Neuroimaging and Fetal Alcohol Spectrum Disorders

ERIC Educational Resources Information Center

Norman, Andria L.; Crocker, Nicole; Mattson, Sarah N.; Riley, Edward P.

2009-01-01

The detrimental effects of prenatal alcohol exposure on the developing brain include structural brain anomalies as well as cognitive and behavioral deficits. Initial neuroimaging studies of fetal alcohol spectrum disorders (FASD) using magnetic resonance imaging (MRI) confirmed previous autopsy reports of overall reduction in brain volume and…

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.

Understanding alcohol use disorders with neuroelectrophysiology

PubMed Central

RANGASWAMY, MADHAVI; PORJESZ, BERNICE

2015-01-01

Neurocognitive deficits associated with impairments in various brain regions and neural circuitries, particularly involving frontal lobes, have been associated with chronic alcoholism, as well as with a predisposition to develop alcohol use and related disorders (AUDs). AUD is a multifactorial disorder caused by complex interactions between behavioral, genetic, and environmental liabilities. Neuroelectrophysiological techniques are instrumental in understanding brain and behavior relationships and have also proved very useful in evaluating the genetic diathesis of alcoholism. This chapter describes findings from neuroelectrophysiological measures (electroencephalogram, event-related potentials, and event-related oscillations) related to acute and chronic effects of alcohol on the brain and those that reflect underlying deficits related to a predisposition to develop AUDs and related disorders. The utility of these measures as effective endophenotypes to identify and understand genes associated with brain electrophysiology, cognitive networks, and AUDs has also been discussed. PMID:25307587

Reframing the Teenage Wasteland: Adolescent Microbiota-Gut-Brain Axis.

PubMed

McVey Neufeld, Karen-Anne; Luczynski, Pauline; Dinan, Timothy G; Cryan, John F

2016-04-01

Human adolescence is arguably one of the most challenging periods of development. The young adult is exposed to a variety of stressors and environmental stimuli on a backdrop of significant physiological change and development, which is especially apparent in the brain. It is therefore unsurprising that many psychiatric disorders are first observable during this time. The human intestine is inhabited by trillions of microorganisms, and evidence from both preclinical and clinical research focusing on the established microbiota-gut-brain axis suggests that the etiology and pathophysiology of psychiatric disorders may be influenced by intestinal dysbiosis. Provocatively, many if not all of the challenges faced by the developing teen have a documented impact on these intestinal commensal microbiota. In this review, we briefly summarize what is known about the developing adolescent brain and intestinal microbiota, discuss recent research investigating the microbiota-gut-brain axis during puberty, and propose that pre- and probiotics may prove useful in both the prevention and treatment of psychiatric disorders specifically benefitting the young adult. © The Author(s) 2016.

Reframing the Teenage Wasteland: Adolescent Microbiota-Gut-Brain Axis

PubMed Central

McVey Neufeld, Karen-Anne; Luczynski, Pauline; Dinan, Timothy G.

2016-01-01

Human adolescence is arguably one of the most challenging periods of development. The young adult is exposed to a variety of stressors and environmental stimuli on a backdrop of significant physiological change and development, which is especially apparent in the brain. It is therefore unsurprising that many psychiatric disorders are first observable during this time. The human intestine is inhabited by trillions of microorganisms, and evidence from both preclinical and clinical research focusing on the established microbiota-gut-brain axis suggests that the etiology and pathophysiology of psychiatric disorders may be influenced by intestinal dysbiosis. Provocatively, many if not all of the challenges faced by the developing teen have a documented impact on these intestinal commensal microbiota. In this review, we briefly summarize what is known about the developing adolescent brain and intestinal microbiota, discuss recent research investigating the microbiota-gut-brain axis during puberty, and propose that pre- and probiotics may prove useful in both the prevention and treatment of psychiatric disorders specifically benefitting the young adult. PMID:27254413

Research Review: Constraining Heterogeneity--The Social Brain and Its Development in Autism Spectrum Disorder

ERIC Educational Resources Information Center

Pelphrey, Kevin A.; Shultz, Sarah; Hudac, Caitlin M.; Vander Wyk, Brent C.

2011-01-01

The expression of autism spectrum disorder (ASD) is highly heterogeneous, owing to the complex interactions between genes, the brain, and behavior throughout development. Here we present a model of ASD that implicates an early and initial failure to develop the specialized functions of one or more of the set of neuroanatomical structures involved…

Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder.

PubMed

Shen, Mark D; Nordahl, Christine W; Young, Gregory S; Wootton-Gorges, Sandra L; Lee, Aaron; Liston, Sarah E; Harrington, Kayla R; Ozonoff, Sally; Amaral, David G

2013-09-01

Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6-9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6-9, 12-15, and 18-24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 'high-risk' infants having an older sibling with autism spectrum disorder and 22 'low-risk' infants having no relatives with autism spectrum disorder) were imaged at 6-9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12-15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18-24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6-9 months, which persisted and remained elevated at 12-15 and 18-24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12-15 and 18-24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.

[Obsessive-compulsive disorder, a new model of basal ganglia dysfunction? Elements from deep brain stimulation studies].

PubMed

Haynes, W I A; Millet, B; Mallet, L

2012-01-01

Deep brain stimulation was first developed for movement disorders but is now being offered as a therapeutic alternative in severe psychiatric disorders after the failure of conventional therapies. One of such pathologies is obsessive-compulsive disorder. This disorder which associates intrusive thoughts (obsessions) and repetitive irrepressible rituals (compulsions) is characterized by a dysfunction of a cortico-subcortical loop. After having reviewed the pathophysiological evidence to show why deep brain stimulation was an interesting path to take for severe and resistant cases of obsessive-compulsive disorder, we will present the results of the different clinical trials. Finally, we will provide possible mechanisms for the effects of deep brain stimulation in this pathology. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Anatomical brain images alone can accurately diagnose chronic neuropsychiatric illnesses.

PubMed

Bansal, Ravi; Staib, Lawrence H; Laine, Andrew F; Hao, Xuejun; Xu, Dongrong; Liu, Jun; Weissman, Myrna; Peterson, Bradley S

2012-01-01

Diagnoses using imaging-based measures alone offer the hope of improving the accuracy of clinical diagnosis, thereby reducing the costs associated with incorrect treatments. Previous attempts to use brain imaging for diagnosis, however, have had only limited success in diagnosing patients who are independent of the samples used to derive the diagnostic algorithms. We aimed to develop a classification algorithm that can accurately diagnose chronic, well-characterized neuropsychiatric illness in single individuals, given the availability of sufficiently precise delineations of brain regions across several neural systems in anatomical MR images of the brain. We have developed an automated method to diagnose individuals as having one of various neuropsychiatric illnesses using only anatomical MRI scans. The method employs a semi-supervised learning algorithm that discovers natural groupings of brains based on the spatial patterns of variation in the morphology of the cerebral cortex and other brain regions. We used split-half and leave-one-out cross-validation analyses in large MRI datasets to assess the reproducibility and diagnostic accuracy of those groupings. In MRI datasets from persons with Attention-Deficit/Hyperactivity Disorder, Schizophrenia, Tourette Syndrome, Bipolar Disorder, or persons at high or low familial risk for Major Depressive Disorder, our method discriminated with high specificity and nearly perfect sensitivity the brains of persons who had one specific neuropsychiatric disorder from the brains of healthy participants and the brains of persons who had a different neuropsychiatric disorder. Although the classification algorithm presupposes the availability of precisely delineated brain regions, our findings suggest that patterns of morphological variation across brain surfaces, extracted from MRI scans alone, can successfully diagnose the presence of chronic neuropsychiatric disorders. Extensions of these methods are likely to provide biomarkers that will aid in identifying biological subtypes of those disorders, predicting disease course, and individualizing treatments for a wide range of neuropsychiatric illnesses.

Mind, brain, and personality disorders.

PubMed

Gabbard, Glen O

2005-04-01

The use of the terms "mind" and "brain" in psychiatry is often associated with a set of polarities. Concepts such as environment, psychosocial, and psychotherapy are linked with "mind," while genes, biology, and medication are often associated with "brain." The author examines these dichotomies as they apply to personality disorders. Research on antisocial and borderline personality disorders that is relevant to these dichotomies is evaluated. The implications of the findings for the understanding of pathogenesis and treatment are reconsidered. In the clinical setting, it is problematic to lump together terms such as "genes," "brain," and "biological" as though they are separate and distinct from terms such as "environment," "mind," and "psychosocial." These dichotomies are problematic, because genes and environment are inextricably intertwined in the pathogenesis of personality disorders, psychosocial experiences may result in permanent changes in the brain, and psychotherapy may have its effect by altering brain structure and function. The "theory of mind" is a useful construct for bridging "mind" and "brain" in the treatment of personality disorders. Severe personality disorders are best understood and treated without "either-or" dichotomies of brain and mind. Each domain has a different language, however, and the language of the mind is necessary to help the patient develop a theory of mind.

The epigenetic switches for neural development and psychiatric disorders.

PubMed

Lv, Jingwen; Xin, Yongjuan; Zhou, Wenhao; Qiu, Zilong

2013-07-20

The most remarkable feature of the nervous system is that the development and functions of the brain are largely reshaped by postnatal experiences, in joint with genetic landscapes. The nature vs. nurture argument reminds us that both genetic and epigenetic information is indispensable for the normal function of the brain. The epigenetic regulatory mechanisms in the central nervous system have been revealed over last a decade. Moreover, the mutations of epigenetic modulator genes have been shown to be implicated in neuropsychiatric disorders, such as autism spectrum disorders. The epigenetic study has initiated in the neuroscience field for a relative short period of time. In this review, we will summarize recent discoveries about epigenetic regulation on neural development, synaptic plasticity, learning and memory, as well as neuropsychiatric disorders. Although the comprehensive view of how epigenetic regulation contributes to the function of the brain is still not completed, the notion that brain, the most complicated organ of organisms, is profoundly shaped by epigenetic switches is widely accepted. Copyright © 2013. Published by Elsevier Ltd.

Genetic and Diagnostic Biomarker Development in ASD Toddlers Using Resting State Functional MRI

DTIC Science & Technology

2016-09-01

networks during resting states. Autism spectrum disorder (ASD) begins prenatal, and early maldevelopment is present in many sites and systems that mediate...molecular and genomic evidence indicates autism spectrum disorder (ASD) begins prenatally, most likely by or before the late second trimester 10-15 as...ages 3 to 4 years. 2. KEYWORDS Autism spectrum disorder, ASD, early brain development, intrinsic functional brain networks, fMRI, infants, toddlers

Brain-CODE: A Secure Neuroinformatics Platform for Management, Federation, Sharing and Analysis of Multi-Dimensional Neuroscience Data.

PubMed

Vaccarino, Anthony L; Dharsee, Moyez; Strother, Stephen; Aldridge, Don; Arnott, Stephen R; Behan, Brendan; Dafnas, Costas; Dong, Fan; Edgecombe, Kenneth; El-Badrawi, Rachad; El-Emam, Khaled; Gee, Tom; Evans, Susan G; Javadi, Mojib; Jeanson, Francis; Lefaivre, Shannon; Lutz, Kristen; MacPhee, F Chris; Mikkelsen, Jordan; Mikkelsen, Tom; Mirotchnick, Nicholas; Schmah, Tanya; Studzinski, Christa M; Stuss, Donald T; Theriault, Elizabeth; Evans, Kenneth R

2018-01-01

Historically, research databases have existed in isolation with no practical avenue for sharing or pooling medical data into high dimensional datasets that can be efficiently compared across databases. To address this challenge, the Ontario Brain Institute's "Brain-CODE" is a large-scale neuroinformatics platform designed to support the collection, storage, federation, sharing and analysis of different data types across several brain disorders, as a means to understand common underlying causes of brain dysfunction and develop novel approaches to treatment. By providing researchers access to aggregated datasets that they otherwise could not obtain independently, Brain-CODE incentivizes data sharing and collaboration and facilitates analyses both within and across disorders and across a wide array of data types, including clinical, neuroimaging and molecular. The Brain-CODE system architecture provides the technical capabilities to support (1) consolidated data management to securely capture, monitor and curate data, (2) privacy and security best-practices, and (3) interoperable and extensible systems that support harmonization, integration, and query across diverse data modalities and linkages to external data sources. Brain-CODE currently supports collaborative research networks focused on various brain conditions, including neurodevelopmental disorders, cerebral palsy, neurodegenerative diseases, epilepsy and mood disorders. These programs are generating large volumes of data that are integrated within Brain-CODE to support scientific inquiry and analytics across multiple brain disorders and modalities. By providing access to very large datasets on patients with different brain disorders and enabling linkages to provincial, national and international databases, Brain-CODE will help to generate new hypotheses about the biological bases of brain disorders, and ultimately promote new discoveries to improve patient care.

Brain-CODE: A Secure Neuroinformatics Platform for Management, Federation, Sharing and Analysis of Multi-Dimensional Neuroscience Data

PubMed Central

Vaccarino, Anthony L.; Dharsee, Moyez; Strother, Stephen; Aldridge, Don; Arnott, Stephen R.; Behan, Brendan; Dafnas, Costas; Dong, Fan; Edgecombe, Kenneth; El-Badrawi, Rachad; El-Emam, Khaled; Gee, Tom; Evans, Susan G.; Javadi, Mojib; Jeanson, Francis; Lefaivre, Shannon; Lutz, Kristen; MacPhee, F. Chris; Mikkelsen, Jordan; Mikkelsen, Tom; Mirotchnick, Nicholas; Schmah, Tanya; Studzinski, Christa M.; Stuss, Donald T.; Theriault, Elizabeth; Evans, Kenneth R.

2018-01-01

Historically, research databases have existed in isolation with no practical avenue for sharing or pooling medical data into high dimensional datasets that can be efficiently compared across databases. To address this challenge, the Ontario Brain Institute’s “Brain-CODE” is a large-scale neuroinformatics platform designed to support the collection, storage, federation, sharing and analysis of different data types across several brain disorders, as a means to understand common underlying causes of brain dysfunction and develop novel approaches to treatment. By providing researchers access to aggregated datasets that they otherwise could not obtain independently, Brain-CODE incentivizes data sharing and collaboration and facilitates analyses both within and across disorders and across a wide array of data types, including clinical, neuroimaging and molecular. The Brain-CODE system architecture provides the technical capabilities to support (1) consolidated data management to securely capture, monitor and curate data, (2) privacy and security best-practices, and (3) interoperable and extensible systems that support harmonization, integration, and query across diverse data modalities and linkages to external data sources. Brain-CODE currently supports collaborative research networks focused on various brain conditions, including neurodevelopmental disorders, cerebral palsy, neurodegenerative diseases, epilepsy and mood disorders. These programs are generating large volumes of data that are integrated within Brain-CODE to support scientific inquiry and analytics across multiple brain disorders and modalities. By providing access to very large datasets on patients with different brain disorders and enabling linkages to provincial, national and international databases, Brain-CODE will help to generate new hypotheses about the biological bases of brain disorders, and ultimately promote new discoveries to improve patient care. PMID:29875648

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

Congenital Amusia Persists in the Developing Brain after Daily Music Listening

PubMed Central

Mignault Goulet, Geneviève; Moreau, Patricia; Robitaille, Nicolas; Peretz, Isabelle

2012-01-01

Congenital amusia is a neurodevelopmental disorder that affects about 3% of the adult population. Adults experiencing this musical disorder in the absence of macroscopically visible brain injury are described as cases of congenital amusia under the assumption that the musical deficits have been present from birth. Here, we show that this disorder can be expressed in the developing brain. We found that (10–13 year-old) children exhibit a marked deficit in the detection of fine-grained pitch differences in both musical and acoustical context in comparison to their normally developing peers comparable in age and general intelligence. This behavioral deficit could be traced down to their abnormal P300 brain responses to the detection of subtle pitch changes. The altered pattern of electrical activity does not seem to arise from an anomalous functioning of the auditory cortex, because all early components of the brain potentials, the N100, the MMN, and the P200 appear normal. Rather, the brain and behavioral measures point to disrupted information propagation from the auditory cortex to other cortical regions. Furthermore, the behavioral and neural manifestations of the disorder remained unchanged after 4 weeks of daily musical listening. These results show that congenital amusia can be detected in childhood despite regular musical exposure and normal intellectual functioning. PMID:22606299

Brain/MINDS: brain-mapping project in Japan

PubMed Central

Okano, Hideyuki; Miyawaki, Atsushi; Kasai, Kiyoto

2015-01-01

There is an emerging interest in brain-mapping projects in countries across the world, including the USA, Europe, Australia and China. In 2014, Japan started a brain-mapping project called Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS). Brain/MINDS aims to map the structure and function of neuronal circuits to ultimately understand the vast complexity of the human brain, and takes advantage of a unique non-human primate animal model, the common marmoset (Callithrix jacchus). In Brain/MINDS, the RIKEN Brain Science Institute acts as a central institute. The objectives of Brain/MINDS can be categorized into the following three major subject areas: (i) structure and functional mapping of a non-human primate brain (the marmoset brain); (ii) development of innovative neurotechnologies for brain mapping; and (iii) human brain mapping; and clinical research. Brain/MINDS researchers are highly motivated to identify the neuronal circuits responsible for the phenotype of neurological and psychiatric disorders, and to understand the development of these devastating disorders through the integration of these three subject areas. PMID:25823872

Clinical application of brain imaging for the diagnosis of mood disorders: the current state of play

PubMed Central

Savitz, J B; Rauch, S L; Drevets, W C

2013-01-01

In response to queries about whether brain imaging technology has reached the point where it is useful for making a clinical diagnosis and for helping to guide treatment selection, the American Psychiatric Association (APA) has recently written a position paper on the Clinical Application of Brain Imaging in Psychiatry. The following perspective piece is based on our contribution to this APA position paper, which specifically emphasized the application of neuroimaging in mood disorders. We present an introductory overview of the challenges faced by researchers in developing valid and reliable biomarkers for psychiatric disorders, followed by a synopsis of the extant neuroimaging findings in mood disorders, and an evidence-based review of the current research on brain imaging biomarkers in adult mood disorders. Although there are a number of promising results, by the standards proposed below, we argue that there are currently no brain imaging biomarkers that are clinically useful for establishing diagnosis or predicting treatment outcome in mood disorders. PMID:23546169

Clinical application of brain imaging for the diagnosis of mood disorders: the current state of play.

PubMed

Savitz, J B; Rauch, S L; Drevets, W C

2013-05-01

In response to queries about whether brain imaging technology has reached the point where it is useful for making a clinical diagnosis and for helping to guide treatment selection, the American Psychiatric Association (APA) has recently written a position paper on the Clinical Application of Brain Imaging in Psychiatry. The following perspective piece is based on our contribution to this APA position paper, which specifically emphasized the application of neuroimaging in mood disorders. We present an introductory overview of the challenges faced by researchers in developing valid and reliable biomarkers for psychiatric disorders, followed by a synopsis of the extant neuroimaging findings in mood disorders, and an evidence-based review of the current research on brain imaging biomarkers in adult mood disorders. Although there are a number of promising results, by the standards proposed below, we argue that there are currently no brain imaging biomarkers that are clinically useful for establishing diagnosis or predicting treatment outcome in mood disorders.

Dermatoglyphics in relation to brain volumes in twins concordant and discordant for bipolar disorder.

