT enables label-free monitoring of hemodynamic and metabolic changes in the brain in vitro and in vivo in animal models. Due to its non-invasiveness nature, OCT enables longitudinal imaging of developing specimens in vivo without potential damage from surgical operation, tissue fixation and processing, and staining with exogenous contrast agents. In this paper, various OCT applications in brain imaging and developmental biology are reviewed, with a particular focus on imaging heart development. In addition, we report findings on the effects of a circadian gene (Clock) and high-fat-diet on heart development in Drosophila melanogaster. These findings contribute to our understanding of the fundamental mechanisms connecting circadian genes and obesity to heart development and cardiac diseases. PMID:27721647

Brain abnormalities and neurodevelopmental delay in congenital heart disease: systematic review and meta-analysis.

PubMed

Khalil, A; Suff, N; Thilaganathan, B; Hurrell, A; Cooper, D; Carvalho, J S

2014-01-01

Studies have demonstrated an association between congenital heart disease (CHD) and neurodevelopmental delay. Neuroimaging studies have also demonstrated a high incidence of preoperative brain abnormalities. The aim of this study was to perform a systematic review to quantify the non-surgical risk of brain abnormalities and of neurodevelopmental delay in infants with CHD. MEDLINE, EMBASE and The Cochrane Library were searched electronically without language restrictions, utilizing combinations of the terms congenital heart, cardiac, neurologic, neurodevelopment, magnetic resonance imaging, ultrasound, neuroimaging, autopsy, preoperative and outcome. Reference lists of relevant articles and reviews were hand-searched for additional reports. Cohort and case-control studies were included. Studies reporting neurodevelopmental outcomes and/or brain lesions on neuroimaging in infants with CHD before heart surgery were included. Cases of chromosomal or genetic abnormalities, case reports and editorials were excluded. Between-study heterogeneity was assessed using the I(2) test. The search yielded 9129 citations. Full text was retrieved for 119 and the following were included in the review: 13 studies (n = 425 cases) reporting on brain abnormalities either preoperatively or in those who did not undergo congenital cardiac surgery and nine (n = 512 cases) reporting preoperative data on neurodevelopmental assessment. The prevalence of brain lesions on neuroimaging was 34% (95% CI, 24-46; I(2) = 0%) in transposition of the great arteries, 49% (95% CI, 25-72; I(2) = 65%) in left-sided heart lesions and 46% (95% CI, 40-52; I(2) =18.1%) in mixed/unspecified cardiac lesions, while the prevalence of neurodevelopmental delay was 42% (95% CI, 34-51; I(2) = 68.9). In the absence of chromosomal or genetic abnormalities, infants with CHD are at increased risk of brain lesions as revealed by neuroimaging and of neurodevelopmental delay. These findings are independent of the surgical risk, but it is unclear whether the time of onset is fetal or postnatal. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Structural brain abnormalities in patients with inflammatory illness acquired following exposure to water-damaged buildings: a volumetric MRI study using NeuroQuant®.

PubMed

Shoemaker, Ritchie C; House, Dennis; Ryan, James C

2014-01-01

Executive cognitive and neurologic abnormalities are commonly seen in patients with a chronic inflammatory response syndrome (CIRS) acquired following exposure to the interior environment of water-damaged buildings (WDB), but a clear delineation of the physiologic or structural basis for these abnormalities has not been defined. Symptoms of affected patients routinely include headache, difficulty with recent memory, concentration, word finding, numbness, tingling, metallic taste and vertigo. Additionally, persistent proteomic abnormalities in inflammatory parameters that can alter permeability of the blood-brain barrier, such as C4a, TGFB1, MMP9 and VEGF, are notably present in cases of CIRS-WDB compared to controls, suggesting a consequent inflammatory injury to the central nervous system. Findings of gliotic areas in MRI scans in over 45% of CIRS-WDB cases compared to 5% of controls, as well as elevated lactate and depressed ratios of glutamate to glutamine, are regularly seen in MR spectroscopy of cases. This study used the volumetric software program NeuroQuant® (NQ) to determine specific brain structure volumes in consecutive patients (N=17) seen in a medical clinic specializing in inflammatory illness. Each of these patients presented for evaluation of an illness thought to be associated with exposure to WDB, and received an MRI that was evaluated by NQ. When compared to those of a medical control group (N=18), statistically significant differences in brain structure proportions were seen for patients in both hemispheres of two of the eleven brain regions analyzed; atrophy of the caudate nucleus and enlargement of the pallidum. In addition, the left amygdala and right forebrain were also enlarged. These volumetric abnormalities, in conjunction with concurrent abnormalities in inflammatory markers, suggest a model for structural brain injury in "mold illness" based on increased permeability of the blood-brain barrier due to chronic, systemic inflammation. Copyright © 2014 Elsevier Inc. All rights reserved.

Vascular alterations underlie developmental problems manifested in cloned cattle before or after birth.