PubMed

Vonk, R; van der Schot, A C; van Baal, G C M; van Oel, C J; Nolen, W A; Kahn, R S

2014-12-01

Palmar and finger dermatoglyphics are formed between the 10th and the 17th weeks of gestation and their morphology can be influenced by genetic or environmental factors, interfering with normal intrauterine development. As both the skin and the brain develop from the same embryonal ectoderm, dermatoglyphic alterations may be informative for early abnormal neurodevelopmental processes in the brain. We investigated whether dermatoglyphic alterations are related to structural brain abnormalities in bipolar disorder and to what extent they are of a genetic and of an environmental origin. Dermatoglyphics and volumetric data from structural MRI were obtained in 53 twin pairs concordant or discordant for bipolar disorder and 51 healthy matched control twin pairs. Structural equation modeling was used. Bipolar disorder was significantly positively associated with palmar a-b ridge count (ABRC), indicating higher ABRC in bipolar patients (rph=.17 (CI .04-.30)). Common genes appear to be involved because the genetic correlation with ABRC was significant (rph-A=.21 (CI .05-.36). Irrespective of disease, ABRC showed a genetically mediated association with brain volume, indicated by a significant genetic correlation rph-A of respectively -.36 (CI -.52 to -.22) for total brain, -.34 (CI -.51 to -.16) total cortical volume, -.27 (CI -.43 to -.08) cortical gray matter and -.23 (CI -.41 to -.04) cortical white matter. In conclusion, a genetically determined abnormal development of the foetal ectoderm between the 10th and 15th week of gestation appears related to smaller brain volumes in (subjects at risk for) bipolar disorder. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Understanding the Impact of Brain Disorders: Towards a ‘Horizontal Epidemiology’ of Psychosocial Difficulties and Their Determinants

PubMed Central

Cieza, Alarcos; Anczewska, Marta; Ayuso-Mateos, Jose Luis; Baker, Mary; Bickenbach, Jerome; Chatterji, Somnath; Hartley, Sally; Leonardi, Matilde; Pitkänen, Tuuli

2015-01-01

Objective To test the hypothesis of ‘horizontal epidemiology’, i.e. that psychosocial difficulties (PSDs), such as sleep disturbances, emotional instability and difficulties in personal interactions, and their environmental determinants are experienced in common across neurological and psychiatric disorders, together called brain disorders. Study Design A multi-method study involving systematic literature reviews, content analysis of patient-reported outcomes and outcome instruments, clinical input and a qualitative study was carried out to generate a pool of PSD and environmental determinants relevant for nine different brain disorders, namely epilepsy, migraine, multiple sclerosis, Parkinson’s disease, stroke, dementia, depression, schizophrenia and substance dependency. Information from these sources was harmonized and compiled, and after feedback from external experts, a data collection protocol including PSD and determinants common across these nine disorders was developed. This protocol was implemented as an interview in a cross-sectional study including a convenience sample of persons with one of the nine brain disorders. PSDs endorsed by at least 25% of patients with a brain disorder were considered associated with the disorder. PSD were considered common across disorders if associated to 5 out of the 9 brain disorders and if among the 5 both neurological and psychiatric conditions were represented. Setting The data collection protocol with 64 PSDs and 20 determinants was used to collect data from a convenience sample of 722 persons in four specialized health care facilities in Europe. Results 57 of the PSDs and 16 of the determinants included in the protocol were found to be experienced across brain disorders. Conclusion This is the first evidence that supports the hypothesis of horizontal epidemiology in brain disorders. This result challenges the brain disorder-specific or vertical approach in which clinical and epidemiological research about psychosocial difficulties experienced in daily life is commonly carried in neurology and psychiatry and the way in which the corresponding health care delivery is practiced in many countries of the world. PMID:26352911

Child Development

MedlinePlus

... ARTICLES Scientific articles. RESEARCH Legacy for Children™ study. Child Development: What's New Article: Differences in health care, family, ... Disorders, Learning Disorders, and other developmental conditions. ... Development Basics Early Brain Development Developmental Screening Screening for ...

Fetal Stress and Programming of Hypoxic/Ischemic-Sensitive Phenotype in the Neonatal Brain: Mechanisms and Possible Interventions

PubMed Central

Li, Yong; Gonzalez, Pablo; Zhang, Lubo

2012-01-01

Growing evidence of epidemiological, clinical and experimental studies has clearly shown a close link between adverse in utero environment and the increased risk of neurological, psychological and psychiatric disorders in later life. Fetal stresses, such as hypoxia, malnutrition, and fetal exposure to nicotine, alcohol, cocaine and glucocorticoids may directly or indirectly act at cellular and molecular levels to alter the brain development and result in programming of heightened brain vulnerability to hypoxic-ischemic encephalopathy and the development of neurological diseases in the postnatal life. The underlying mechanisms are not well understood. However, glucocorticoids may play a crucial role in epigenetic programming of neurological disorders of fetal origins. This review summarizes the recent studies about the effects of fetal stress on the abnormal brain development, focusing on the cellular, molecular and epigenetic mechanisms and highlighting the central effects of glucocorticoids on programming of hypoxicischemic-sensitive phenotype in the neonatal brain, which may enhance the understanding of brain pathophysiology resulting from fetal stress and help explore potential targets of timely diagnosis, prevention and intervention in neonatal hypoxic-ischemic encephalopathy and other for brain disorders. PMID:22627492

Genetic disorders of thyroid metabolism and brain development

PubMed Central

Kurian, Manju A; Jungbluth, Heinz

2014-01-01

Normal thyroid metabolism is essential for human development, including the formation and functioning of the central and peripheral nervous system. Disorders of thyroid metabolism are increasingly recognized within the spectrum of paediatric neurological disorders. Both hypothyroid and hyperthyroid disease states (resulting from genetic and acquired aetiologies) can lead to characteristic neurological syndromes, with cognitive delay, extrapyramidal movement disorders, neuropsychiatric symptoms, and neuromuscular manifestations. In this review, the neurological manifestations of genetic disorders of thyroid metabolism are outlined, with particular focus on Allan-Herndon-Dudley syndrome and benign hereditary chorea. We report in detail the clinical features, major neurological and neuropsychiatric manifestations, molecular genetic findings, disease mechanisms, and therapeutic strategies for these emerging genetic ‘brain-thyroid’ disorders. PMID:24665922

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.

[Roles of Aquaporins in Brain Disorders].

PubMed

Yasui, Masato

2015-06-01

Aquaporin (AQP) is a water channel protein that is expressed in the cell membranes. AQPs are related to several kinds of human diseases such as cataract. In the mammalian central nervous system (CNS), AQP4 is specifically expressed in the astrocyte membranes lining the perivascular and periventricular structures. AQP4 plays a role in the development of brain edema associated with certain brain disorders. Neuromyelitis optica (NMO) is a demyelinating disorder, and patients with NMO develop autoimmune antibodies against AQP4 in their serum. Therefore, AQP4 is involved in NMO pathogenesis. A new concept referred to as "glymphatic pathway" has been recently proposed to explain the lymphatic system in the CNS. Dysfunction of the "glymphatic pathway" may cause several neurodegenerative diseases and mood disorders. Importantly, AQP4 may play a role in the "glymphatic pathway". Further investigation of AQP4 in CNS disorders is necessary, and a new drug against AQP4 is expected.

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.

Social Outcomes in Childhood Brain Disorder: A Heuristic Integration of Social Neuroscience and Developmental Psychology

PubMed Central

Yeates, Keith Owen; Bigler, Erin D.; Dennis, Maureen; Gerhardt, Cynthia A.; Rubin, Kenneth H.; Stancin, Terry; Taylor, H. Gerry; Vannatta, Kathryn

2010-01-01

The authors propose a heuristic model of the social outcomes of childhood brain disorder that draws on models and methods from both the emerging field of social cognitive neuroscience and the study of social competence in developmental psychology/psychopathology. The heuristic model characterizes the relationships between social adjustment, peer interactions and relationships, social problem solving and communication, social-affective and cognitive-executive processes, and their neural substrates. The model is illustrated by research on a specific form of childhood brain disorder, traumatic brain injury. The heuristic model may promote research regarding the neural and cognitive-affective substrates of children’s social development. It also may engender more precise methods of measuring impairments and disabilities in children with brain disorder and suggest ways to promote their social adaptation. PMID:17469991

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.

Predictors of Major Depression and Posttraumatic Stress Disorder Following Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

PubMed

Cnossen, Maryse C; Scholten, Annemieke C; Lingsma, Hester F; Synnot, Anneliese; Haagsma, Juanita; Steyerberg, Prof Ewout W; Polinder, Suzanne

2017-01-01

Although major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are prevalent after traumatic brain injury (TBI), little is known about which patients are at risk for developing them. The authors systematically reviewed the literature on predictors and multivariable models for MDD and PTSD after TBI. The authors included 26 observational studies. MDD was associated with female gender, preinjury depression, postinjury unemployment, and lower brain volume, whereas PTSD was related to shorter posttraumatic amnesia, memory of the traumatic event, and early posttraumatic symptoms. Risk of bias ratings for most studies were acceptable, although studies that developed a multivariable model suffered from methodological shortcomings.

Effects of DTNBP1 Genotype on Brain Development in Children

ERIC Educational Resources Information Center

Tognin, Stefania; Viding, Essi; McCrory, Eamon J.; Taylor, Lauren; O'Donovan, Michael C.; McGuire, Philip; Mechelli, Andrea

2011-01-01

Background: Schizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin-binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain development is poorly…

Innovations in deep brain stimulation methodology.

PubMed

Kühn, Andrea A; Volkmann, Jens

2017-01-01

Deep brain stimulation is a powerful clinical method for movement disorders that no longer respond satisfactorily to pharmacological management, but its progress has been hampered by stagnation in technological procedure solutions and device development. Recently, the combined research efforts of bioengineers, neuroscientists, and clinicians have helped to better understand the mechanisms of deep brain stimulation, and solutions for the translational roadblock are emerging. Here, we define the needs for methodological advances in deep brain stimulation from a neurophysiological perspective and describe technological solutions that are currently evaluated for near-term clinical application. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

Nanoparticle transport across the blood brain barrier.

PubMed

Grabrucker, Andreas M; Ruozi, Barbara; Belletti, Daniela; Pederzoli, Francesca; Forni, Flavio; Vandelli, Maria Angela; Tosi, Giovanni

2016-01-01

While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes.

The Importance of Brain Banks for Molecular Neuropathological Research: The New South Wales Tissue Resource Centre Experience

PubMed Central

Dedova, Irina; Harding, Antony; Sheedy, Donna; Garrick, Therese; Sundqvist, Nina; Hunt, Clare; Gillies, Juliette; Harper, Clive G.

2009-01-01

New developments in molecular neuropathology have evoked increased demands for postmortem human brain tissue. The New South Wales Tissue Resource Centre (TRC) at The University of Sydney has grown from a small tissue collection into one of the leading international brain banking facilities, which operates with best practice and quality control protocols. The focus of this tissue collection is on schizophrenia and allied disorders, alcohol use disorders and controls. This review highlights changes in TRC operational procedures dictated by modern neuroscience, and provides examples of applications of modern molecular techniques to study the neuropathogenesis of many different brain disorders. PMID:19333451

Effect of Transcranial Magnetic Stimulation on Neuronal Networks

NASA Astrophysics Data System (ADS)

Unsal, Ahmet; Hadimani, Ravi; Jiles, David

2013-03-01

The human brain contains around 100 billion nerve cells controlling our day to day activities. Consequently, brain disorders often result in impairments such as paralysis, loss of coordination and seizure. It has been said that 1 in 5 Americans suffer some diagnosable mental disorder. There is an urgent need to understand the disorders, prevent them and if possible, develop permanent cure for them. As a result, a significant amount of research activities is being directed towards brain research. Transcranial Magnetic Stimulation (TMS) is a promising tool for diagnosing and treating brain disorders. It is a non-invasive treatment method that produces a current flow in the brain which excites the neurons. Even though TMS has been verified to have advantageous effects on various brain related disorders, there have not been enough studies on the impact of TMS on cells. In this study, we are investigating the electrophysiological effects of TMS on one dimensional neuronal culture grown in a circular pathway. Electrical currents are produced on the neuronal networks depending on the directionality of the applied field. This aids in understanding how neuronal networks react under TMS treatment.

Modern network science of neurological disorders.

PubMed

Stam, Cornelis J

2014-10-01

Modern network science has revealed fundamental aspects of normal brain-network organization, such as small-world and scale-free patterns, hierarchical modularity, hubs and rich clubs. The next challenge is to use this knowledge to gain a better understanding of brain disease. Recent developments in the application of network science to conditions such as Alzheimer's disease, multiple sclerosis, traumatic brain injury and epilepsy have challenged the classical concept of neurological disorders being either 'local' or 'global', and have pointed to the overload and failure of hubs as a possible final common pathway in neurological disorders.

Cross-hemispheric functional connectivity in the human fetal brain.

PubMed

Thomason, Moriah E; Dassanayake, Maya T; Shen, Stephen; Katkuri, Yashwanth; Alexis, Mitchell; Anderson, Amy L; Yeo, Lami; Mody, Swati; Hernandez-Andrade, Edgar; Hassan, Sonia S; Studholme, Colin; Jeong, Jeong-Won; Romero, Roberto

2013-02-20

Compelling evidence indicates that psychiatric and developmental disorders are generally caused by disruptions in the functional connectivity (FC) of brain networks. Events occurring during development, and in particular during fetal life, have been implicated in the genesis of such disorders. However, the developmental timetable for the emergence of neural FC during human fetal life is unknown. We present the results of resting-state functional magnetic resonance imaging performed in 25 healthy human fetuses in the second and third trimesters of pregnancy (24 to 38 weeks of gestation). We report the presence of bilateral fetal brain FC and regional and age-related variation in FC. Significant bilateral connectivity was evident in half of the 42 areas tested, and the strength of FC between homologous cortical brain regions increased with advancing gestational age. We also observed medial to lateral gradients in fetal functional brain connectivity. These findings improve understanding of human fetal central nervous system development and provide a basis for examining the role of insults during fetal life in the subsequent development of disorders in neural FC.

Detection of atypical network development patterns in children with autism spectrum disorder using magnetoencephalography

PubMed Central

Watanabe, Katsumi; Yoshimura, Yuko; Kikuchi, Mitsuru; Minabe, Yoshio; Aihara, Kazuyuki

2017-01-01

Autism spectrum disorder (ASD) is a developmental disorder that involves developmental delays. It has been hypothesized that aberrant neural connectivity in ASD may cause atypical brain network development. Brain graphs not only describe the differences in brain networks between clinical and control groups, but also provide information about network development within each group. In the present study, graph indices of brain networks were estimated in children with ASD and in typically developing (TD) children using magnetoencephalography performed while the children viewed a cartoon video. We examined brain graphs from a developmental point of view, and compared the networks between children with ASD and TD children. Network development patterns (NDPs) were assessed by examining the association between the graph indices and the raw scores on the achievement scale or the age of the children. The ASD and TD groups exhibited different NDPs at both network and nodal levels. In the left frontal areas, the nodal degree and efficiency of the ASD group were negatively correlated with the achievement scores. Reduced network connections were observed in the temporal and posterior areas of TD children. These results suggested that the atypical network developmental trajectory in children with ASD is associated with the development score rather than age. PMID:28886147

78 FR 32670 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-31

... Scientific Review Special Emphasis Panel; Fellowships: Brain Disorders, Language, Communication, and Related...: Center for Scientific Review Special Emphasis Panel; PAR Panel: Brain Disorders in the Developing World... Review Special Emphasis Panel; Small Business: Health Informatics. Date: June 28, 2013. Time: 8:30 a.m...

Do (epi)genetics impact the brain in functional neurologic disorders?

PubMed

Frodl, T

2016-01-01

Advances in neuropsychiatric research are supposed to lead to significant improvements in understanding functional neurologic disorders and their diagnosis. However, epigenetic and genetic research on conversion disorders and somatoform disorders is only at its start. This review demonstrates the current state within this field and tries to bridge a gap from what is known on gene-stress interactions in other psychiatric disorders like depression. The etiology of conversion disorders is hypothesized to be multifactorial. These considerations also suggest that potential etiologic factors lead to alterations in brain function, either episodically or chronically, eventually leading to structural brain changes. In particular, the knowledge of how the environment influences brain structure and function, e.g., via epigenetic regulation, may be interesting for future research in functional neurologic disorders. Reviewing the literature results in evidence that childhood adversities play a role in the development of functional neurologic disorders, whereby at present no reports exist about the interactive effect between childhood adversity and genetic factors or about the impact of epigenetics. © 2016 Elsevier B.V. All rights reserved.

Genomic connectivity networks based on the BrainSpan atlas of the developing human brain

NASA Astrophysics Data System (ADS)

Mahfouz, Ahmed; Ziats, Mark N.; Rennert, Owen M.; Lelieveldt, Boudewijn P. F.; Reinders, Marcel J. T.

2014-03-01

The human brain comprises systems of networks that span the molecular, cellular, anatomic and functional levels. Molecular studies of the developing brain have focused on elucidating networks among gene products that may drive cellular brain development by functioning together in biological pathways. On the other hand, studies of the brain connectome attempt to determine how anatomically distinct brain regions are connected to each other, either anatomically (diffusion tensor imaging) or functionally (functional MRI and EEG), and how they change over development. A global examination of the relationship between gene expression and connectivity in the developing human brain is necessary to understand how the genetic signature of different brain regions instructs connections to other regions. Furthermore, analyzing the development of connectivity networks based on the spatio-temporal dynamics of gene expression provides a new insight into the effect of neurodevelopmental disease genes on brain networks. In this work, we construct connectivity networks between brain regions based on the similarity of their gene expression signature, termed "Genomic Connectivity Networks" (GCNs). Genomic connectivity networks were constructed using data from the BrainSpan Transcriptional Atlas of the Developing Human Brain. Our goal was to understand how the genetic signatures of anatomically distinct brain regions relate to each other across development. We assessed the neurodevelopmental changes in connectivity patterns of brain regions when networks were constructed with genes implicated in the neurodevelopmental disorder autism (autism spectrum disorder; ASD). Using graph theory metrics to characterize the GCNs, we show that ASD-GCNs are relatively less connected later in development with the cerebellum showing a very distinct expression of ASD-associated genes compared to other brain regions.

Delineation of early brain development from fetuses to infants with diffusion MRI and beyond.

PubMed

Ouyang, Minhui; Dubois, Jessica; Yu, Qinlin; Mukherjee, Pratik; Huang, Hao

2018-04-12

Dynamic macrostructural and microstructural changes take place from the mid-fetal stage to 2 years after birth. Delineating structural changes of the brain during early development provides new insights into the complicated processes of both typical development and the pathological mechanisms underlying various psychiatric and neurological disorders including autism, attention deficit hyperactivity disorder and schizophrenia. Decades of histological studies have identified strong spatial and functional maturation gradients in human brain gray and white matter. The recent improvements in magnetic resonance imaging (MRI) techniques, especially diffusion MRI (dMRI), relaxometry imaging, and magnetization transfer imaging (MTI) have provided unprecedented opportunities to non-invasively quantify and map the early developmental changes at whole brain and regional levels. Here, we review the recent advances in understanding early brain structural development during the second half of gestation and the first two postnatal years using modern MR techniques. Specifically, we review studies that delineate the emergence and microstructural maturation of white matter tracts, as well as dynamic mapping of inhomogeneous cortical microstructural organization unique to fetuses and infants. These imaging studies converge into maturational curves of MRI measurements that are distinctive across different white matter tracts and cortical regions. Furthermore, contemporary models offering biophysical interpretations of the dMRI-derived measurements are illustrated to infer the underlying microstructural changes. Collectively, this review summarizes findings that contribute to charting spatiotemporally heterogeneous gray and white matter structural development, offering MRI-based biomarkers of typical brain development and setting the stage for understanding aberrant brain development in neurodevelopmental disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

A Developmental Neuroscience Approach to the Search for Biomarkers in Autism Spectrum Disorder

PubMed Central

Varcin, Kandice J.; Nelson, Charles A.

2016-01-01

Purpose of review The delineation of biomarkers in autism spectrum disorder (ASD) offers a promising approach to inform precision-medicine based approaches to ASD diagnosis and treatment and to move toward a mechanistic description of the disorder. However, biomarkers with sufficient sensitivity or specificity for clinical application in ASD are yet to be realized. Here, we review recent evidence for early, low-level alterations in brain and behavior development that may offer promising avenues for biomarker development in ASD. Recent findings Accumulating evidence suggests that signs associated with ASD may unfold in a manner that maps onto the hierarchical organization of brain development. Genetic and neuroimaging evidence points towards perturbations in brain development early in life, and emerging evidence indicates that sensorimotor development may be amongst the earliest emerging signs associated with ASD, preceding social and cognitive impairment. Summary The search for biomarkers of risk, prediction and stratification in ASD may be advanced through a developmental neuroscience approach that looks outside of the core signs of ASD and considers the bottom-up nature of brain development alongside the dynamic nature of development over time. We provide examples of assays that could be incorporated in studies to target low-level circuits. PMID:26953849

A starring role for microglia in brain sex differences.

PubMed

Lenz, Kathryn M; McCarthy, Margaret M

2015-06-01

Microglia, the resident innate immune cells in the brain, have long been understood to be crucial to maintenance in the nervous system, by clearing debris, monitoring for infiltration of infectious agents, and mediating the brain's inflammatory and repair response to traumatic injury, stroke, or neurodegeneration. A wave of new research has shown that microglia are also active players in many basic processes in the healthy brain, including cell proliferation, synaptic connectivity, and physiology. Microglia, both in their capacity as phagocytic cells and via secretion of many neuroactive molecules, including cytokines and growth factors, play a central role in early brain development, including sexual differentiation of the brain. In this review, we present the vast roles microglia play in normal brain development and how perturbations in the normal neuroimmune environment during development may contribute to the etiology of brain-based disorders. There are notable differences between microglia and neuroimmune signaling in the male and female brain throughout the life span, and these differences may contribute to the vast differences in the incidence of neuropsychiatric and neurological disorders between males and females. © The Author(s) 2014.

Molecular genetics in fetal neurology.

PubMed

Huang, Jin; Wah, Isabella Y M; Pooh, Ritsuko K; Choy, Kwong Wai

2012-12-01

Brain malformations, particularly related to early brain development, are a clinically and genetically heterogeneous group of fetal neurological disorders. Fetal cerebral malformation, predominantly of impaired prosencephalic development namely agenesis of the corpus callosum and septo-optic dysplasia, is the main pathological feature in fetus, and causes prominent neurodevelopmental retardation, and associated with congenital facial anomalies and visual disorders. Differential diagnosis of brain malformations can be extremely difficult even through magnetic resonance imaging. Advances in genomic and molecular genetics technologies have led to the identification of the sonic hedgehog pathways and genes critical to the normal brain development. Molecular cytogenetic and genetic studies have identified numeric and structural chromosomal abnormalities as well as mutations in genes important for the etiology of fetal neurological disorders. In this review, we update the molecular genetics findings of three common fetal neurological abnormalities, holoprosencephaly, lissencephaly and agenesis of the corpus callosum, in an attempt to assist in perinatal and prenatal diagnosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

The Major Histocompatibility Complex and Autism Spectrum Disorder

PubMed Central

Needleman, Leigh A.; McAllister, A. Kimberley

2015-01-01

Autism spectrum disorder (ASD) is a complex disorder that appears to be caused by interactions between genetic changes and environmental insults during early development. A wide range of factors have been linked to the onset of ASD, but recently both genetic associations and environmental factors point to a central role for immune- related genes and immune responses to environmental stimuli. Specifically, many of the proteins encoded by the major histocompatibility complex (MHC) play a vital role in the formation, refinement, maintenance, and plasticity of the brain. Manipulations of levels of MHC molecules have illustrated how disrupted MHC signaling can significantly alter brain connectivity and function. Thus, an emerging hypothesis in our field is that disruptions in MHC expression in the developing brain caused by mutations and/or immune dysregulation may contribute to the altered brain connectivity and function characteristic of ASD. This review provides an overview of the structure and function of the three classes of MHC molecules in the immune system, healthy brain, and their possible involvement in ASD. PMID:22760919

Brain “fog,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin

PubMed Central

Theoharides, Theoharis C.; Stewart, Julia M.; Hatziagelaki, Erifili; Kolaitis, Gerasimos

2015-01-01

Brain “fog” is a constellation of symptoms that include reduced cognition, inability to concentrate and multitask, as well as loss of short and long term memory. Brain “fog” characterizes patients with autism spectrum disorders (ASDs), celiac disease, chronic fatigue syndrome, fibromyalgia, mastocytosis, and postural tachycardia syndrome (POTS), as well as “minimal cognitive impairment,” an early clinical presentation of Alzheimer's disease (AD), and other neuropsychiatric disorders. Brain “fog” may be due to inflammatory molecules, including adipocytokines and histamine released from mast cells (MCs) further stimulating microglia activation, and causing focal brain inflammation. Recent reviews have described the potential use of natural flavonoids for the treatment of neuropsychiatric and neurodegenerative diseases. The flavone luteolin has numerous useful actions that include: anti-oxidant, anti-inflammatory, microglia inhibition, neuroprotection, and memory increase. A liposomal luteolin formulation in olive fruit extract improved attention in children with ASDs and brain “fog” in mastocytosis patients. Methylated luteolin analogs with increased activity and better bioavailability could be developed into effective treatments for neuropsychiatric disorders and brain “fog.” PMID:26190965

Functional brain correlates of motor response inhibition in children with developmental coordination disorder and attention deficit/hyperactivity disorder.

PubMed

Thornton, Siobhan; Bray, Signe; Langevin, Lisa Marie; Dewey, Deborah

2018-06-01

Motor impairment is associated with developmental coordination disorder (DCD), and to a lesser extent with attention-deficit/hyperactivity disorder (ADHD). Previous functional imaging studies investigated children with DCD or ADHD only; however, these two disorders co-occur in up to 50% of cases, suggesting that similar neural correlates are associated with these disorders. This study compared functional brain activation in children and adolescents (age range 8-17, M = 11.73, SD = 2.88) with DCD (n = 9), ADHD (n = 20), co-occurring DCD and ADHD (n = 18) and typically developing (TD) controls (n = 20). When compared to TD controls, children with co-occurring DCD/ADHD showed decreased activation during response inhibition in primary motor and sensory cortices. These findings suggest that children with co-occurring DCD and ADHD display significant functional changes in brain activation that could interfere with inhibition of erroneous motor responses. In contrast to previous studies, significant alterations in brain activation relative to TD controls, were not found in children with isolated DCD or ADHD. These findings highlight the importance of considering co-occurring disorders when investigating brain function in children with neurodevelopmental disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

Autism BrainNet: A network of postmortem brain banks established to facilitate autism research.

PubMed

Amaral, David G; Anderson, Matthew P; Ansorge, Olaf; Chance, Steven; Hare, Carolyn; Hof, Patrick R; Miller, Melissa; Nagakura, Ikue; Pickett, Jane; Schumann, Cynthia; Tamminga, Carol

2018-01-01

Autism spectrum disorder (ASD or autism) is a neurodevelopmental condition that affects over 1% of the population worldwide. Developing effective preventions and treatments for autism will depend on understanding the genetic perturbations and underlying neuropathology of the disorder. While evidence from magnetic resonance imaging and other noninvasive techniques points to altered development and organization of the autistic brain, these tools lack the resolution for identifying the cellular and molecular underpinnings of the disorder. Postmortem studies of high-quality human brain tissue currently represent the only viable option to pursuing these types of studies. However, the availability of high-quality ASD brain tissue has been extremely limited. Here we describe the establishment of a privately funded tissue bank, Autism BrainNet, a network of brain collection sites that work in a coordinated fashion to develop an adequate library of human postmortem brain tissues. Autism BrainNet was initiated as a collaboration between the Simons Foundation and Autism Speaks, and is currently funded by the Simons Foundation Autism Research Initiative. Autism BrainNet has collection sites (nodes) in California, Texas, New York, and Massachusetts; an affiliated, international node is located in Oxford, England. All donations to this network become part of a consolidated pool of tissue that is distributed to qualified investigators worldwide to carry out autism research. An essential component of this program is a widespread outreach program that highlights the need for postmortem brain donations to families affected by autism, led by the Autism Science Foundation. Challenges include an outreach campaign that deals with a disorder beginning in early childhood, collecting an adequate number of donations to deal with the high level of biologic heterogeneity of autism, and preparing this limited resource for optimal distribution to the greatest number of investigators. Copyright © 2018 Elsevier B.V. All rights reserved.

Nanoparticle transport across the blood brain barrier

PubMed Central

Grabrucker, Andreas M; Ruozi, Barbara; Belletti, Daniela; Pederzoli, Francesca; Forni, Flavio; Vandelli, Maria Angela; Tosi, Giovanni

2016-01-01

ABSTRACT While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes. PMID:27141426

Attention-deficit hyperactivity disorder (ADHD) and tuberous sclerosis complex.

PubMed

D'Agati, Elisa; Moavero, Romina; Cerminara, Caterina; Curatolo, Paolo

2009-10-01

The neurobiological basis of attention-deficit hyperactivity disorder (ADHD) in tuberous sclerosis complex is still largely unknown. Cortical tubers may disrupt several brain networks that control different types of attention. Frontal lobe dysfunction due to seizures or epileptiform electroencephalographic discharges may perturb the development of brain systems that underpin attentional and hyperactive functions during a critical early stage of brain maturation. Comorbidity of attention-deficit hyperactivity disorder (ADHD) with mental retardation and autism spectrum disorders is frequent in children with tuberous sclerosis. Attention-deficit hyperactivity disorder (ADHD) may also reflect a direct effect of the abnormal genetic program. Treatment of children with tuberous sclerosis complex with combined symptoms of attention-deficit hyperactivity disorder (ADHD) and epilepsy may represent a challenge for clinicians, because antiepileptic therapy and drugs used to treat attention-deficit hyperactivity disorder (ADHD) may aggravate the clinical picture of each other.

Are Mental Disorders Brain Diseases, and What Does This Mean? A Clinical-Neuropsychological Perspective.

PubMed

Frisch, Stefan

Neuroscientific research has substantially increased our knowledge about mental disorders in recent years. Along with these benefits, radical postulates have been articulated according to which understanding and treatment of mental disorders should generally be based on biological terms, such as neurons/brain areas, transmitters, genes etc. Proponents of such a 'biological psychiatry' claim that mental disorders are analogous to neurological disorders and refer to neurology and neuropsychology to corroborate their claims. The present article argues that, from a clinical-neuropsychological perspective, 'biological psychiatry' is based on a mechanistic, 'cerebrocentric' framework of brain (dys-)function which has its roots in experimental neuroscience but runs up against narrow limits in clinical neurology and neuropsychology. In fact, understanding and treating neurological disorders generally demands a systems perspective including brain, organism and environment as intrinsically entangled. In this way, 'biological' characterizes a 'holistic', nonreductionist level of explanation, according to which the significance of particular mechanisms can only be estimated in the context of the organism (or person). This is evident in the common observation that local brain damage does not just lead to an isolated loss of function, but to multiple attempts of reorganization and readaptation; it initiates new developments. Furthermore, treating brain disorders necessarily includes aspects of individuality and subjectivity, a conclusion that contradicts the purely 'objectivist', third-person stance put forward by some proponents of biological psychiatry. In sum, understanding and treating brain damage sequelae in the clinical neurosciences demands a biopsychosocial perspective, for both conceptual and historical reasons. The same may hold for psychiatry when adopting a brain-based view on mental disorders. In such a perspective, biological psychiatry seems an interesting project but falls short of its original claims. © 2016 S. Karger AG, Basel.

Intrinsic brain connectivity predicts impulse control disorders in patients with Parkinson's disease.

PubMed

Tessitore, Alessandro; De Micco, Rosa; Giordano, Alfonso; di Nardo, Federica; Caiazzo, Giuseppina; Siciliano, Mattia; De Stefano, Manuela; Russo, Antonio; Esposito, Fabrizio; Tedeschi, Gioacchino

2017-12-01

Impulse control disorders can be triggered by dopamine replacement therapies in patients with PD. Using resting-state functional MRI, we investigated the intrinsic brain network connectivity at baseline in a cohort of drug-naive PD patients who successively developed impulse control disorders over a 36-month follow-up period compared with patients who did not. Baseline 3-Tesla MRI images of 30 drug-naive PD patients and 20 matched healthy controls were analyzed. The impulse control disorders' presence and severity at follow-up were assessed by the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale. Single-subject and group-level independent component analysis was used to investigate functional connectivity differences within the major resting-state networks. We also compared internetwork connectivity between patients. Finally, a multivariate Cox regression model was used to investigate baseline predictors of impulse control disorder development. At baseline, decreased connectivity in the default-mode and right central executive networks and increased connectivity in the salience network were detected in PD patients with impulse control disorders at follow-up compared with those without. Increased default-mode/central executive internetwork connectivity was significantly associated with impulse control disorders development (P < 0.05). Our findings demonstrated that abnormal brain connectivity in the three large-scale networks characterizes drug-naive PD patients who will eventually develop impulse control disorders while on dopaminergic treatment. We hypothesize that these divergent cognitive and limbic network connectivity changes could represent a potential biomarker and an additional risk factor for the emergence of impulse control disorders. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

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.

MicroRNAs in neuronal function and dysfunction

PubMed Central

Im, Heh-In; Kenny, Paul J.

2012-01-01

MicroRNAs (miRNAs) are small noncoding RNA transcripts expressed throughout the brain that can regulate neuronal gene expression at the post-transcriptional level. Here, we provide an overview of the role for miRNAs in brain development and function, and review evidence suggesting that dysfunction in miRNA signaling contributes to neurodevelopment disorders such as Rett and fragile X syndromes, as well as complex behavioral disorders including schizophrenia, depression and drug addiction. A better understanding of how miRNAs influence the development of neuropsychiatric disorders may reveal fundamental insights into the causes of these devastating illnesses and offer novel targets for therapeutic development. PMID:22436491

A Starring Role for Microglia in Brain Sex Differences

PubMed Central

Lenz, Kathryn M.; McCarthy, Margaret M.

2017-01-01

Microglia, the resident innate immune cells in the brain, have long been understood to be crucial to maintenance in the nervous system, by clearing debris, monitoring for infiltration of infectious agents, and mediating the brain’s inflammatory and repair response to traumatic injury, stroke, or neurodegeneration. A wave of new research has shown that microglia are also active players in many basic processes in the healthy brain, including cell proliferation, synaptic connectivity, and physiology. Microglia, both in their capacity as phagocytic cells and via secretion of many neuroactive molecules, including cytokines and growth factors, play a central role in early brain development, including sexual differentiation of the brain. In this review, we present the vast roles microglia play in normal brain development and how perturbations in the normal neuroimmune environment during development may contribute to the etiology of brain-based disorders. There are notable differences between microglia and neuroimmune signaling in the male and female brain throughout the life span, and these differences may contribute to the vast differences in the incidence of neuropsychiatric and neurological disorders between males and females. PMID:24871624

Nanomedicine in Central Nervous System (CNS) Disorders: A Present and Future Prospective

PubMed Central

Soni, Shringika; Ruhela, Rakesh Kumar; Medhi, Bikash

2016-01-01

Purpose: For the past few decades central nervous system disorders were considered as a major strike on human health and social system of developing countries. The natural therapeutic methods for CNS disorders limited for many patients. Moreover, nanotechnology-based drug delivery to the brain may an exciting and promising platform to overcome the problem of BBB crossing. In this review, first we focused on the role of the blood-brain barrier in drug delivery; and second, we summarized synthesis methods of nanomedicine and their role in different CNS disorder. Method: We reviewed the PubMed databases and extracted several kinds of literature on neuro nanomedicines using keywords, CNS disorders, nanomedicine, and nanotechnology. The inclusion criteria included chemical and green synthesis methods for synthesis of nanoparticles encapsulated drugs and, their in-vivo and in-vitro studies. We excluded nanomedicine gene therapy and nanomaterial in brain imaging. Results: In this review, we tried to identify a highly efficient method for nanomedicine synthesis and their efficacy in neuronal disorders. SLN and PNP encapsulated drugs reported highly efficient by easily crossing BBB. Although, these neuro-nanomedicine play significant role in therapeutics but some metallic nanoparticles reported the adverse effect on developing the brain. Conclusion: Although impressive advancement has made via innovative potential drug development, but their efficacy is still moderate due to limited brain permeability. To overcome this constraint,powerful tool in CNS therapeutic intervention provided by nanotechnology-based drug delivery methods. Due to its small and biofunctionalization characteristics, nanomedicine can easily penetrate and facilitate the drug through the barrier. But still, understanding of their toxicity level, optimization and standardization are a long way to go. PMID:27766216

Deep brain stimulation for psychiatric disorders: where we are now.

PubMed

Cleary, Daniel R; Ozpinar, Alp; Raslan, Ahmed M; Ko, Andrew L

2015-06-01

Fossil records showing trephination in the Stone Age provide evidence that humans have sought to influence the mind through physical means since before the historical record. Attempts to treat psychiatric disease via neurosurgical means in the 20th century provided some intriguing initial results. However, the indiscriminate application of these treatments, lack of rigorous evaluation of the results, and the side effects of ablative, irreversible procedures resulted in a backlash against brain surgery for psychiatric disorders that continues to this day. With the advent of psychotropic medications, interest in invasive procedures for organic brain disease waned. Diagnosis and classification of psychiatric diseases has improved, due to a better understanding of psychiatric patho-physiology and the development of disease and treatment biomarkers. Meanwhile, a significant percentage of patients remain refractory to multiple modes of treatment, and psychiatric disease remains the number one cause of disability in the world. These data, along with the safe and efficacious application of deep brain stimulation (DBS) for movement disorders, in principle a reversible process, is rekindling interest in the surgical treatment of psychiatric disorders with stimulation of deep brain sites involved in emotional and behavioral circuitry. This review presents a brief history of psychosurgery and summarizes the development of DBS for psychiatric disease, reviewing the available evidence for the current application of DBS for disorders of the mind.

Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders.

PubMed

Bao, Ai-Min; Swaab, Dick F

2011-04-01

During the intrauterine period a testosterone surge masculinizes the fetal brain, whereas the absence of such a surge results in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other. Sex differences in cognition, gender identity (an individual's perception of their own sexual identity), sexual orientation (heterosexuality, homosexuality or bisexuality), and the risks of developing neuropsychiatric disorders are programmed into our brain during early development. There is no evidence that one's postnatal social environment plays a crucial role in gender identity or sexual orientation. We discuss the relationships between structural and functional sex differences of various brain areas and the way they change along with any changes in the supply of sex hormones on the one hand and sex differences in behavior in health and disease on the other. Copyright © 2011 Elsevier Inc. All rights reserved.

Developmental neurotoxicity of industrial chemicals.

PubMed

Grandjean, P; Landrigan, P J

2006-12-16

Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.

Using real-time fMRI brain-computer interfacing to treat eating disorders.

PubMed

Sokunbi, Moses O

2018-05-15

Real-time functional magnetic resonance imaging based brain-computer interfacing (fMRI neurofeedback) has shown encouraging outcomes in the treatment of psychiatric and behavioural disorders. However, its use in the treatment of eating disorders is very limited. Here, we give a brief overview of how to design and implement fMRI neurofeedback intervention for the treatment of eating disorders, considering the basic and essential components. We also attempt to develop potential adaptations of fMRI neurofeedback intervention for the treatment of anorexia nervosa, bulimia nervosa and binge eating disorder. Copyright © 2018 Elsevier B.V. All rights reserved.

Is fetal brain monoamine oxidase inhibition the missing link between maternal smoking and conduct disorders?

PubMed Central

Baler, Ruben D.; Volkow, Nora D.; Fowler, Joanna S.; Benveniste, Helene

2008-01-01

Smoking is the leading cause of preventable illness in the world today. Prenatal cigarette smoke exposure (PCSE) is a particularly insidious form because so many of its associated health effects befall the unborn child and produce behavioural outcomes that manifest themselves only years later. Among these are the associations between PCSE and conduct disorders, which have been mostly ascribed to the deleterious effects of nicotine on the fetal brain. Here we hypothesize that inhibition of brain monoamine oxidase (MAO) during fetal brain development, secondary to maternal cigarette smoking and in addition to nicotine, is a likely contributor to this association. MAOs play a central role in monoaminergic balance in the brain, and their inhibition during fetal development — but not during adult life — is known to result in an aggressive phenotype in laboratory animals. This paper provides theoretical and experimental support for the notion that cigarette smoke–induced inhibition of MAO in the fetal brain, particularly when it occurs in combination with polymorphisms in the MAOA gene that lead to lower enzyme concentration in the brain, may result in brain morphologic and functional changes that enhance the risk of irritability, poor self-control and aggression in the offspring. It also encourages research to evaluate whether the interaction of smoking exposure during fetal development and MAOA genotype increases the risk for conduct disorder over that incurred by mere fetal exposure to tobacco smoke. PMID:18592036

Schizophrenia and the neurodevelopmental continuum:evidence from genomics.

PubMed

Owen, Michael J; O'Donovan, Michael C

2017-10-01

The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention-deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as "neurodevelopmental disorders". An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research. © 2017 World Psychiatric Association.

Local brain connectivity across development in autism spectrum disorder: A cross-sectional investigation

PubMed Central

Dajani, Dina R.; Uddin, Lucina Q.