PubMed

Maiorka, Paulo Cesar; Favaron, Phelipe Oliveira; Mess, Andrea Maria; dos Santos, Caio Rodrigues; Alberto, Miryan Lanca; Meirelles, Flavio Vieira; Miglino, Maria Angelica

2015-01-01

Although assisted reproductive techniques are commonly applied in humans and animals, they are frequently associated with major developmental deficits and reduced viability. To explore abnormalities associated with cloning or nuclear transfer (NT) as the most invasive of these methods, we used a bovine model to characterize abnormalities. Detailed necropsy examinations were done on 13 calves that died soon after birth; in addition, we included data from embryos and fetuses (produced by NT) that terminated prematurely. Bovine clones that survived until the neonatal period differed quantitatively and qualitatively from in-vivo-derived cattle. Although alterations affected a variety of organs (e.g. heart, lung and liver), there was a clear association with abberant vascular developmental during the early intrauterine phase. Therefore, we concluded that vascular problems were key alterations induced by cloning (presumably via epigenetic modifications).

Vascular Alterations Underlie Developmental Problems Manifested in Cloned Cattle before or after Birth

PubMed Central

Favaron, Phelipe Oliveira; dos Santos, Caio Rodrigues; Alberto, Miryan Lanca; Meirelles, Flavio Vieira; Miglino, Maria Angelica

2015-01-01

Although assisted reproductive techniques are commonly applied in humans and animals, they are frequently associated with major developmental deficits and reduced viability. To explore abnormalities associated with cloning or nuclear transfer (NT) as the most invasive of these methods, we used a bovine model to characterize abnormalities. Detailed necropsy examinations were done on 13 calves that died soon after birth; in addition, we included data from embryos and fetuses (produced by NT) that terminated prematurely. Bovine clones that survived until the neonatal period differed quantitatively and qualitatively from in-vivo-derived cattle. Although alterations affected a variety of organs (e.g. heart, lung and liver), there was a clear association with abberant vascular developmental during the early intrauterine phase. Therefore, we concluded that vascular problems were key alterations induced by cloning (presumably via epigenetic modifications). PMID:25584533

Extreme developmental temperatures result in morphological abnormalities in painted turtles (Chrysemys picta): a climate change perspective.

PubMed

Telemeco, Rory S; Warner, Daniel A; Reida, Molly K; Janzen, Fredric J

2013-06-01

Increases in extreme environmental events are predicted to be major results of ongoing global climate change and may impact the persistence of species. We examined the effects of heat and cold waves during embryonic development of painted turtles (Chrysemys picta) in natural nests on the occurrence of abnormal shell morphologies in hatchlings. We found that nests exposed to extreme hot temperatures for >60 h produced more hatchlings with abnormalities than nests exposed to extreme hot temperatures for shorter periods, regardless of whether or not nesting females displayed abnormal morphologies. We observed no effect of extreme cold nest temperatures on the occurrence of hatchlings with abnormalities. Moreover, the frequency of nesting females with abnormal shell morphologies was approximately 2-fold lower than that of their offspring, suggesting that such abnormalities are negatively correlated with survival and fitness. Female turtles could potentially buffer their offspring from extreme heat by altering aspects of nesting behavior, such as choosing shadier nesting sites. We addressed this hypothesis by examining the effects of shade cover on extreme nest temperatures and the occurrence of hatchling abnormalities. While shade cover was negatively correlated with the occurrence of extreme hot nest temperatures, it was not significantly correlated with abnormalities. Therefore, female choice of shade cover does not appear to be a viable target for selection to reduce hatchling abnormalities. Our results suggest that increases in the frequency and intensity of heat waves associated with climate change might perturb developmental programs and thereby reduce the fitness of entire cohorts of turtles. © 2012 Wiley Publishing Asia Pty Ltd, ISZS and IOZ/CAS.

Corpus callosum vasculature predicts white matter microstructure abnormalities following pediatric mild traumatic brain injury.

PubMed

Wendel, Kara M; Lee, Jeong Bin; Affeldt, Bethann; Hamer, Mary; Harahap-Carrillo, Indira S; Pardo, Andrea C; Obenaus, Andre

2018-05-09

Emerging data suggest that pediatric traumatic brain injury (TBI) is associated with impaired developmental plasticity and poorer neuropsychological outcomes than adults with similar head injuries. Unlike adult mild TBI (mTBI), the effects of mTBI on white matter (WM) microstructure and vascular supply are not well-understood in the pediatric population. The cerebral vasculature plays an important role providing necessary nutrients and removing waste. To address this critical element, we examined the microstructure of the corpus callosum (CC) following pediatric mTBI using diffusion tensor imaging (DTI), and investigated myelin, oligodendrocytes, and vasculature of WM with immunohistochemistry. We hypothesized that pediatric mTBI leads to abnormal WM microstructure and impacts the vasculature within the CC, and that these alterations to WM vasculature contribute to the long-term altered microstructure. We induced a closed head injury mTBI at postnatal day 14, then at 4, 14, and 60 days post injury (DPI) mice were sacrificed for analysis. We observed persistent changes in apparent diffusion coefficient (ADC) within the ipsilateral CC following mTBI, indicating microstructural changes, but surprisingly changes in myelin and oligodendrocyte densities were minimal. However, vasculature features of the ipsilateral CC such as vessel density, length, and number of junctions were persistently altered following mTBI. Correlative analysis showed a strong inverse relationship between ADC and vessel density at 60 DPI, suggesting increased vessel density following mTBI may restrict WM diffusion characteristics. Our findings suggest that WM vasculature contributes to the long-term microstructural changes within the ipsilateral CC following mTBI.

Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome.

PubMed

Oddi, Diego; Subashi, Enejda; Middei, Silvia; Bellocchio, Luigi; Lemaire-Mayo, Valerie; Guzmán, Manuel; Crusio, Wim E; D'Amato, Francesca R; Pietropaolo, Susanna

2015-03-13

Converging lines of evidence support the use of environmental stimulation to ameliorate the symptoms of a variety of neurodevelopmental disorders. Applying these interventions at very early ages is critical to achieve a marked reduction of the pathological phenotypes. Here we evaluated the impact of early social enrichment in Fmr1-KO mice, a genetic mouse model of fragile X syndrome (FXS), a major developmental disorder and the most frequent monogenic cause of autism. Enrichment was achieved by providing male KO pups and their WT littermates with enhanced social stimulation, housing them from birth until weaning with the mother and an additional nonlactating female. At adulthood they were tested for locomotor, social, and cognitive abilities; furthermore, dendritic alterations were assessed in the hippocampus and amygdala, two brain regions known to be involved in the control of the examined behaviors and affected by spine pathology in Fmr1-KOs. Enrichment rescued the behavioral FXS-like deficits displayed in adulthood by Fmr1-KO mice, that is, hyperactivity, reduced social interactions, and cognitive deficits. Early social enrichment also eliminated the abnormalities shown by adult KO mice in the morphology of hippocampal and amygdala dendritic spines, namely an enhanced density of immature vs mature types. Importantly, enrichment did not induce neurobehavioral changes in WT mice, thus supporting specific effects on FXS-like pathology. These findings show that early environmental stimulation has profound and long-term beneficial effects on the pathological FXS phenotype, thereby encouraging the use of nonpharmacological interventions for the treatment of this and perhaps other neurodevelopmental diseases.

Absent circle of Willis with vascular pollarding in an adult with colpocephaly: A developmental perspective

PubMed Central

Verghese, Renjan; Paul, Divyan

2015-01-01

Absent circle of Willis (COW) has been described in cases of severe forms of cerebral developmental anomalies such as alobar prosencephaly. However, there are no reports of absent COW in patients with a milder form of cerebral abnormality such as colpocephaly. We report a unique case of an adult with colpocephaly and absent COW and discuss their association from a developmental perspective. PMID:26443299

Magnetic resonance imaging findings in pediatric bilateral vocal fold dysfunction.

PubMed

Steiner, Joel I; Fink, A Michelle; Berkowitz, Robert G

2013-07-01

We studied the findings of brain magnetic resonance imaging (MRI) in infants with idiopathic congenital bilateral vocal fold dysfunction (CBVFD). We performed a retrospective investigation of a case series. We identified 26 children (14 male, 12 female) over 11 years. Three children were excluded. Thirteen patients required airway interventions, including continuous positive airway pressure (4 patients), endotracheal intubation (1), and tracheostomy (8). The findings on brain MRI were abnormal in 8 patients (35%). Tracheostomy was required in 3 patients (38%) with abnormal MRI findings, as compared with 5 of 15 patients (33%) with normal MRI findings. The MRI abnormalities involved evidence of white matter injury (2), abnormal white matter signal (1), subdural blood (3), cerebral swelling (1), and perisylvian polymicrogyria (1). The cranial ultrasound findings were abnormal in 4 of 11 patients. The MRI findings were abnormal in 2 of 7 children in whom the cranial ultrasound findings were normal, and in 2 of the 4 patients in whom the cranial ultrasound findings were abnormal. The MRI abnormalities were nonspecific; however, they may indicate unrecognized perinatal intracranial injury as being related to CBVFD. In addition, MRI may reveal an underlying structural brain anomaly. Cranial ultrasound has poor sensitivity and specificity. Hence, MRI should be considered as part of the routine assessment of neonates with CBVFD.

P300 event-related potentials in children with dyslexia.

PubMed

Papagiannopoulou, Eleni A; Lagopoulos, Jim

2017-04-01

To elucidate the timing and the nature of neural disturbances in dyslexia and to further understand the topographical distribution of these, we examined entire brain regions employing the non-invasive auditory oddball P300 paradigm in children with dyslexia and neurotypical controls. Our findings revealed abnormalities for the dyslexia group in (i) P300 latency, globally, but greatest in frontal brain regions and (ii) decreased P300 amplitude confined to the central brain regions (Fig. 1). These findings reflect abnormalities associated with a diminished capacity to process mental workload as well as delayed processing of this information in children with dyslexia. Furthermore, the topographical distribution of these findings suggests a distinct spatial distribution for the observed P300 abnormalities. This information may be useful in future therapeutic or brain stimulation intervention trials.