2015-01-01

Lay Abstract There is a general consensus that autism spectrum disorder (ASD) is accompanied by alterations in brain connectivity. Much of the neuroimaging work has focused on assessing long-range connectivity disruptions in ASD. However, evidence from both animal models and postmortem examination of the human brain suggests that local connections may also be disrupted in individuals with ASD. Here we investigated the development of local connectivity across three age cohorts of individuals with ASD and typically developing (TD) individuals. We find that in typical development, children exhibit high levels of local connectivity across the brain, while adolescents exhibit lower levels of local connectivity, similar to adult levels. On the other hand, children with ASD exhibit marginally lower local connectivity than TD children, and adolescents and adults with ASD exhibit levels of local connectivity comparable to that observed in neurotypical individuals. During all developmental stages -- childhood, adolescence, and adulthood -- individuals with ASD exhibited lower local connectivity in brain regions involved in sensory processing and higher local connectivity in brain regions involved in complex information processing. Further, higher local connectivity in ASD corresponded to more severe ASD symptomatology. Thus we demonstrate that local connectivity is disrupted in autism across development, with the most pronounced differences occurring in childhood. Scientific Abstract There is a general consensus that autism spectrum disorder (ASD) is accompanied by alterations in brain connectivity. Much of the neuroimaging work has focused on assessing long-range connectivity disruptions in ASD. However, evidence from both animal models and postmortem examination of the human brain suggests that local connections may also be disrupted in individuals with the disorder. Here we investigated how regional homogeneity (ReHo), a measure of similarity of a voxel’s timeseries to its nearest neighbors, varies across age in individuals with ASD and typically developing (TD) individuals using a cross-sectional design. Resting-state fMRI data obtained from a publicly available database were analyzed to determine group differences in ReHo between three age cohorts: children, adolescents, and adults. In typical development, ReHo across the entire brain was higher in children than in adolescents and adults. In contrast, children with ASD exhibited marginally lower ReHo than TD children, while adolescents and adults with ASD exhibited similar levels of local connectivity as age-matched neurotypical individuals. During all developmental stages, individuals with ASD exhibited lower local connectivity in sensory processing brain regions and higher local connectivity in complex information processing regions. Further, higher local connectivity in ASD corresponded to more severe ASD symptomatology. These results demonstrate that local connectivity is disrupted in ASD across development, with the most pronounced differences occurring in childhood. Developmental changes in ReHo do not mirror findings from fMRI studies of long-range connectivity in ASD, pointing to a need for more nuanced accounts of brain connectivity alterations in the disorder. PMID:26058882

Scientific and ethical issues related to deep brain stimulation for disorders of mood, behavior, and thought.

PubMed

Rabins, Peter; Appleby, Brian S; Brandt, Jason; DeLong, Mahlon R; Dunn, Laura B; Gabriëls, Loes; Greenberg, Benjamin D; Haber, Suzanne N; Holtzheimer, Paul E; Mari, Zoltan; Mayberg, Helen S; McCann, Evelyn; Mink, Sallie P; Rasmussen, Steven; Schlaepfer, Thomas E; Vawter, Dorothy E; Vitek, Jerrold L; Walkup, John; Mathews, Debra J H

2009-09-01

A 2-day consensus conference was held to examine scientific and ethical issues in the application of deep brain stimulation for treating mood and behavioral disorders, such as major depression, obsessive-compulsive disorder, and Tourette syndrome. The primary objectives of the conference were to (1) establish consensus among participants about the design of future clinical trials of deep brain stimulation for disorders of mood, behavior, and thought and (2) develop standards for the protection of human subjects participating in such studies. Conference participants identified 16 key points for guiding research in this growing field. The adoption of the described guidelines would help to protect the safety and rights of research subjects who participate in clinical trials of deep brain stimulation for disorders of mood, behavior, and thought and have further potential to benefit other stakeholders in the research process, including clinical researchers and device manufactures. That said, the adoption of the guidelines will require broad and substantial commitment from many of these same stakeholders.

Future Directions for Examination of Brain Networks in Neurodevelopmental Disorders.

PubMed

Uddin, Lucina Q; Karlsgodt, Katherine H

2018-01-01

Neurodevelopmental disorders are associated with atypical development and maturation of brain networks. A recent focus on human connectomics research and the growing popularity of open science initiatives has created the ideal climate in which to make real progress toward understanding the neurobiology of disorders affecting youth. Here we outline future directions for neuroscience researchers examining brain networks in neurodevelopmental disorders, highlighting gaps in the current literature. We emphasize the importance of leveraging large neuroimaging and phenotypic data sets recently made available to the research community, and we suggest specific novel methodological approaches, including analysis of brain dynamics and structural connectivity, that have the potential to produce the greatest clinical insight. Transdiagnostic approaches will also become increasingly necessary as the Research Domain Criteria framework put forth by the National Institute of Mental Health permeates scientific discourse. During this exciting era of big data and increased computational sophistication of analytic tools, the possibilities for significant advancement in understanding neurodevelopmental disorders are limitless.

Local brain connectivity across development in autism spectrum disorder: A cross-sectional investigation.

PubMed

Dajani, Dina R; Uddin, Lucina Q

2016-01-01

There is a general consensus that autism spectrum disorder (ASD) is accompanied by alterations in brain connectivity. Much of the neuroimaging work has focused on assessing long-range connectivity disruptions in ASD. However, evidence from both animal models and postmortem examination of the human brain suggests that local connections may also be disrupted in individuals with the disorder. Here, we investigated how regional homogeneity (ReHo), a measure of similarity of a voxel's timeseries to its nearest neighbors, varies across age in individuals with ASD and typically developing (TD) individuals using a cross-sectional design. Resting-state fMRI data obtained from a publicly available database were analyzed to determine group differences in ReHo between three age cohorts: children, adolescents, and adults. In typical development, ReHo across the entire brain was higher in children than in adolescents and adults. In contrast, children with ASD exhibited marginally lower ReHo than TD children, while adolescents and adults with ASD exhibited similar levels of local connectivity as age-matched neurotypical individuals. During all developmental stages, individuals with ASD exhibited lower local connectivity in sensory processing brain regions and higher local connectivity in complex information processing regions. Further, higher local connectivity in ASD corresponded to more severe ASD symptomatology. These results demonstrate that local connectivity is disrupted in ASD across development, with the most pronounced differences occurring in childhood. Developmental changes in ReHo do not mirror findings from fMRI studies of long-range connectivity in ASD, pointing to a need for more nuanced accounts of brain connectivity alterations in the disorder. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Zinc in Gut-Brain Interaction in Autism and Neurological Disorders

PubMed Central

Vela, Guillermo; Stark, Peter; Socha, Michael; Sauer, Ann Katrin; Hagmeyer, Simone; Grabrucker, Andreas M.

2015-01-01

A growing amount of research indicates that abnormalities in the gastrointestinal (GI) system during development might be a common factor in multiple neurological disorders and might be responsible for some of the shared comorbidities seen among these diseases. For example, many patients with Autism Spectrum Disorder (ASD) have symptoms associated with GI disorders. Maternal zinc status may be an important factor given the multifaceted effect of zinc on gut development and morphology in the offspring. Zinc status influences and is influenced by multiple factors and an interdependence of prenatal and early life stress, immune system abnormalities, impaired GI functions, and zinc deficiency can be hypothesized. In line with this, systemic inflammatory events and prenatal stress have been reported to increase the risk for ASD. Thus, here, we will review the current literature on the role of zinc in gut formation, a possible link between gut and brain development in ASD and other neurological disorders with shared comorbidities, and tie in possible effects on the immune system. Based on these data, we present a novel model outlining how alterations in the maternal zinc status might pathologically impact the offspring leading to impairments in brain functions later in life. PMID:25878905

Zinc in gut-brain interaction in autism and neurological disorders.

PubMed

Vela, Guillermo; Stark, Peter; Socha, Michael; Sauer, Ann Katrin; Hagmeyer, Simone; Grabrucker, Andreas M

2015-01-01

A growing amount of research indicates that abnormalities in the gastrointestinal (GI) system during development might be a common factor in multiple neurological disorders and might be responsible for some of the shared comorbidities seen among these diseases. For example, many patients with Autism Spectrum Disorder (ASD) have symptoms associated with GI disorders. Maternal zinc status may be an important factor given the multifaceted effect of zinc on gut development and morphology in the offspring. Zinc status influences and is influenced by multiple factors and an interdependence of prenatal and early life stress, immune system abnormalities, impaired GI functions, and zinc deficiency can be hypothesized. In line with this, systemic inflammatory events and prenatal stress have been reported to increase the risk for ASD. Thus, here, we will review the current literature on the role of zinc in gut formation, a possible link between gut and brain development in ASD and other neurological disorders with shared comorbidities, and tie in possible effects on the immune system. Based on these data, we present a novel model outlining how alterations in the maternal zinc status might pathologically impact the offspring leading to impairments in brain functions later in life.

Chronic Stress in Adolescents and Its Neurobiological and Psychopathological Consequences: An RDoC Perspective.

PubMed

Sheth, Chandni; McGlade, Erin; Yurgelun-Todd, Deborah

2017-01-01

The Research Domain Criteria (RDoC) initiative provides a strategy for classifying psychopathology based on behavioral dimensions and neurobiological measures. Neurodevelopment is an orthogonal dimension in the current RDoC framework; however, it has not yet been fully incorporated into the RDoC approach. A combination of both a neurodevelopmental and RDoC approach offers a multidimensional perspective for understanding the emergence of psychopathology during development. Environmental influence (e.g., stress) has a profound impact on the risk for development of psychiatric illnesses. It has been shown that chronic stress interacts with the developing brain, producing significant changes in neural circuits that eventually increase the susceptibility for development of psychiatric disorders. This review highlights effects of chronic stress on the adolescent brain, as adolescence is a period characterized by a combination of significant brain alterations, high levels of stress, and emergence of psychopathology. The literature synthesized in this review suggests that chronic stress-induced changes in neurobiology and behavioral constructs underlie the shared vulnerability across a number of disorders in adolescence. The review particularly focuses on depression and substance use disorders; however, a similar argument can also be made for other psychopathologies, including anxiety disorders. The summarized findings underscore the need for a framework to integrate neurobiological findings from disparate psychiatric disorders and to target transdiagnostic mechanisms across disorders.

A role for the serotonin reuptake transporter in the brain and intestinal features of autism spectrum disorders and developmental antidepressant exposure.

PubMed

Margolis, Kara Gross

2017-10-01

Many disease conditions considered CNS-predominant harbor significant intestinal comorbidities. Serotonin (5-HT) and the serotonin reuptake transporter (SERT) have increasingly been shown to play important roles in both brain and intestinal development and long-term function. 5-HT and SERT may thus modulate critical functions in the development and perpetuation of brain-gut axis disease. We discuss the potential roles of 5-HT and SERT in the brain and intestinal manifestations of autism spectrum disorders and developmental antidepressant exposure. The potential therapeutic value of 5-HT 4 modulation in the subsequent treatment of these conditions is also addressed. Copyright © 2017 Elsevier B.V. All rights reserved.

Emerging Roles of BAI Adhesion-GPCRs in Synapse Development and Plasticity.

PubMed

Duman, Joseph G; Tu, Yen-Kuei; Tolias, Kimberley F

2016-01-01

Synapses mediate communication between neurons and enable the brain to change in response to experience, which is essential for learning and memory. The sites of most excitatory synapses in the brain, dendritic spines, undergo rapid remodeling that is important for neural circuit formation and synaptic plasticity. Abnormalities in synapse and spine formation and plasticity are associated with a broad range of brain disorders, including intellectual disabilities, autism spectrum disorders (ASD), and schizophrenia. Thus, elucidating the mechanisms that regulate these neuronal processes is critical for understanding brain function and disease. The brain-specific angiogenesis inhibitor (BAI) subfamily of adhesion G-protein-coupled receptors (adhesion-GPCRs) has recently emerged as central regulators of synapse development and plasticity. In this review, we will summarize the current knowledge regarding the roles of BAIs at synapses, highlighting their regulation, downstream signaling, and physiological functions, while noting the roles of other adhesion-GPCRs at synapses. We will also discuss the relevance of BAIs in various neurological and psychiatric disorders and consider their potential importance as pharmacological targets in the treatment of these diseases.

Differential Fairness Decisions and Brain Responses after Expressed Emotions of Others in Boys with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Klapwijk, Eduard T.; Aghajani, Moji; Lelieveld, Gert-Jan; van Lang, Natasja D. J.; Popma, Arne; van der Wee, Nic J. A.; Colins, Olivier F.; Vermeiren, Robert R. J. M.

2017-01-01

Little is known about how emotions expressed by others influence social decisions and associated brain responses in autism spectrum disorders (ASD). We investigated the neural mechanisms underlying fairness decisions in response to explicitly expressed emotions of others in boys with ASD and typically developing (TD) boys. Participants with ASD…

Imaging functional and structural brain connectomics in attention-deficit/hyperactivity disorder.

PubMed

Cao, Miao; Shu, Ni; Cao, Qingjiu; Wang, Yufeng; He, Yong

2014-12-01

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopment disorders in childhood. Clinically, the core symptoms of this disorder include inattention, hyperactivity, and impulsivity. Previous studies have documented that these behavior deficits in ADHD children are associated with not only regional brain abnormalities but also changes in functional and structural connectivity among regions. In the past several years, our understanding of how ADHD affects the brain's connectivity has been greatly advanced by mapping topological alterations of large-scale brain networks (i.e., connectomes) using noninvasive neurophysiological and neuroimaging techniques (e.g., electroencephalograph, functional MRI, and diffusion MRI) in combination with graph theoretical approaches. In this review, we summarize the recent progresses of functional and structural brain connectomics in ADHD, focusing on graphic analysis of large-scale brain systems. Convergent evidence suggests that children with ADHD had abnormal small-world properties in both functional and structural brain networks characterized by higher local clustering and lower global integrity, suggesting a disorder-related shift of network topology toward regular configurations. Moreover, ADHD children showed the redistribution of regional nodes and connectivity involving the default-mode, attention, and sensorimotor systems. Importantly, these ADHD-associated alterations significantly correlated with behavior disturbances (e.g., inattention and hyperactivity/impulsivity symptoms) and exhibited differential patterns between clinical subtypes. Together, these connectome-based studies highlight brain network dysfunction in ADHD, thus opening up a new window into our understanding of the pathophysiological mechanisms of this disorder. These works might also have important implications on the development of imaging-based biomarkers for clinical diagnosis and treatment evaluation in ADHD.

Multivariate analyses applied to fetal, neonatal and pediatric MRI of neurodevelopmental disorders

PubMed Central

Levman, Jacob; Takahashi, Emi

2015-01-01

Multivariate analysis (MVA) is a class of statistical and pattern recognition methods that involve the processing of data that contains multiple measurements per sample. MVA can be used to address a wide variety of medical neuroimaging-related challenges including identifying variables associated with a measure of clinical importance (i.e. patient outcome), creating diagnostic tests, assisting in characterizing developmental disorders, understanding disease etiology, development and progression, assisting in treatment monitoring and much more. Compared to adults, imaging of developing immature brains has attracted less attention from MVA researchers. However, remarkable MVA research growth has occurred in recent years. This paper presents the results of a systematic review of the literature focusing on MVA technologies applied to neurodevelopmental disorders in fetal, neonatal and pediatric magnetic resonance imaging (MRI) of the brain. The goal of this manuscript is to provide a concise review of the state of the scientific literature on studies employing brain MRI and MVA in a pre-adult population. Neurological developmental disorders addressed in the MVA research contained in this review include autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, schizophrenia and more. While the results of this review demonstrate considerable interest from the scientific community in applications of MVA technologies in pediatric/neonatal/fetal brain MRI, the field is still young and considerable research growth remains ahead of us. PMID:26640765

Multivariate analyses applied to fetal, neonatal and pediatric MRI of neurodevelopmental disorders.

PubMed

Levman, Jacob; Takahashi, Emi

2015-01-01

Multivariate analysis (MVA) is a class of statistical and pattern recognition methods that involve the processing of data that contains multiple measurements per sample. MVA can be used to address a wide variety of medical neuroimaging-related challenges including identifying variables associated with a measure of clinical importance (i.e. patient outcome), creating diagnostic tests, assisting in characterizing developmental disorders, understanding disease etiology, development and progression, assisting in treatment monitoring and much more. Compared to adults, imaging of developing immature brains has attracted less attention from MVA researchers. However, remarkable MVA research growth has occurred in recent years. This paper presents the results of a systematic review of the literature focusing on MVA technologies applied to neurodevelopmental disorders in fetal, neonatal and pediatric magnetic resonance imaging (MRI) of the brain. The goal of this manuscript is to provide a concise review of the state of the scientific literature on studies employing brain MRI and MVA in a pre-adult population. Neurological developmental disorders addressed in the MVA research contained in this review include autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, schizophrenia and more. While the results of this review demonstrate considerable interest from the scientific community in applications of MVA technologies in pediatric/neonatal/fetal brain MRI, the field is still young and considerable research growth remains ahead of us.

Leptin and the brain: influences on brain development, cognitive functioning and psychiatric disorders.

PubMed

Farr, Olivia M; Tsoukas, Michael A; Mantzoros, Christos S

2015-01-01

Receptors of leptin, the prototypical adipokine, are expressed throughout the cortex and several other areas of the brain. Although typically studied for its role in energy intake and expenditure, leptin plays a critical role in many other neurocognitive processes and interacts with various other hormones and neurotransmitters to perform these functions. Here, we review the literature on how leptin influences brain development, neural degradation, Alzheimer's disease, psychiatric disorders, and more complicated cognitive functioning and feeding behaviors. We also discuss modulators of leptin and the leptin receptor as they relate to normal cognitive functioning and may mediate some of the actions of leptin in the brain. Although we are beginning to better understand the critical role leptin plays in normal cognitive functioning, there is much to be discovered. Copyright © 2015 Elsevier Inc. All rights reserved.

The social brain in psychiatric and neurological disorders

PubMed Central

Kennedy, Daniel P.; Adolphs, Ralph

2013-01-01

Psychiatric and neurological disorders have historically provided key insights into the structure-function relationships that subserve human social cognition and behavior, informing the concept of the ‘social brain’. In this review, we take stock of the current status of this concept, retaining a focus on disorders that impact social behavior. We discuss how the social brain, social cognition, and social behavior are interdependent, and emphasize the important role of development and compensation. We suggest that the social brain, and its dysfunction and recovery, must be understood not in terms of specific structures, but rather in terms of their interaction in large-scale networks. PMID:23047070

Schizophrenia and the neurodevelopmental continuum:evidence from genomics

PubMed Central

Owen, Michael J.; O'Donovan, Michael C.

2017-01-01

The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention‐deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as “neurodevelopmental disorders”. An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research. PMID:28941101

Early executive function deficit in preterm children and its association with neurodevelopmental disorders in childhood: a literature review.

PubMed

Sun, Jing; Buys, Nicholas

2012-01-01

The purpose of this study is to examine the association of deficits of executive function (EF) and neurodevelopmental disorders in preterm children and the potential of assessing EF in infants as means of early identification. EF refers to a collection of related but somewhat discrete abilities, the main ones being working memory, inhibition, and planning. There is a general consensus that EF governs goal-directed behavior that requires holding those plans or programs on-line until executed, inhibiting irrelevant action and planning a sequence of actions. EF plays an essential role in cognitive development and is vital to individual social and intellectual success. Most researchers believe in the coordination and integrate cognitive-perceptual processes in relation to time and space, thus regulating higher-order cognitive processes, such as problem solving, reasoning, logical and flexible thinking, and decision-making. The importance of the maturation of the frontal lobe, particularly the prefrontal cortex, to the development of EF in childhood has been emphasized. Therefore, any abnormal development in the prefrontal lobes of infants and children could be expected to result in significant deficits in cognitive functioning. As this is a late-maturing part of the brain, various neurodevelopmental disorders, such as autism spectrum disorders, attention deficit hyperactivity disorder, language disorders, and schizophrenia, as well as acquired disorders of the right brain (and traumatic brain injury) impair EF, and the prefrontal cortex may be particularly susceptible to delayed development in these populations. The deficits of EF in infants are persistent into childhood and related to neurodevelopmental disorders in childhood and adolescence.

The Role of BDNF in the Development of Fear Learning.

PubMed

Dincheva, Iva; Lynch, Niccola B; Lee, Francis S

2016-10-01

Brain-derived neurotrophic factor (BDNF) is a growth factor that is dynamically expressed in the brain across postnatal development, regulating neuronal differentiation and synaptic plasticity. The neurotrophic hypothesis of psychiatric mood disorders postulates that in the adult brain, decreased BDNF levels leads to altered neural plasticity, contributing to disease. Although BDNF has been established as a key factor regulating the critical period plasticity in the developing visual system, it has recently been shown to also play a role in fear circuitry maturation, which has implications for the emergence of fear-related mood disorders. This review provides a detailed overview of developmental changes in expression of BDNF isoforms, as well as their receptors across postnatal life. In addition, recent developmental studies utilizing a genetic BDNF single nucleotide polymorphism (Val66Met) knock-in mouse highlight the impact of BDNF on fear learning during a sensitive period spanning the transition into adolescent time frame. We hypothesize that BDNF in the developing brain regulates fear circuit plasticity during a sensitive period in early adolescence, and alterations in BDNF expression (genetic or environmental) have a persistent impact on fear behavior and fear-related disorders. © 2016 Wiley Periodicals, Inc.

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.

Multimodal Approaches to Define Network Oscillations in Depression

PubMed Central

Smart, Otis Lkuwamy; Tiruvadi, Vineet Ravi; Mayberg, Helen S.

2018-01-01

The renaissance in the use of encephalography-based research methods to probe the pathophysiology of neuropsychiatric disorders is well afoot and continues to advance. Building on the platform of neuroimaging evidence on brain circuit models, magnetoencephalography, scalp electroencephalography, and even invasive electroencephalography are now being used to characterize brain network dysfunctions that underlie major depressive disorder using brain oscillation measurements and associated treatment responses. Such multiple encephalography modalities provide avenues to study pathologic network dynamics with high temporal resolution and over long time courses, opportunities to complement neuroimaging methods and findings, and new approaches to identify quantitative biomarkers that indicate critical targets for brain therapy. Such goals have been facilitated by the ongoing testing of novel invasive neuromodulation therapies, notably, deep brain stimulation, where clinically relevant treatment effects can be monitored at multiple brain sites in a time-locked causal manner. We review key brain rhythms identified in major depressive disorder as foundation for development of putative biomarkers for objectively evaluating neuromodulation success and for guiding deep brain stimulation or other target-based neuromodulation strategies for treatment-resistant depression patients. PMID:25681871

A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders.

PubMed

Reinhard, Sarah M; Razak, Khaleel; Ethell, Iryna M

2015-01-01

The extracellular matrix (ECM) is a critical regulator of neural network development and plasticity. As neuronal circuits develop, the ECM stabilizes synaptic contacts, while its cleavage has both permissive and active roles in the regulation of plasticity. Matrix metalloproteinase 9 (MMP-9) is a member of a large family of zinc-dependent endopeptidases that can cleave ECM and several cell surface receptors allowing for synaptic and circuit level reorganization. It is becoming increasingly clear that the regulated activity of MMP-9 is critical for central nervous system (CNS) development. In particular, MMP-9 has a role in the development of sensory circuits during early postnatal periods, called 'critical periods.' MMP-9 can regulate sensory-mediated, local circuit reorganization through its ability to control synaptogenesis, axonal pathfinding and myelination. Although activity-dependent activation of MMP-9 at specific synapses plays an important role in multiple plasticity mechanisms throughout the CNS, misregulated activation of the enzyme is implicated in a number of neurodegenerative disorders, including traumatic brain injury, multiple sclerosis, and Alzheimer's disease. Growing evidence also suggests a role for MMP-9 in the pathophysiology of neurodevelopmental disorders including Fragile X Syndrome. This review outlines the various actions of MMP-9 during postnatal brain development, critical for future studies exploring novel therapeutic strategies for neurodevelopmental disorders.

Identification of autism spectrum disorder using deep learning and the ABIDE dataset.

PubMed

Heinsfeld, Anibal Sólon; Franco, Alexandre Rosa; Craddock, R Cameron; Buchweitz, Augusto; Meneguzzi, Felipe

2018-01-01

The goal of the present study was to apply deep learning algorithms to identify autism spectrum disorder (ASD) patients from large brain imaging dataset, based solely on the patients brain activation patterns. We investigated ASD patients brain imaging data from a world-wide multi-site database known as ABIDE (Autism Brain Imaging Data Exchange). ASD is a brain-based disorder characterized by social deficits and repetitive behaviors. According to recent Centers for Disease Control data, ASD affects one in 68 children in the United States. We investigated patterns of functional connectivity that objectively identify ASD participants from functional brain imaging data, and attempted to unveil the neural patterns that emerged from the classification. The results improved the state-of-the-art by achieving 70% accuracy in identification of ASD versus control patients in the dataset. The patterns that emerged from the classification show an anticorrelation of brain function between anterior and posterior areas of the brain; the anticorrelation corroborates current empirical evidence of anterior-posterior disruption in brain connectivity in ASD. We present the results and identify the areas of the brain that contributed most to differentiating ASD from typically developing controls as per our deep learning model.

Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder.

PubMed

Forbes, Erika E; Hariri, Ahmad R; Martin, Samantha L; Silk, Jennifer S; Moyles, Donna L; Fisher, Patrick M; Brown, Sarah M; Ryan, Neal D; Birmaher, Boris; Axelson, David A; Dahl, Ronald E

2009-01-01

Alterations in reward-related brain function and phenomenological aspects of positive affect are increasingly examined in the development of major depressive disorder. The authors tested differences in reward-related brain function in healthy and depressed adolescents, and the authors examined direct links between reward-related brain function and positive mood that occurred in real-world contexts. Fifteen adolescents with major depressive disorder and 28 adolescents with no history of psychiatric disorder, ages 8-17 years, completed a functional magnetic resonance imaging guessing task involving monetary reward. Participants also reported their subjective positive affect in natural environments during a 4-day cell-phone-based ecological momentary assessment. Adolescents with major depressive disorder exhibited less striatal response than healthy comparison adolescents during reward anticipation and reward outcome, but more response in dorsolateral and medial prefrontal cortex. Diminished activation in a caudate region associated with this depression group difference was correlated with lower subjective positive affect in natural environments, particularly within the depressed group. Results support models of altered reward processing and related positive affect in young people with major depressive disorder and indicate that depressed adolescents' brain response to monetary reward is related to their affective experience in natural environments. Additionally, these results suggest that reward-processing paradigms capture brain function relevant to real-world positive affect.

Morphometric brain abnormalities in boys with conduct disorder.

PubMed

Huebner, Thomas; Vloet, Timo D; Marx, Ivo; Konrad, Kerstin; Fink, Gereon R; Herpertz, Sabine C; Herpertz-Dahlmann, Beate

2008-05-01

Children with the early-onset type of conduct disorder (CD) are at high risk for developing an antisocial personality disorder. Although there have been several neuroimaging studies on morphometric differences in adults with antisocial personality disorder, little is known about structural brain aberrations in boys with CD. Magnetic resonance imaging and voxel-based morphometry were used to assess abnormalities in gray matter volumes in 23 boys ages 12 to 17 years with CD (17 comorbid for attention-deficit/hyperactivity disorder) in comparison with age- and IQ-matched controls. Compared with healthy controls, mean gray matter volume was 6% smaller in the clinical group. Compared with controls, reduced gray matter volumes were found in the left orbitofrontal region and bilaterally in the temporal lobes, including the amygdala and hippocampus on the left side in the CD group. Regression analyses in the clinical group indicated an inverse association of hyperactive/impulsive symptoms and widespread gray matter abnormalities in the frontoparietal and temporal cortices. By contrast, CD symptoms correlated primarily with gray matter reductions in limbic brain structures. The data suggest that boys with CD and comorbid attention-deficit/hyperactivity disorder show brain abnormalities in frontolimbic areas that resemble structural brain deficits, which are typically observed in adults with antisocial behavior.

Development of visual-motor perception in pupils with expressive writing disorder and pupils without expressive writing disorder: a comparative statistical analysis.

PubMed

Mesrahi, Tahereh; Sedighi, Mohammadreza

2013-08-01

Learning disability is one of the most noticed subjects for behavioral specialists. Most of thelearning difficulties are caused by senso-motor development and neurological organization. The main purposeof the present research is to examine the role of delayed perceptual-motor development and brain damage inorigination of expressive writing disorder (EWD). The studied sample is 89 pupils divided into two groups, one of which is pupils with expressivewriting disorder (n=43) and the other is pupils without expressive writing disorder (n=46), consisted of secondand third grade elementary school students. First of all, students with EWD are selected through dictation testand intelligence test, and then the two groups, students with and without EWD, would take the Bender Gestalttest. The average score of perceptual visual-motor development and brain damage of two groups is comparedusing T test for independent groups and χ2 test. Results show that there is a significant difference in perceptual visual-motor development betweenstudents with EWD and students without EWD (p<0.01). Based on the results, perceptual-motor development ofstudents with EWD is lower than students without EWD. There is no significant difference in brain damagebetween those with EWD and healthy people, (p> 0.05). Based on our findings it could be concluded that those who are relatively more developed thantheir peers, in terms of visual-motor perception, are more successful in education, especially in expressive writing.

Neurodevelopmental Versus Neurodegenerative Model of Schizophrenia and Bipolar Disorder: Comparison with Physiological Brain Development and Aging.

PubMed

Buoli, Massimiliano; Serati, Marta; Caldiroli, Alice; Cremaschi, Laura; Altamura, Alfredo Carlo

2017-03-01

Available data support a contribution of both neurodevelopmental and neurodegenerative factors in the etiology of schizophrenia (SCH) and bipolar disorder (BD). Of note, one of the most important issue of the current psychiatric research is to identify the specific factors that contribute to impaired brain development and neurodegeneration in SCH and BD, and especially how these factors alter normal brain development and physiological aging process. Our hypothesis is that only specific damages, taking place in precise brain development stages, are associated with future SCH /BD onset and that neurodegeneration consists of an acceleration of brain aging after SCH /BD onset. In support of our hypothesis, the results of the present narrative mini-review shows as neurodevelopmental damages generally contribute to neuropsychiatric syndromes (e.g. hypothyroidism or treponema pallidum), but only some of them are specifically associated with adult SCH and BD (e.g. toxoplasma or substance abuse), particularly if they happen in specific stages of brain development. On the other hand, cognitive impairment and brain changes, associated with long duration of SCH /BD, look like what happens during aging: memory, executive domains and prefrontal cortex are implicated both in aging and in SCH /BD progression. Future research will explore possible validity of this etiological model for SCH and BD.

Advances in Electrophysiological Research

PubMed Central

Kamarajan, Chella; Porjesz, Bernice

2015-01-01

Electrophysiological measures of brain function are effective tools to understand neurocognitive phenomena and sensitive indicators of pathophysiological processes associated with various clinical conditions, including alcoholism. Individuals with alcohol use disorder (AUD) and their high-risk offspring have consistently shown dysfunction in several electrophysiological measures in resting state (i.e., electroencephalogram) and during cognitive tasks (i.e., event-related potentials and event-related oscillations). Researchers have recently developed sophisticated signal-processing techniques to characterize different aspects of brain dynamics, which can aid in identifying the neural mechanisms underlying alcoholism and other related complex disorders. These quantitative measures of brain function also have been successfully used as endophenotypes to identify and help understand genes associated with AUD and related disorders. Translational research also is examining how brain electrophysiological measures potentially can be applied to diagnosis, prevention, and treatment. PMID:26259089

The Multidimensional Therapeutic Potential of Targeting the Brain Oxytocin System for the Treatment of Substance Use Disorders.

PubMed

Bowen, Michael T; Neumann, Inga D

2017-09-24

The neuropeptide oxytocin is released both into the blood and within the brain in response to reproductive stimuli, such as birth, suckling and sex, but also in response to social interaction and stressors. Substance use disorders, or addictions, are chronic, relapsing brain disorders and are one of the major causes of global burden of disease. Unfortunately, current treatment options for substance use disorders are extremely limited and a treatment breakthrough is sorely needed. There is mounting preclinical evidence that targeting the brain oxytocin system may provide that breakthrough. Substance use disorders are characterised by a viscous cycle of bingeing and intoxication, followed by withdrawal and negative affect, and finally preoccupation and anticipation that triggers relapse and further consumption. Administration of oxytocin has been shown to have a potential therapeutic benefit at each stage of this addiction cycle for numerous drugs of abuse. This multidimensional therapeutic utility is likely due to oxytocin's interactions with key biological systems that underlie the development and maintenance of addiction. Only a few human trials of oxytocin in addicted populations have been completed with the results thus far being mixed. There are numerous other trials underway, and the results are eagerly awaited. However, the ability to fully harness the potential therapeutic benefit of targeting the brain oxytocin system may depend on the development of molecules that selectively stimulate the oxytocin system, but that have superior pharmacokinetic properties to oxytocin itself.

Developmental and perinatal brain diseases.

PubMed

Adle-Biassette, Homa; Golden, Jeffery A; Harding, Brian

2017-01-01

This chapter briefly describes the normal development of the nervous system, the neuropathology and pathophysiology of acquired and secondary disorders affecting the embryo, fetus, and child. They include CNS manifestations of chromosomal change; forebrain patterning defects; disorders of the brain size; cell migration and specification disorders; cerebellum, hindbrain and spinal patterning defects; hydrocephalus; secondary malformations and destructive pathologies; vascular malformations; arachnoid cysts and infectious diseases. The distinction between malformations and disruptions is important for pathogenesis and genetic counseling. Copyright © 2017 Elsevier B.V. All rights reserved.

[Brain imaging in autism spectrum disorders. A review].

PubMed

Dziobek, I; Köhne, S

2011-05-01

In the past two decades, an increasing number of functional and structural brain imaging studies has provided insights into the neurobiological basis of autism spectrum disorders (ASD). This article summarizes pertinent functional brain imaging studies addressing the neuronal underpinnings of ASD symptomatology (impairments in social interaction and communication, repetitive and restrictive behavior) and associated neuropsychological deficits (theory of mind, executive functions, central coherence), complemented by relevant structural imaging findings. The results of these studies show that although cognitive functions in ASD are generally mediated by the same brain regions as in typically developed individuals, the degree and especially the patterns of brain activation often differ. Therefore, a hypothesis of aberrant network connectivity has increasingly been favored over one of focal brain dysfunction.

[Developmental neurotoxicity of industrial chemicals].

PubMed

Labie, Dominique

2007-10-01

"A Silent Pandemic : Industrial Chemicals Are Impairing the Brain Development of Children Worldwide" Fetal and early childhood exposures to industrial chemicals in the environment can damage the developing brain and can lead to neurodevelopmental disorders (NDDs)--autism, attention deficit disorder (ADHD), and mental retardation. In a new review study, published in The Lancet, Philip Grandjean and Philip Landrigan from the Harvard School of Public Health systematically examined publicly available data on chemical toxicity in order to identify the industrial chemicals that are the most likely to damage the developing brain. The researchers found that 202 industrial chemicals have the capacity to damage the human brain, and they conclude that chemical pollution may have harmed the brains of millions of children worldwide. The authors conclude further that the toxic effects of industrial chemicals on children have generally been overlooked. In North Amercia, the commission for environmental cooperation, and in European Union the DEVNERTOX projects had reached to the same conclusions. We analyse this review and discuss these rather pessimistic conclusions.

Face processing in autism spectrum disorders: from brain regions to brain networks

PubMed Central

Nomi, Jason S.; Uddin, Lucina Q.

2015-01-01

Autism spectrum disorder (ASD) is characterized by reduced attention to social stimuli including the human face. This hypo-responsiveness to stimuli that are engaging to typically developing individuals may result from dysfunctioning motivation, reward, and attention systems in the brain. Here we review an emerging neuroimaging literature that emphasizes a shift from focusing on hypo-activation of isolated brain regions such as the fusiform gyrus, amygdala, and superior temporal sulcus in ASD to a more holistic approach to understanding face perception as a process supported by distributed cortical and subcortical brain networks. We summarize evidence for atypical activation patterns within brain networks that may contribute to social deficits characteristic of the disorder. We conclude by pointing to gaps in the literature and future directions that will continue to shed light on aspects of face processing in autism that are still under-examined. In particular, we highlight the need for more developmental studies and studies examining ecologically valid and naturalistic social stimuli. PMID:25829246

In Vitro Cerebrovascular Modeling in the 21st Century: Current and Prospective Technologies

PubMed Central

Palmiotti, Christopher A.; Prasad, Shikha; Naik, Pooja; Abul, Kaisar MD; Sajja, Ravi K.; Achyuta, Anilkumar H.; Cucullo, Luca

2014-01-01

The blood-brain barrier (BBB) maintains the brain homeostasis and dynamically responds to events associated with systemic and/or rheological impairments (e.g., inflammation, ischemia) including the exposure to harmful xenobiotics. Thus, understanding the BBB physiology is crucial for the resolution of major central nervous system CNS) disorders challenging both health care providers and the pharmaceutical industry. These challenges include drug delivery to the brain, neurological disorders, toxicological studies, and biodefense. Studies aimed at advancing our understanding of CNS diseases and promoting the development of more effective therapeutics are primarily performed in laboratory animals. However, there are major hindering factors inherent to in vivo studies such as cost, limited throughput and translational significance to humans. These factors promoted the development of alternative in vitro strategies for studying the physiology and pathophysiology of the BBB in relation to brain disorders as well as screening tools to aid in the development of novel CNS drugs. Herein, we provide a detailed review including pros and cons of current and prospective technologies for modelling the BBB in vitro including ex situ, cell based and computational (in silico) models. A special section is dedicated to microfluidic systems including micro-BBB, BBB-on-a-chip, Neurovascular Unit-on-a-Chip and Synthetic Microvasculature Blood-Brain Barrier. PMID:25098812

In vitro cerebrovascular modeling in the 21st century: current and prospective technologies.

PubMed

Palmiotti, Christopher A; Prasad, Shikha; Naik, Pooja; Abul, Kaisar M D; Sajja, Ravi K; Achyuta, Anilkumar H; Cucullo, Luca

2014-12-01

The blood-brain barrier (BBB) maintains the brain homeostasis and dynamically responds to events associated with systemic and/or rheological impairments (e.g., inflammation, ischemia) including the exposure to harmful xenobiotics. Thus, understanding the BBB physiology is crucial for the resolution of major central nervous system CNS) disorders challenging both health care providers and the pharmaceutical industry. These challenges include drug delivery to the brain, neurological disorders, toxicological studies, and biodefense. Studies aimed at advancing our understanding of CNS diseases and promoting the development of more effective therapeutics are primarily performed in laboratory animals. However, there are major hindering factors inherent to in vivo studies such as cost, limited throughput and translational significance to humans. These factors promoted the development of alternative in vitro strategies for studying the physiology and pathophysiology of the BBB in relation to brain disorders as well as screening tools to aid in the development of novel CNS drugs. Herein, we provide a detailed review including pros and cons of current and prospective technologies for modelling the BBB in vitro including ex situ, cell based and computational (in silico) models. A special section is dedicated to microfluidic systems including micro-BBB, BBB-on-a-chip, Neurovascular Unit-on-a-Chip and Synthetic Microvasculature Blood-brain Barrier.

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.

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.

Gaining Insight of Fetal Brain Development with Diffusion MRI and Histology

PubMed Central

Huang, Hao; Vasung, Lana

2013-01-01

Human brain is extraordinarily complex and yet its origin is a simple tubular structure. Its development during the fetal period is characterized by a series of accurately organized events which underlie the mechanisms of dramatic structural changes during fetal development. Revealing detailed anatomy at different stages of human fetal brain development provides insight on understanding not only this highly ordered process, but also the neurobiological foundations of cognitive brain disorders such as mental retardation, autism, schizophrenia, bipolar and language impairment. Diffusion tensor imaging (DTI) and histology are complementary tools which are capable of delineating the fetal brain structures at both macroscopic and microscopic level. In this review, the structural development of the fetal brains has been characterized with DTI and histology. Major components of the fetal brain, including cortical plate, fetal white matter and cerebral wall layer between the ventricle and subplate, have been delineated with DTI and histology. Anisotropic metrics derived from DTI were used to quantify the microstructural changes during the dynamic process of human fetal cortical development and prenatal development of other animal models. Fetal white matter pathways have been traced with DTI-based tractography to reveal growth patterns of individual white matter tracts and corticocortical connectivity. These detailed anatomical accounts of the structural changes during fetal period may provide the clues of detecting developmental and cognitive brain disorders at their early stages. The anatomical information from DTI and histology may also provide reference standards for diagnostic radiology of premature newborns. PMID:23796901

Hepatic Encephalopathy

MedlinePlus Videos and Cool Tools

... Now Hepatic Encephalopathy Back Hepatic Encephalopathy is a brain disorder that develops in some individuals with liver ... is a condition that causes temporary worsening of brain function in people with advanced liver disease. When ...

Temporal Lobe and “Default” Hemodynamic Brain Modes Discriminate Between Schizophrenia and Bipolar Disorder

PubMed Central

Calhoun, Vince D.; Maciejewski, Paul K.; Pearlson, Godfrey D.; Kiehl, Kent A.

2009-01-01

Schizophrenia and bipolar disorder are currently diagnosed on the basis of psychiatric symptoms and longitudinal course. The determination of a reliable, biologically-based diagnostic indicator of these diseases (a biomarker) could provide the groundwork for developing more rigorous tools for differential diagnosis and treatment assignment. Recently, methods have been used to identify distinct sets of brain regions or “spatial modes” exhibiting temporally coherent brain activity. Using functional magnetic resonance imaging (fMRI) data and a multivariate analysis method, independent component analysis, we combined the temporal lobe and the default modes to discriminate subjects with bipolar disorder, chronic schizophrenia, and healthy controls. Temporal lobe and default mode networks were reliably identified in all participants. Classification results on an independent set of individuals revealed an average sensitivity and specificity of 90 and 95%, respectively. The use of coherent brain networks such as the temporal lobe and default mode networks may provide a more reliable measure of disease state than task-correlated fMRI activity. A combination of two such hemodynamic brain networks shows promise as a biomarker for schizophrenia and bipolar disorder. PMID:17894392

Temporal lobe and "default" hemodynamic brain modes discriminate between schizophrenia and bipolar disorder.

PubMed

Calhoun, Vince D; Maciejewski, Paul K; Pearlson, Godfrey D; Kiehl, Kent A

2008-11-01

Schizophrenia and bipolar disorder are currently diagnosed on the basis of psychiatric symptoms and longitudinal course. The determination of a reliable, biologically-based diagnostic indicator of these diseases (a biomarker) could provide the groundwork for developing more rigorous tools for differential diagnosis and treatment assignment. Recently, methods have been used to identify distinct sets of brain regions or "spatial modes" exhibiting temporally coherent brain activity. Using functional magnetic resonance imaging (fMRI) data and a multivariate analysis method, independent component analysis, we combined the temporal lobe and the default modes to discriminate subjects with bipolar disorder, chronic schizophrenia, and healthy controls. Temporal lobe and default mode networks were reliably identified in all participants. Classification results on an independent set of individuals revealed an average sensitivity and specificity of 90 and 95%, respectively. The use of coherent brain networks such as the temporal lobe and default mode networks may provide a more reliable measure of disease state than task-correlated fMRI activity. A combination of two such hemodynamic brain networks shows promise as a biomarker for schizophrenia and bipolar disorder.

Absence of sex differences in mental rotation performance in autism spectrum disorder.

PubMed

Rohde, Melanie S; Georgescu, Alexandra L; Vogeley, Kai; Fimmers, Rolf; Falter-Wagner, Christine M

2017-08-01

Mental rotation is one of the most investigated cognitive functions showing consistent sex differences. The 'Extreme Male Brain' hypothesis attributes the cognitive profile of individuals with autism spectrum disorder to an extreme version of the male cognitive profile. Previous investigations focused almost exclusively on males with autism spectrum disorder with only limited implications for affected females. This study is the first testing a sample of 12 female adults with high-functioning autism spectrum disorder compared to 14 males with autism spectrum disorder, 12 typically developing females and 14 typically developing males employing a computerised version of the mental rotation test. Reaction time and accuracy served as dependent variables. Their linear relationship with degree of rotation allows separation of rotational aspects of the task, indicated by slopes of the psychometric function, and non-rotational aspects, indicated by intercepts of the psychometric function. While the typical and expected sex difference for rotational task aspects was corroborated in typically developing individuals, no comparable sex difference was found in autism spectrum disorder individuals. Autism spectrum disorder and typically developing individuals did not differ in mental rotation performance. This finding does not support the extreme male brain hypothesis of autism.

Maternal High-Fat Diet Programming of the Neuroendocrine System and Behavior

PubMed Central

Sullivan, Elinor L.; Riper, Kellie M.; Lockard, Rachel; Valleau, Jeanette C.

2015-01-01

Maternal obesity, metabolic state, and diet during gestation have profound effects on offspring development. The prevalence of neurodevelopmental and mental health disorders has risen rapidly in the last several decades in parallel with the rise in obesity rates. Evidence from epidemiological studies indicates that maternal obesity and metabolic complications increase the risk of offspring developing behavioral disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and schizophrenia. Animal models show that a maternal diet high in fat similarly disrupts behavioral programming of offspring, with animals showing social impairments, increased anxiety and depressive behaviors, reduced cognitive development, and hyperactivity. Maternal obesity, metabolic conditions, and high fat diet consumption increase maternal leptin, insulin, glucose, triglycerides, and inflammatory cytokines. This leads to increased risk of placental dysfunction, and altered fetal neuroendocrine development. Changes in brain development that likely contribute to the increased risk of behavioral and mental health disorders include increased inflammation in the brain, as well as alterations in the serotonergic system, dopaminergic system and hypothalamic pituitary adrenal (HPA) axis. PMID:25913366

The functional neuroanatomy of bipolar disorder: a consensus model

PubMed Central

Strakowski, Stephen M; Adler, Caleb M; Almeida, Jorge; Altshuler, Lori L; Blumberg, Hilary P; Chang, Kiki D; DelBello, Melissa P; Frangou, Sophia; McIntosh, Andrew; Phillips, Mary L; Sussman, Jessika E; Townsend, Jennifer D

2013-01-01

Objectives Functional neuroimaging methods have proliferated in recent years, such that functional magnetic resonance imaging, in particular, is now widely used to study bipolar disorder. However, discrepant findings are common. A workgroup was organized by the Department of Psychiatry, University of Cincinnati (Cincinnati, OH, USA) to develop a consensus functional neuroanatomic model of bipolar I disorder based upon the participants’ work as well as that of others. Methods Representatives from several leading bipolar disorder neuroimaging groups were organized to present an overview of their areas of expertise as well as focused reviews of existing data. The workgroup then developed a consensus model of the functional neuroanatomy of bipolar disorder based upon these data. Results Among the participants, a general consensus emerged that bipolar I disorder arises from abnormalities in the structure and function of key emotional control networks in the human brain. Namely, disruption in early development (e.g., white matter connectivity, prefrontal pruning) within brain networks that modulate emotional behavior leads to decreased connectivity among ventral prefrontal networks and limbic brain regions, especially amygdala. This developmental failure to establish healthy ventral prefrontal–limbic modulation underlies the onset of mania and ultimately, with progressive changes throughout these networks over time and with affective episodes, a bipolar course of illness. Conclusions This model provides a potential substrate to guide future investigations and areas needing additional focus are identified. PMID:22631617

The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.

PubMed

Chang, H; Hoshina, N; Zhang, C; Ma, Y; Cao, H; Wang, Y; Wu, D-D; Bergen, S E; Landén, M; Hultman, C M; Preisig, M; Kutalik, Z; Castelao, E; Grigoroiu-Serbanescu, M; Forstner, A J; Strohmaier, J; Hecker, J; Schulze, T G; Müller-Myhsok, B; Reif, A; Mitchell, P B; Martin, N G; Schofield, P R; Cichon, S; Nöthen, M M; Walter, H; Erk, S; Heinz, A; Amin, N; van Duijn, C M; Meyer-Lindenberg, A; Tost, H; Xiao, X; Yamamoto, T; Rietschel, M; Li, M

2018-02-01

Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.

Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

PubMed Central

2014-01-01

Background Repetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood. Results Here we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically. Conclusions Deep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models. PMID:24512669

Emotional Face Identification in Youths with Primary Bipolar Disorder or Primary Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Seymour, Karen E.; Pescosolido, Matthew F.; Reidy, Brooke L.; Galvan, Thania; Kim, Kerri L.; Young, Matthew; Dickstein, Daniel P.

2013-01-01

Objective: Bipolar disorder (BD) and attention-deficit/hyperactivity disorder (ADHD) are often comorbid or confounded; therefore, we evaluated emotional face identification to better understand brain/behavior interactions in children and adolescents with either primary BD, primary ADHD, or typically developing controls (TDC). Method: Participants…

Implementation and clinical characteristics of a posttraumatic stress disorder brain collection.

PubMed

Mighdoll, Michelle I; Deep-Soboslay, Amy; Bharadwaj, Rahul A; Cotoia, John A; Benedek, David M; Hyde, Thomas M; Kleinman, Joel E

2018-01-01

A postmortem human brain collection to study posttraumatic stress disorder (PTSD) is critical for uncovering the molecular mechanisms that contribute to this psychiatric disorder. We describe here the PTSD brain collection at the Lieber Institute for Brain Development in Baltimore, Maryland, consisting of postmortem brain donations acquired between 2012 and 2017. Thus far, 87 brains from individuals meeting DSM-5 criteria for PTSD were collected after consent was obtained from legal next-of-kin, and subsequently clinically characterized for molecular studies. PTSD brain donors had high rates of comorbid diagnoses, including depression (62.1%), substance abuse (74.7%), drug-related death (69.0%), and suicide completion (17.2%). PTSD cases were subdivided into two categories: combat-related PTSD (n = 24) and noncombat/domestic PTSD (n = 63). The major differences between the combat-related and domestic PTSD cohorts were sex, drug-related death, and the prevalence of bipolar disorder (BPD) comorbidity. The combat-related group was entirely male, with only one BPD subject (4.2%), and had significantly fewer drug-related deaths (45.8%) in contrast to the domestic group (31.8% male, 36.5% bipolar, and 77.8% drug-related deaths). Medical examiners' offices, particularly in areas with higher military populations, are an excellent source for PTSD brain donations of both combat-related and domestic PTSD. © 2017 Wiley Periodicals, Inc.

Development of minimally invasive surgery for intractable epilepsy

NASA Astrophysics Data System (ADS)

Yamakawa, Takeshi

2009-04-01

Epilepsy is a chronic brain disorder characterized by recurrent seizures. The seizure is shot down by the surgical removal of the region which is so called "epileptogenc focus". However, the accuracy to detect the focus is not good (order of cm). Thus the extirpation of focus with significant margin causes the removal of normal brain and leads to the severe aftereffects such as restricted vision, motor dysfunction, disorder of memory, and so on. To cope with this problem, we should develop the technology of (1) detecting the epileptogenic focus, and (2) necrotizing the epileptogenic focus excluding normal brain by (a) colliquative necrosis with flash freezing and melting or (b) cauterizing by focused laser beam.

Behavioural medicine and gastrointestinal disorders: the promise of positive psychology.

PubMed

Keefer, Laurie

2018-04-12

Psychosocial risk factors linked to brain-gut dysregulation are prevalent across the spectrum of gastrointestinal disorders and are associated with poor patient outcomes. Robust and reproducible data in the areas of behavioural intervention science and the brain-gut axis have led to major advances in patient care, including the routine use of brain-gut psychotherapies to manage digestive symptoms and optimize coping. The logical next step for the emerging field of psychogastroenterology is to develop a scientific framework that enables the identification of those individual characteristics and coping styles that buffer patients against the negative psychological effects of chronic gastrointestinal disorders. A shift towards a strength-based, positive psychological science of gastrointestinal disorders could facilitate the integration of early, effective psychological care into gastroenterology practice. In this Perspective, I discuss the potential role of three human strengths with relevance to gastrointestinal health - resilience, optimism and self-regulation - and how these three constructs can be cultivated through existing or emerging brain-gut psychotherapies.

Altered behavior and neural activity in conspecific cagemates co-housed with mouse models of brain disorders.

PubMed

Yang, Hyunwoo; Jung, Seungmoon; Seo, Jinsoo; Khalid, Arshi; Yoo, Jung-Seok; Park, Jihyun; Kim, Soyun; Moon, Jangsup; Lee, Soon-Tae; Jung, Keun-Hwa; Chu, Kon; Lee, Sang Kun; Jeon, Daejong

2016-09-01

The psychosocial environment is one of the major contributors of social stress. Family members or caregivers who consistently communicate with individuals with brain disorders are considered at risk for physical and mental health deterioration, possibly leading to mental disorders. However, the underlying neural mechanisms of this phenomenon remain poorly understood. To address this, we developed a social stress paradigm in which a mouse model of epilepsy or depression was housed long-term (>4weeks) with normal conspecifics. We characterized the behavioral phenotypes and electrophysiologically investigated the neural activity of conspecific cagemate mice. The cagemates exhibited deficits in behavioral tasks assessing anxiety, locomotion, learning/memory, and depression-like behavior. Furthermore, they showed severe social impairment in social behavioral tasks involving social interaction or aggression. Strikingly, behavioral dysfunction remained in the cagemates 4weeks following co-housing cessation with the mouse models. In an electrophysiological study, the cagemates showed an increased number of spikes in medial prefrontal cortex (mPFC) neurons. Our results demonstrate that conspecifics co-housed with mouse models of brain disorders develop chronic behavioral dysfunctions, and suggest a possible association between abnormal mPFC neural activity and their behavioral pathogenesis. These findings contribute to the understanding of the psychosocial and psychiatric symptoms frequently present in families or caregivers of patients with brain disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Intranasal Inhalations of Bioactive Factors Produced by M2 Macrophages in Patients With Organic Brain Syndrome

ClinicalTrials.gov

2017-11-06

Organic Brain Syndrome, Nonpsychotic; Neurocognitive Disorders; Mental Disorder, Organic; Delirium, Dementia, Amnestic, Cognitive Disorders; Nonpsychotic Organic Brain Syndrome; Organic Mental Disorder; Encephalopathy, Post-Traumatic, Chronic; Encephalopathy, Ischemic; Brain Ischemia

dbMDEGA: a database for meta-analysis of differentially expressed genes in autism spectrum disorder.

PubMed

Zhang, Shuyun; Deng, Libin; Jia, Qiyue; Huang, Shaoting; Gu, Junwang; Zhou, Fankun; Gao, Meng; Sun, Xinyi; Feng, Chang; Fan, Guangqin

2017-11-16

Autism spectrum disorders (ASD) are hereditary, heterogeneous and biologically complex neurodevelopmental disorders. Individual studies on gene expression in ASD cannot provide clear consensus conclusions. Therefore, a systematic review to synthesize the current findings from brain tissues and a search tool to share the meta-analysis results are urgently needed. Here, we conducted a meta-analysis of brain gene expression profiles in the current reported human ASD expression datasets (with 84 frozen male cortex samples, 17 female cortex samples, 32 cerebellum samples and 4 formalin fixed samples) and knock-out mouse ASD model expression datasets (with 80 collective brain samples). Then, we applied R language software and developed an interactive shared and updated database (dbMDEGA) displaying the results of meta-analysis of data from ASD studies regarding differentially expressed genes (DEGs) in the brain. This database, dbMDEGA ( https://dbmdega.shinyapps.io/dbMDEGA/ ), is a publicly available web-portal for manual annotation and visualization of DEGs in the brain from data from ASD studies. This database uniquely presents meta-analysis values and homologous forest plots of DEGs in brain tissues. Gene entries are annotated with meta-values, statistical values and forest plots of DEGs in brain samples. This database aims to provide searchable meta-analysis results based on the current reported brain gene expression datasets of ASD to help detect candidate genes underlying this disorder. This new analytical tool may provide valuable assistance in the discovery of DEGs and the elucidation of the molecular pathogenicity of ASD. This database model may be replicated to study other disorders.

A Developmental and Genetic Classification for Malformations of Cortical Development: Update 2012

ERIC Educational Resources Information Center

Barkovich, A. James; Guerrini, Renzo; Kuzniecky, Ruben I.; Jackson, Graeme D.; Dobyns, William B.

2012-01-01

Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics…

What Is ADHD?

MedlinePlus

... español TDAH What Is ADHD? ADHD stands for attention deficit hyperactivity disorder. It is a medical condition. ... in brain development and brain activity that affect attention, the ability to sit still, and self-control. ...

The Indispensable Roles of Microglia and Astrocytes during Brain Development

PubMed Central

Reemst, Kitty; Noctor, Stephen C.; Lucassen, Paul J.; Hol, Elly M.

2016-01-01

Glia are essential for brain functioning during development and in the adult brain. Here, we discuss the various roles of both microglia and astrocytes, and their interactions during brain development. Although both cells are fundamentally different in origin and function, they often affect the same developmental processes such as neuro-/gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis and synaptic pruning. Due to their important instructive roles in these processes, dysfunction of microglia or astrocytes during brain development could contribute to neurodevelopmental disorders and potentially even late-onset neuropathology. A better understanding of the origin, differentiation process and developmental functions of microglia and astrocytes will help to fully appreciate their role both in the developing as well as in the adult brain, in health and disease. PMID:27877121

Neuroendocrinology and brain imaging of reward in eating disorders: A possible key to the treatment of anorexia nervosa and bulimia nervosa.

PubMed

Monteleone, Alessio Maria; Castellini, Giovanni; Volpe, Umberto; Ricca, Valdo; Lelli, Lorenzo; Monteleone, Palmiero; Maj, Mario

2018-01-03

Anorexia nervosa and bulimia nervosa are severe eating disorders whose etiopathogenesis is still unknown. Clinical features suggest that eating disorders may develop as reward-dependent syndromes, since eating less food is perceived as rewarding in anorexia nervosa while consumption of large amounts of food during binge episodes in bulimia nervosa aims at reducing the patient's negative emotional states. Therefore, brain reward mechanisms have been a major focus of research in the attempt to contribute to the comprehension of the pathophysiology of these disorders. Structural brain imaging data provided the evidence that brain reward circuits may be altered in patients with anorexia or bulimia nervosa. Similarly, functional brain imaging studies exploring the activation of brain reward circuits by food stimuli as well as by stimuli recognized to be potentially rewarding for eating disordered patients, such as body image cues or stimuli related to food deprivation and physical hyperactivity, showed several dysfunctions in ED patients. Moreover, very recently, it has been demonstrated that some of the biochemical homeostatic modulators of eating behavior are also implicated in the regulation of food-related and non-food-related reward, representing a possible link between the aberrant behaviors of ED subjects and their hypothesized deranged reward processes. In particular, changes in leptin and ghrelin occur in patients with anorexia or bulimia nervosa and have been suggested to represent not only homeostatic adaptations to an altered energy balance but to contribute also to the acquisition and/or maintenance of persistent starvation, binge eating and physical hyperactivity, which are potentially rewarding for ED patients. On the basis of such findings new pathogenetic models of EDs have been proposed, and these models may provide new theoretical basis for the development of innovative treatment strategies, either psychological and pharmacological, with the aim to improve the outcomes of so severe disabling disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Connectivity dynamics in typical development and its relationship to autistic traits and autism spectrum disorder.

PubMed

Rashid, Barnaly; Blanken, Laura M E; Muetzel, Ryan L; Miller, Robyn; Damaraju, Eswar; Arbabshirani, Mohammad R; Erhardt, Erik B; Verhulst, Frank C; van der Lugt, Aad; Jaddoe, Vincent W V; Tiemeier, Henning; White, Tonya; Calhoun, Vince

2018-03-30

Recent advances in neuroimaging techniques have provided significant insights into developmental trajectories of human brain function. Characterizations of typical neurodevelopment provide a framework for understanding altered neurodevelopment, including differences in brain function related to developmental disorders and psychopathology. Historically, most functional connectivity studies of typical and atypical development operate under the assumption that connectivity remains static over time. We hypothesized that relaxing stationarity assumptions would reveal novel features of both typical brain development related to children on the autism spectrum. We employed a "chronnectomic" (recurring, time-varying patterns of connectivity) approach to evaluate transient states of connectivity using resting-state functional MRI in a population-based sample of 774 6- to 10-year-old children. Dynamic connectivity was evaluated using a sliding-window approach, and revealed four transient states. Internetwork connectivity increased with age in modularized dynamic states, illustrating an important pattern of connectivity in the developing brain. Furthermore, we demonstrated that higher levels of autistic traits and ASD diagnosis were associated with longer dwell times in a globally disconnected state. These results provide a roadmap to the chronnectomic organization of the developing brain and suggest that characteristics of functional brain connectivity are related to children on the autism spectrum. © 2018 Wiley Periodicals, Inc.

Acute in utero exposure to lipopolysaccharide induces inflammation in the pre- and postnatal brain and alters the glial cytoarchitecture in the developing amygdala.

PubMed

O'Loughlin, Elaine; Pakan, Janelle M P; Yilmazer-Hanke, Deniz; McDermott, Kieran W

2017-11-02

Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders such as autism and schizophrenia, as well as seizure development. The amygdala is a brain region involved in the regulation of emotions, and amygdalar maldevelopment due to infection-induced MIA may lead to amygdala-related disorders. MIA priming of glial cells during development has been linked to abnormalities seen in later life; however, little is known about its effects on amygdalar biochemical and cytoarchitecture integrity. Time-mated C57BL6J mice were administered a single intraperitoneal injection of 50 μg/kg lipopolysaccharide (LPS) on embryonic day 12 (E12), and the effects of MIA were examined at prenatal, neonatal, and postnatal developmental stages using immunohistochemistry, real-time quantitative PCR, and stereological quantification of cytoarchitecture changes. Fetal brain expression of pro-inflammatory cytokines (IL-1β, TNFα, and IL-6) was significantly upregulated at 4 h postinjection (E12) and remained elevated until the day of birth (P0). In offspring from LPS-treated dams, amygdalar expression of pro-inflammatory cytokines was also increased on day 7 (P7) and expression was sustained on day 40 (P40). Toll-like receptor (TLR-2, TLR-4) expression was also upregulated in fetal brains and in the postnatal amygdala in LPS-injected animals. Morphological examination of cells expressing ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) suggested long-term microglial activation and astrogliosis in postnatal amygdalar regions. Our results showed that LPS-induced MIA at E12 induces a pro-inflammatory cytokine profile in the developing fetal brain that continues up to early adulthood in the amygdala. Inflammation elicited by MIA may activate cells in the fetal brain and lead to alterations in glial (microglia and astrocyte) cells observed in the postnatal amygdala. Moreover, increased pro-inflammatory cytokines and their effects on glial subpopulations may in turn have deleterious consequences for neuronal viability. These MIA-induced changes may predispose offspring to amygdala-related disorders such as heightened anxiety and depression and also neurodevelopmental disorders, such as autism spectrum disorders.

Nuclear Receptor TLX in Development and Diseases.

PubMed

Sun, Guoqiang; Cui, Qi; Shi, Yanhong

2017-01-01

The nuclear receptor TLX (NR2E1) is a transcription factor that is critical for neural development and adult neurogenesis through its actions in regulating neural stem cell proliferation, self-renewal, and fate determination. These roles are primarily executed by regulating TLX downstream target genes involved in myriad pathways such as cell cycle progression, RNA processing, angiogenesis, and senescence. Recent studies suggest that dysregulation of TLX pathways plays an important role in the pathogenesis of human neurological disorders and brain tumors. Here, we will highlight recent progress in the roles of TLX in brain development and adult neurogenesis, and the relevance of TLX to neurological diseases and brain tumors. We will also discuss the potential of TLX as a therapeutic target for these disorders. © 2017 Elsevier Inc. All rights reserved.

A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders

PubMed Central

Reinhard, Sarah M.; Razak, Khaleel; Ethell, Iryna M.

2015-01-01

The extracellular matrix (ECM) is a critical regulator of neural network development and plasticity. As neuronal circuits develop, the ECM stabilizes synaptic contacts, while its cleavage has both permissive and active roles in the regulation of plasticity. Matrix metalloproteinase 9 (MMP-9) is a member of a large family of zinc-dependent endopeptidases that can cleave ECM and several cell surface receptors allowing for synaptic and circuit level reorganization. It is becoming increasingly clear that the regulated activity of MMP-9 is critical for central nervous system (CNS) development. In particular, MMP-9 has a role in the development of sensory circuits during early postnatal periods, called ‘critical periods.’ MMP-9 can regulate sensory-mediated, local circuit reorganization through its ability to control synaptogenesis, axonal pathfinding and myelination. Although activity-dependent activation of MMP-9 at specific synapses plays an important role in multiple plasticity mechanisms throughout the CNS, misregulated activation of the enzyme is implicated in a number of neurodegenerative disorders, including traumatic brain injury, multiple sclerosis, and Alzheimer’s disease. Growing evidence also suggests a role for MMP-9 in the pathophysiology of neurodevelopmental disorders including Fragile X Syndrome. This review outlines the various actions of MMP-9 during postnatal brain development, critical for future studies exploring novel therapeutic strategies for neurodevelopmental disorders. PMID:26283917

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

[Complex application 2-ethyl-6-methyl-3-hydroxypyridine-succinate and vinpocetine in cerebrovascular disorder.

PubMed

Solovyeva, E Yu; Karneev, A N; Chekanov, A V; Baranova, O A; Choi, I V

Developing brain ischemia due to cerebral vascularization leads to disruption of brain metabolism. Chronic cerebral hypoperfusion leads to irreversible brain damage and plays an important role in the development of some types of dementia. Early use of antioxidants such as ethyl ether apovincamine acid (vinpocetine) and 2-ethyl-6-methyl-3-hydroxypyridine-succinate in the treatment of this pathology is seen as a real pathogenetically based method of correction of cerebral metabolism with cerebral vascular disorders, demonstrating the increase in cerebral blood flow and also neuroprotective effects. Clinical studies and studies on biological models show that the main mechanisms of action of vinpocetine and 2-ethyl-6-methyl-3-hydroxypyridine-succinate, although have a similar focus, but implementing neuroprotective and nootropic effects via various links in the pathogenesis of ischemic brain damage.

Epigenetic Basis of Neuronal and Synaptic Plasticity.

PubMed

Karpova, Nina N; Sales, Amanda J; Joca, Samia R

2017-01-01

Neuronal network and plasticity change as a function of experience. Altered neural connectivity leads to distinct transcriptional programs of neuronal plasticity-related genes. The environmental challenges throughout life may promote long-lasting reprogramming of gene expression and the development of brain disorders. The modifications in neuronal epigenome mediate gene-environmental interactions and are required for activity-dependent regulation of neuronal differentiation, maturation and plasticity. Here, we highlight the latest advances in understanding the role of the main players of epigenetic machinery (DNA methylation and demethylation, histone modifications, chromatin-remodeling enzymes, transposons, and non-coding RNAs) in activity-dependent and long- term neural and synaptic plasticity. The review focuses on both the transcriptional and post-transcriptional regulation of gene expression levels, including the processes of promoter activation, alternative splicing, regulation of stability of gene transcripts by natural antisense RNAs, and alternative polyadenylation. Further, we discuss the epigenetic aspects of impaired neuronal plasticity and the pathogenesis of neurodevelopmental (Rett syndrome, Fragile X Syndrome, genomic imprinting disorders, schizophrenia, and others), stressrelated (mood disorders) and neurodegenerative Alzheimer's, Parkinson's and Huntington's disorders. The review also highlights the pharmacological compounds that modulate epigenetic programming of gene expression, the potential treatment strategies of discussed brain disorders, and the questions that should be addressed during the development of effective and safe approaches for the treatment of brain disorders.

BRAIN MYELINATION IN PREVALENT NEUROPSYCHIATRIC DEVELOPMENTAL DISORDERS

PubMed Central

BARTZOKIS, GEORGE

2008-01-01

Current concepts of addiction focus on neuronal neurocircuitry and neurotransmitters and are largely based on animal model data, but the human brain is unique in its high myelin content and extended developmental (myelination) phase that continues until middle age. The biology of our exceptional myelination process and factors that influence it have been synthesized into a recently published myelin model of human brain evolution and normal development that cuts across the current symptom-based classification of neuropsychiatric disorders. The developmental perspective of the model suggests that dysregulations in the myelination process contribute to prevalent early-life neuropsychiatric disorders, as well as to addictions. These disorders share deficits in inhibitory control functions that likely contribute to their high rates of comorbidity with addiction and other impulsive behaviors. The model posits that substances such as alcohol and psychostimulants are toxic to the extremely vulnerable myelination process and contribute to the poor outcomes of primary and comorbid addictive disorders in susceptible individuals. By increasing the scientific focus on myelination, the model provides a rational biological framework for the development of novel, myelin-centered treatments that may have widespread efficacy across multiple disease states and could potentially be used in treating, delaying, or even preventing some of the most prevalent and devastating neuropsychiatric disorders. PMID:18668184

Brain stimulation in posttraumatic stress disorder

PubMed Central

Novakovic, Vladan; Sher, Leo; Lapidus, Kyle A.B.; Mindes, Janet; A.Golier, Julia; Yehuda, Rachel

2011-01-01

Posttraumatic stress disorder (PTSD) is a complex, heterogeneous disorder that develops following trauma and often includes perceptual, cognitive, affective, physiological, and psychological features. PTSD is characterized by hyperarousal, intrusive thoughts, exaggerated startle response, flashbacks, nightmares, sleep disturbances, emotional numbness, and persistent avoidance of trauma-associated stimuli. The efficacy of available treatments for PTSD may result in part from relief of associated depressive and anxiety-related symptoms in addition to treatment of core symptoms that derive from reexperiencing, numbing, and hyperarousal. Diverse, heterogeneous mechanisms of action and the ability to act broadly or very locally may enable brain stimulation devices to address PTSD core symptoms in more targeted ways. To achieve this goal, specific theoretical bases derived from novel, well-designed research protocols will be necessary. Brain stimulation devices include both long-used and new electrical and magnetic devices. Electroconvulsive therapy (ECT) and Cranial electrotherapy stimulation (CES) have both been in use for decades; transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), deep brain stimulation (DBS), transcranial Direct Current Stimulation (tDCS), and vagus nerve stimulation (VNS) have been developed recently, over approximately the past twenty years. The efficacy of brain stimulation has been demonstrated as a treatment for psychiatric and neurological disorders such as anxiety (CES), depression (ECT, CES, rTMS, VNS, DBS), obsessive-compulsive disorder (OCD) (DBS), essential tremor, dystonia (DBS), epilepsy (DBS, VNS), Parkinson Disease (DBS), pain (CES), and insomnia (CES). To date, limited data on brain stimulation for PTSD offer only modest guidance. ECT has shown some efficacy in reducing comorbid depression in PTSD patients but has not been demonstrated to improve most core PTSD symptoms. CES and VNS have shown some efficacy in reducing anxiety, findings that may suggest possible utility in relieving PTSD-associated anxiety. Treatment of animal models of PTSD with DBS suggests potential human benefit. Additional research and novel treatment options for PTSD are urgently needed. The potential usefulness of brain stimulation in treating PTSD deserves further exploration. PMID:22893803

brain-coX: investigating and visualising gene co-expression in seven human brain transcriptomic datasets.

PubMed

Freytag, Saskia; Burgess, Rosemary; Oliver, Karen L; Bahlo, Melanie

2017-06-08

The pathogenesis of neurological and mental health disorders often involves multiple genes, complex interactions, as well as brain- and development-specific biological mechanisms. These characteristics make identification of disease genes for such disorders challenging, as conventional prioritisation tools are not specifically tailored to deal with the complexity of the human brain. Thus, we developed a novel web-application-brain-coX-that offers gene prioritisation with accompanying visualisations based on seven gene expression datasets in the post-mortem human brain, the largest such resource ever assembled. We tested whether our tool can correctly prioritise known genes from 37 brain-specific KEGG pathways and 17 psychiatric conditions. We achieved average sensitivity of nearly 50%, at the same time reaching a specificity of approximately 75%. We also compared brain-coX's performance to that of its main competitors, Endeavour and ToppGene, focusing on the ability to discover novel associations. Using a subset of the curated SFARI autism gene collection we show that brain-coX's prioritisations are most similar to SFARI's own curated gene classifications. brain-coX is the first prioritisation and visualisation web-tool targeted to the human brain and can be freely accessed via http://shiny.bioinf.wehi.edu.au/freytag.s/ .

1H-Magnetic resonance spectroscopy study of stimulant medication effect on brain metabolites in French Canadian children with attention deficit hyperactivity disorder

PubMed Central

Benamor, Leila

2014-01-01

Background Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in school aged children. Functional abnormalities have been reported in brain imaging studies in ADHD populations. Psychostimulants are considered as the first line treatment for ADHD. However, little is known of the effect of stimulants on brain metabolites in ADHD patients. Objectives To compare the brain metabolite concentrations in children with ADHD and on stimulants with those of drug naïve children with ADHD, versus typically developed children, in a homogenous genetic sample of French Canadians. Methods Children with ADHD on stimulants (n=57) and drug naïve children with ADHD (n=45) were recruited, as well as typically developed children (n=38). The presence or absence of ADHD diagnosis (Diagnostic and Statistical Manual of Mental Disorders IV criteria) was based on clinical evaluation and The Diagnostic Interview Schedule for Children IV. All children (n=140) underwent a proton magnetic resonance spectroscopy session to measure the ratio of N-acetyl-aspartate, choline, glutamate, and glutamate–glutamine to creatine, respectively, in the left and right prefrontal and striatal regions of the brain, as well as in the left cerebellum. Results When compared with drug naïve children with ADHD, children with ADHD on stimulants and children typically developed were found to have higher choline ratios in the left prefrontal region (P=0.04) and lower N-acetyl-aspartate ratios in the left striatum region (P=0.01), as well as lower glutamate–glutamine ratios in the left cerebellum (P=0.05). In these three regions, there was no difference between children with ADHD on stimulants and typically developed children. Conclusion Therapeutic psychostimulant effects in children with ADHD may be mediated by normalization of brain metabolite levels, particularly in the left fronto-striato-cerebellar regions. PMID:24476627

Gaining insight of fetal brain development with diffusion MRI and histology.

PubMed

Huang, Hao; Vasung, Lana

2014-02-01

Human brain is extraordinarily complex and yet its origin is a simple tubular structure. Its development during the fetal period is characterized by a series of accurately organized events which underlie the mechanisms of dramatic structural changes during fetal development. Revealing detailed anatomy at different stages of human fetal brain development provides insight on understanding not only this highly ordered process, but also the neurobiological foundations of cognitive brain disorders such as mental retardation, autism, schizophrenia, bipolar and language impairment. Diffusion tensor imaging (DTI) and histology are complementary tools which are capable of delineating the fetal brain structures at both macroscopic and microscopic levels. In this review, the structural development of the fetal brains has been characterized with DTI and histology. Major components of the fetal brain, including cortical plate, fetal white matter and cerebral wall layer between the ventricle and subplate, have been delineated with DTI and histology. Anisotropic metrics derived from DTI were used to quantify the microstructural changes during the dynamic process of human fetal cortical development and prenatal development of other animal models. Fetal white matter pathways have been traced with DTI-based tractography to reveal growth patterns of individual white matter tracts and corticocortical connectivity. These detailed anatomical accounts of the structural changes during fetal period may provide the clues of detecting developmental and cognitive brain disorders at their early stages. The anatomical information from DTI and histology may also provide reference standards for diagnostic radiology of premature newborns. Copyright © 2013 ISDN. Published by Elsevier Ltd. All rights reserved.

Reduced Prefrontal Hemodynamic Response in Pediatric Obsessive-Compulsive Disorder as Measured by Near-Infrared Spectroscopy

ERIC Educational Resources Information Center

Ota, Toyosaku; Iida, Junzo; Sawada, Masayuki; Suehiro, Yuko; Yamamuro, Kazuhiko; Matsuura, Hiroki; Tanaka, Shohei; Kishimoto, Naoko; Negoro, Hideki; Kishimoto, Toshifumi

2013-01-01

Recent developments in near-infrared spectroscopy (NIRS) have enabled non-invasive clarification of brain functions in psychiatric disorders. Functional neuroimaging studies of patients with obsessive-compulsive disorder (OCD) have suggested that the frontal cortex and subcortical structures may play a role in the pathophysiology of the disorder.…

[The Role of Physician In Enhancement of Rehabilitation of Disabled Children].

PubMed

Nizova, L M; Kislisyna, I G

2017-09-01

The national and international experience of rehabilitation of disabled children was investigated. On the basis of monitoring data problem of increasing of number of children with diagnosis of infantile cerebral paralysis, including necessity of development of new methods of their rehabilitation was established. The comparative dynamics of nosology of disabled children permitted to detect diseases of nervous system and congenital abnormalities (malformations), deformations and chromosomal disorders, psychological disorders and behavioral disorders mostly specific for urban and rural area. The model of institutional environment of rehabilitation of disabled children was developed including system of formal (state, legislative acts, health institutions, organizations of social support of population)and non-formal (public, non-commercial and social psychological organizations) institutions impacted by economic, social,legal and demographic factors. The role of physician is substantiated concerning increasing of quality of rehabilitation services: diagnostic of disordered functions, detection of optimal volume of medical, psychological and pedagogue activities in patients with severe speech disorders, motoric and and neuro-censorial disorders developed as a result of early organic damage of brain, neuro-infections, strokes, and other affection of brain. The adequate curative rehabilitative complex programs were developed of social everyday and social labor rehabilitation.

75 FR 76994 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-10

... Committee: Brain Disorders and Clinical Neuroscience Integrated Review Group Developmental Brain Disorders....gov . Name of Committee: Brain Disorders and Clinical Neuroscience Integrated Review Group, Cell [email protected] . Name of Committee: Brain Disorders and Clinical Neuroscience Integrated Review Group...

Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network.

PubMed

McConnell, Michael J; Moran, John V; Abyzov, Alexej; Akbarian, Schahram; Bae, Taejeong; Cortes-Ciriano, Isidro; Erwin, Jennifer A; Fasching, Liana; Flasch, Diane A; Freed, Donald; Ganz, Javier; Jaffe, Andrew E; Kwan, Kenneth Y; Kwon, Minseok; Lodato, Michael A; Mills, Ryan E; Paquola, Apua C M; Rodin, Rachel E; Rosenbluh, Chaggai; Sestan, Nenad; Sherman, Maxwell A; Shin, Joo Heon; Song, Saera; Straub, Richard E; Thorpe, Jeremy; Weinberger, Daniel R; Urban, Alexander E; Zhou, Bo; Gage, Fred H; Lehner, Thomas; Senthil, Geetha; Walsh, Christopher A; Chess, Andrew; Courchesne, Eric; Gleeson, Joseph G; Kidd, Jeffrey M; Park, Peter J; Pevsner, Jonathan; Vaccarino, Flora M

2017-04-28

Neuropsychiatric disorders have a complex genetic architecture. Human genetic population-based studies have identified numerous heritable sequence and structural genomic variants associated with susceptibility to neuropsychiatric disease. However, these germline variants do not fully account for disease risk. During brain development, progenitor cells undergo billions of cell divisions to generate the ~80 billion neurons in the brain. The failure to accurately repair DNA damage arising during replication, transcription, and cellular metabolism amid this dramatic cellular expansion can lead to somatic mutations. Somatic mutations that alter subsets of neuronal transcriptomes and proteomes can, in turn, affect cell proliferation and survival and lead to neurodevelopmental disorders. The long life span of individual neurons and the direct relationship between neural circuits and behavior suggest that somatic mutations in small populations of neurons can significantly affect individual neurodevelopment. The Brain Somatic Mosaicism Network has been founded to study somatic mosaicism both in neurotypical human brains and in the context of complex neuropsychiatric disorders. Copyright © 2017, American Association for the Advancement of Science.

Early behavioral intervention, brain plasticity, and the prevention of autism spectrum disorder.

PubMed

Dawson, Geraldine

2008-01-01

Advances in the fields of cognitive and affective developmental neuroscience, developmental psychopathology, neurobiology, genetics, and applied behavior analysis have contributed to a more optimistic outcome for individuals with autism spectrum disorder (ASD). These advances have led to new methods for early detection and more effective treatments. For the first time, prevention of ASD is plausible. Prevention will entail detecting infants at risk before the full syndrome is present and implementing treatments designed to alter the course of early behavioral and brain development. This article describes a developmental model of risk, risk processes, symptom emergence, and adaptation in ASD that offers a framework for understanding early brain plasticity in ASD and its role in prevention of the disorder.

Resting-State Functional Connectivity in the Human Connectome Project: Current Status and Relevance to Understanding Psychopathology.

PubMed

Barch, Deanna M

A key tenet of modern psychiatry is that psychiatric disorders arise from abnormalities in brain circuits that support human behavior. Our ability to examine hypotheses around circuit-level abnormalities in psychiatric disorders has been made possible by advances in human neuroimaging technologies. These advances have provided the basis for recent efforts to develop a more complex understanding of the function of brain circuits in health and of their relationship to behavior-providing, in turn, a foundation for our understanding of how disruptions in such circuits contribute to the development of psychiatric disorders. This review focuses on the use of resting-state functional connectivity MRI to assess brain circuits, on the advances generated by the Human Connectome Project, and on how these advances potentially contribute to understanding neural circuit dysfunction in psychopathology. The review gives particular attention to the methods developed by the Human Connectome Project that may be especially relevant to studies of psychopathology; it outlines some of the key findings about what constitutes a brain region; and it highlights new information about the nature and stability of brain circuits. Some of the Human Connectome Project's new findings particularly relevant to psychopathology-about neural circuits and their relationships to behavior-are also presented. The review ends by discussing the extension of Human Connectome Project methods across the lifespan and into manifest illness. Potential treatment implications are also considered.

Attention-Deficit Hyperactivity Disorder.

ERIC Educational Resources Information Center

Barkley, Russell A.

1998-01-01

Attention deficit hyperactivity disorder (ADHD) may arise when key brain circuits do not develop properly, perhaps due to an altered gene or genes. Describes ADHD in detail and introduces a psychological model of ADHD. (ASK)

Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics

PubMed Central

Hernandez, Leanna M; Rudie, Jeffrey D; Green, Shulamite A; Bookheimer, Susan; Dapretto, Mirella

2015-01-01

Neuroimaging investigations of autism spectrum disorders (ASDs) have advanced our understanding of atypical brain function and structure, and have recently converged on a model of altered network-level connectivity. Traditional task-based functional magnetic resonance imaging (MRI) and volume-based structural MRI studies have identified widespread atypicalities in brain regions involved in social behavior and other core ASD-related behavioral deficits. More recent advances in MR-neuroimaging methods allow for quantification of brain connectivity using diffusion tensor imaging, functional connectivity, and graph theoretic methods. These newer techniques have moved the field toward a systems-level understanding of ASD etiology, integrating functional and structural measures across distal brain regions. Neuroimaging findings in ASD as a whole have been mixed and at times contradictory, likely due to the vast genetic and phenotypic heterogeneity characteristic of the disorder. Future longitudinal studies of brain development will be crucial to yield insights into mechanisms of disease etiology in ASD sub-populations. Advances in neuroimaging methods and large-scale collaborations will also allow for an integrated approach linking neuroimaging, genetics, and phenotypic data. PMID:25011468

Prescription Stimulants and the Development of Post-Traumatic Stress Disorder among U.S. Service Members

DTIC Science & Technology

2013-08-13

attention deficit disorder (ADD)/ attention deficit hyperactivity disorder ( ADHD ) or to enhance performance, and such use has...individuals with and without attention deficit hyperactivity disorder : misuse, cognitive impact, and adverse effects. Brain Behav 2012, 2(5), 661-77. 11...36. Antshel KM, Kaul P, Biederman J, et al., Posttraumatic stress disorder in adult attention - deficit / hyperactivity

The FMRP regulon: from targets to disease convergence

PubMed Central

Fernández, Esperanza; Rajan, Nicholas; Bagni, Claudia

2013-01-01

The fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates mRNA metabolism. FMRP has been largely studied in the brain, where the absence of this protein leads to fragile X syndrome, the most frequent form of inherited intellectual disability. Since the identification of the FMRP gene in 1991, many studies have primarily focused on understanding the function/s of this protein. Hundreds of potential FMRP mRNA targets and several interacting proteins have been identified. Here, we report the identification of FMRP mRNA targets in the mammalian brain that support the key role of this protein during brain development and in regulating synaptic plasticity. We compared the genes from databases and genome-wide association studies with the brain FMRP transcriptome, and identified several FMRP mRNA targets associated with autism spectrum disorders, mood disorders and schizophrenia, showing a potential common pathway/s for these apparently different disorders. PMID:24167470

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

Posttraumatic stress disorder in patients with traumatic brain injury and amnesia for the event?

PubMed

Warden, D L; Labbate, L A; Salazar, A M; Nelson, R; Sheley, E; Staudenmeier, J; Martin, E

1997-01-01

Frequency of DSM-III-R posttraumatic stress disorder (PTSD) was studied in 47 active-duty service members (46 male, 1 female; mean age 27 = 7) with moderate traumatic brain injury and neurogenic amnesia for the event. Patients had attained "oriented and cooperative" recovery level. When evaluated with a modified Present State Examination and other questions at various points from study entry to 24-month follow-up, no patients met full criteria for PTSD or met criterion B (reexperience); 6 (13%) met both C (avoidance) and D (arousal) criteria. Five of these 6 also had organic mood disorder, depressed type, and/or organic anxiety disorder. Posttraumatic amnesia following moderate head injury may protect against recurring memories and the development of PTSD. Some patients with neurogenic amnesia may develop a form of PTSD without the reexperiencing symptoms.

Comparison of Coil Designs for Transcranial Magnetic Stimulation on Mice

NASA Astrophysics Data System (ADS)

Rastogi, Priyam; Hadimani, Ravi; Jiles, David

2015-03-01

Transcranial magnetic stimulation (TMS) is a non-invasive treatment for neurological disorders using time varying magnetic field. The electric field generated by the time varying magnetic field is used to depolarize the brain neurons which can lead to measurable effects. TMS provides a surgical free method for the treatment of neurological brain disorders like depression, post-traumatic stress disorder, traumatic brain injury and Parkinson's disease. Before using TMS on human subjects, it is appropriate that its effects are verified on animals such as mice. The magnetic field intensity and stimulated region of the brain can be controlled by the shape, position and current in the coils. There are few reports on the designs of the coils for mice. In this paper, different types of coils are developed and compared using an anatomically realistic mouse model derived from MRI images. Parameters such as focality, depth of the stimulation, electric field strength on the scalp and in the deep brain regions, are taken into account. These parameters will help researchers to determine the most suitable coil design according to their need. This should result in improvements in treatment of specific disorders. Carver Charitable Trust.

Unusual developmental pattern of brain lateralization in young boys with autism spectrum disorder: Power analysis with child-sized magnetoencephalography.

PubMed

Hiraishi, Hirotoshi; Kikuchi, Mitsuru; Yoshimura, Yuko; Kitagawa, Sachiko; Hasegawa, Chiaki; Munesue, Toshio; Takesaki, Natsumi; Ono, Yasuki; Takahashi, Tsutomu; Suzuki, Michio; Higashida, Haruhiro; Asada, Minoru; Minabe, Yoshio

2015-03-01

Autism spectrum disorder (ASD) is often described as comprising an unusual brain growth pattern and aberrant brain lateralization. Although it is important to study the pathophysiology of the developing ASD cortex, examples of physiological brain lateralization in young children with ASD have yet to be well examined. Thirty-eight boys with ASD (aged 3-7 years) and 38 typically developing (TD) boys (aged 3-8 years) concentrated on video programs and their brain activities were measured non-invasively. We employed a customized child-sized magnetoencephalography system in which the sensors were located as close to the brain as possible for optimal recording in young children. To produce a credible laterality index of the brain oscillations, we defined two clusters of sensors corresponding to the right and left hemispheres. We focused on the laterality index ([left - right]/[left+right]) of the relative power band in seven frequency bands. The TD group displayed significantly rightward lateralized brain oscillations in the theta-1 frequency bands compared to the ASD group. This is the first study to demonstrate unusual brain lateralization of brain oscillations measured by magnetoencephalography in young children with ASD. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

60 years of advances in neuropsychopharmacology for improving brain health, renewed hope for progress.

PubMed

Millan, Mark J; Goodwin, Guy M; Meyer-Lindenberg, Andreas; Ögren, Sven Ove

2015-05-01

Pharmacotherapy is effective in helping many patients suffering from psychiatric and neurological disorders, and both psychotherapeutic and stimulation-based techniques likewise have important roles to play in their treatment. However, therapeutic progress has recently been slow. Future success for improving the control and prevention of brain disorders will depend upon deeper insights into their causes and pathophysiological substrates. It will also necessitate new and more rigorous methods for identifying, validating, developing and clinically deploying new treatments. A field of Research and Development (R and D) that remains critical to this endeavour is Neuropsychopharmacology which transformed the lives of patients by introducing pharmacological treatments for psychiatric disorder some 60 years ago. For about half of this time, the European College of Neuropsychopharmacology (ECNP) has fostered efforts to enhance our understanding of the brain, and to improve the management of psychiatric disorders. Further, together with partners in academia and industry, and in discussions with regulators and patients, the ECNP is implicated in new initiatives to achieve this goal. This is then an opportune moment to survey the field, to analyse what we have learned from the achievements and failures of the past, and to identify major challenges for the future. It is also important to highlight strategies that are being put in place in the quest for more effective treatment of brain disorders: from experimental research and drug discovery to clinical development and collaborative ventures for reinforcing "R and D". The present article sets the scene, then introduces and interlinks the eight articles that comprise this Special Volume of European Neuropsychopharmacology. A broad-based suite of themes is covered embracing: the past, present and future of "R and D" for psychiatric disorders; complementary contributions of genetics and epigenetics; efforts to improve the treatment of depression, neurodevelopmental and neurodegenerative disorders; and advances in the analysis and neuroimaging of cellular and cerebral circuits. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Annual Research Review: The neurobehavioral development of multiple memory systems: implications for childhood and adolescent psychiatric disorders

PubMed Central

Goodman, Jarid; Marsh, Rachel; Peterson, Bradley S.; Packard, Mark G.

2014-01-01

Extensive evidence indicates that mammalian memory is organized into multiple brains systems, including a “cognitive” memory system that depends upon the hippocampus and a stimulus-response “habit” memory system that depends upon the dorsolateral striatum. Dorsal striatal-dependent habit memory may in part influence the development and expression of some human psychopathologies, particularly those characterized by strong habit-like behavioral features. The present review considers this hypothesis as it pertains to psychopathologies that typically emerge during childhood and adolescence. These disorders include Tourette syndrome, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, eating disorders, and autism spectrum disorders. Human and nonhuman animal research shows that the typical development of memory systems comprises the early maturation of striatal-dependent habit memory and the relatively late maturation of hippocampal-dependent cognitive memory. We speculate that the differing rates of development of these memory systems may in part contribute to the early emergence of habit-like symptoms in childhood and adolescence. In addition, abnormalities in hippocampal and striatal brain regions have been observed consistently in youth with these disorders, suggesting that the aberrant development of memory systems may also contribute to the emergence of habit-like symptoms as core pathological features of these illnesses. Considering these disorders within the context of multiple memory systems may help elucidate the pathogenesis of habit-like symptoms in childhood and adolescence, and lead to novel treatments that lessen the habit-like behavioral features of these disorders. PMID:24286520

Comprehensive transcriptional map of primate brain development

PubMed Central

Bakken, Trygve E.; Miller, Jeremy A.; Ding, Song-Lin; Sunkin, Susan M.; Smith, Kimberly A.; Ng, Lydia; Szafer, Aaron; Dalley, Rachel A.; Royall, Joshua J.; Lemon, Tracy; Shapouri, Sheila; Aiona, Kaylynn; Arnold, James; Bennett, Jeffrey L.; Bertagnolli, Darren; Bickley, Kristopher; Boe, Andrew; Brouner, Krissy; Butler, Stephanie; Byrnes, Emi; Caldejon, Shiella; Carey, Anita; Cate, Shelby; Chapin, Mike; Chen, Jefferey; Dee, Nick; Desta, Tsega; Dolbeare, Tim A.; Dotson, Nadia; Ebbert, Amanda; Fulfs, Erich; Gee, Garrett; Gilbert, Terri L.; Goldy, Jeff; Gourley, Lindsey; Gregor, Ben; Gu, Guangyu; Hall, Jon; Haradon, Zeb; Haynor, David R.; Hejazinia, Nika; Hoerder-Suabedissen, Anna; Howard, Robert; Jochim, Jay; Kinnunen, Marty; Kriedberg, Ali; Kuan, Chihchau L.; Lau, Christopher; Lee, Chang-Kyu; Lee, Felix; Luong, Lon; Mastan, Naveed; May, Ryan; Melchor, Jose; Mosqueda, Nerick; Mott, Erika; Ngo, Kiet; Nyhus, Julie; Oldre, Aaron; Olson, Eric; Parente, Jody; Parker, Patrick D.; Parry, Sheana; Pendergraft, Julie; Potekhina, Lydia; Reding, Melissa; Riley, Zackery L.; Roberts, Tyson; Rogers, Brandon; Roll, Kate; Rosen, David; Sandman, David; Sarreal, Melaine; Shapovalova, Nadiya; Shi, Shu; Sjoquist, Nathan; Sodt, Andy J.; Townsend, Robbie; Velasquez, Lissette; Wagley, Udi; Wakeman, Wayne B.; White, Cassandra; Bennett, Crissa; Wu, Jennifer; Young, Rob; Youngstrom, Brian L.; Wohnoutka, Paul; Gibbs, Richard A.; Rogers, Jeffrey; Hohmann, John G.; Hawrylycz, Michael J.; Hevner, Robert F.; Molnár, Zoltán; Phillips, John W.; Dang, Chinh; Jones, Allan R.; Amaral, David G.; Bernard, Amy; Lein, Ed S.

2017-01-01

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high resolution transcriptional atlas of rhesus monkey brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical parcellation of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons, and cortical layers and areas acquire adult-like molecular profiles surprisingly late postnatally. Disparate cell populations exhibit distinct developmental timing but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, and approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny. PMID:27409810

Molecular Magnetic Resonance Imaging of Endothelial Activation in the Central Nervous System

PubMed Central

Gauberti, Maxime; Fournier, Antoine P.; Docagne, Fabian; Vivien, Denis; Martinez de Lizarrondo, Sara

2018-01-01

Endothelial cells of the central nervous system over-express surface proteins during neurological disorders, either as a cause, or a consequence, of the disease. Since the cerebral vasculature is easily accessible by large contrast-carrying particles, it constitutes a target of choice for molecular magnetic resonance imaging (MRI). In this review, we highlight the most recent advances in molecular MRI of brain endothelial activation and focus on the development of micro-sized particles of iron oxide (MPIO) targeting adhesion molecules including intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), P-Selectin and E-Selectin. We also discuss the perspectives and challenges for the clinical application of this technology in neurovascular disorders (ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage, diabetes mellitus), neuroinflammatory disorders (multiple sclerosis, brain infectious diseases, sepsis), neurodegenerative disorders (Alzheimer's disease, vascular dementia, aging) and brain cancers (primitive neoplasms, metastasis). PMID:29507614

[Deep brain stimulation in the treatment of movement disorders].

PubMed

Goto, Satoshi

2007-11-01

The introduction of deep brain stimulation (DBS) was a historical step forward for the treatment of advanced and medically intractable movement disorders that include Parkinson's disease, dystonias, essential tremor, and Holmes' tremor. DBS is able to modulate the target region electrically in a reversible and adjustable fashion in contrast to an irreversible and destructive lesioning procedure. In the treatment of movement disorders, the potential targets are the thalamic ventral intermediate nucleus (Vim), globus pallidus internus (GPi), subthalamic nucleus (STN), pedunculopontine nucleus (PPN), and thalamic Vo-complex nucleus. With the development of DBS technology and stereotactic neurosurgical techniques, its therapeutic efficacy has been increased while reducing surgical complications. DBS has become an established therapy for disabling movement disorders and is currently being used to treat neuropsychiatric disorders.

Brain hyperconnectivity in children with autism and its links to social deficits.

PubMed

Supekar, Kaustubh; Uddin, Lucina Q; Khouzam, Amirah; Phillips, Jennifer; Gaillard, William D; Kenworthy, Lauren E; Yerys, Benjamin E; Vaidya, Chandan J; Menon, Vinod

2013-11-14

Autism spectrum disorder (ASD), a neurodevelopmental disorder affecting nearly 1 in 88 children, is thought to result from aberrant brain connectivity. Remarkably, there have been no systematic attempts to characterize whole-brain connectivity in children with ASD. Here, we use neuroimaging to show that there are more instances of greater functional connectivity in the brains of children with ASD in comparison to those of typically developing children. Hyperconnectivity in ASD was observed at the whole-brain and subsystems levels, across long- and short-range connections, and was associated with higher levels of fluctuations in regional brain signals. Brain hyperconnectivity predicted symptom severity in ASD, such that children with greater functional connectivity exhibited more severe social deficits. We replicated these findings in two additional independent cohorts, demonstrating again that at earlier ages, the brain of children with ASD is largely functionally hyperconnected in ways that contribute to social dysfunction. Our findings provide unique insights into brain mechanisms underlying childhood autism. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Brain State Differentiation and Behavioral Inflexibility in Autism†

PubMed Central

Uddin, Lucina Q.; Supekar, Kaustubh; Lynch, Charles J.; Cheng, Katherine M.; Odriozola, Paola; Barth, Maria E.; Phillips, Jennifer; Feinstein, Carl; Abrams, Daniel A.; Menon, Vinod

2015-01-01

Autism spectrum disorders (ASDs) are characterized by social impairments alongside cognitive and behavioral inflexibility. While social deficits in ASDs have extensively been characterized, the neurobiological basis of inflexibility and its relation to core clinical symptoms of the disorder are unknown. We acquired functional neuroimaging data from 2 cohorts, each consisting of 17 children with ASDs and 17 age- and IQ-matched typically developing (TD) children, during stimulus-evoked brain states involving performance of social attention and numerical problem solving tasks, as well as during intrinsic, resting brain states. Effective connectivity between key nodes of the salience network, default mode network, and central executive network was used to obtain indices of functional organization across evoked and intrinsic brain states. In both cohorts examined, a machine learning algorithm was able to discriminate intrinsic (resting) and evoked (task) functional brain network configurations more accurately in TD children than in children with ASD. Brain state discriminability was related to severity of restricted and repetitive behaviors, indicating that weak modulation of brain states may contribute to behavioral inflexibility in ASD. These findings provide novel evidence for a potential link between neurophysiological inflexibility and core symptoms of this complex neurodevelopmental disorder. PMID:25073720

Brain imaging research in autism spectrum disorders: in search of neuropathology and health across the lifespan.

PubMed

Lainhart, Janet E

2015-03-01

Advances in brain imaging research in autism spectrum disorders (ASD) are rapidly occurring, and the amount of neuroimaging research has dramatically increased over the past 5 years. In this review, advances during the past 12 months and longitudinal studies are highlighted. Cross-sectional neuroimaging research provides evidence that the neural underpinnings of the behavioral signs of ASD involve not only dysfunctional integration of information across distributed brain networks but also basic dysfunction in primary cortices.Longitudinal studies of ASD show abnormally enlarged brain volumes and increased rates of brain growth during early childhood in only a small minority of ASD children. There is evidence of disordered development of white matter microstructure and amygdala growth, and at 2 years of age, network inefficiencies in posterior cerebral regions.From older childhood into adulthood, atypical age-variant and age-invariant changes in the trajectories of total and regional brain volumes and cortical thickness are apparent at the group level. There is evidence of abnormalities in posterior lobes and posterior brain networks during the first 2 years of life in ASD and, even in older children and adults, dysfunction in primary cortical areas.

Bipolar disorder: a neural network perspective on a disorder of emotion and motivation.

PubMed

Wessa, Michèle; Kanske, Philipp; Linke, Julia

2014-01-01

Bipolar disorder (BD) is a severe, chronic disease with a heritability of 60-80%. BD is frequently misdiagnosed due to phenomenological overlap with other psychopathologies, an important issue that calls for the identification of biological and psychological vulnerability and disease markers. Altered structural and functional connectivity, mainly between limbic and prefrontal brain areas, have been proposed to underlie emotional and motivational dysregulation in BD and might represent relevant vulnerability and disease markers. In the present laboratory review we discuss functional and structural neuroimaging findings on emotional and motivational dysregulation from our research group in BD patients and healthy individuals at risk to develop BD. As a main result of our studies, we observed altered orbitofrontal and limbic activity and reduced connectivity between dorsal prefrontal and limbic brain regions, as well as reduced integrity of fiber tracts connecting prefrontal and subcortical brain structures in BD patients and high-risk individuals. Our results provide novel insights into pathophysiological mechanisms of bipolar disorder. The current laboratory review provides a specific view of our group on altered brain connectivity and underlying psychological processes in bipolar disorder based on our own work, integrating relevant findings from others. Thereby we attempt to advance neuropsychobiological models of BD.

Cytokines and the neurodevelopmental basis of mental illness

PubMed Central

Ratnayake, Udani; Quinn, Tracey; Walker, David W.; Dickinson, Hayley

2013-01-01

Epidemiological studies suggest that prenatal exposure to different types of viral or bacterial infections may be associated with similar outcomes; i.e., an increased risk of mental illness disorders in the offspring. Infections arising from various causes have similar debilitating effects in later life, suggesting that the exact pathogen may not be the critical factor in determining the neurological and cognitive outcome in the offspring. Instead, it is thought that response of the innate immune system, specifically the increased production of inflammatory cytokines, may be the critical mediator in altering fetal brain development pre-disposing the offspring to mental illness disorders later in life. Inflammatory cytokines are essential for normal brain development. Factors such as the site of cytokine production, a change in balance between anti- and pro- inflammatory cytokines, placental transfer of cytokines, the effects of cytokines on glial cells, and the effects of glucocorticoids are important when evaluating the impact of maternal infection on fetal brain development. Although it is clear that cytokines are altered in the fetal brain following maternal infection, further evidence is required to determine if cytokines are the critical factor that alters the trajectory of brain development, subsequently leading to postnatal behavioral and neurological abnormalities. PMID:24146637

Effects of chromosomal sex and hormonal influences on shaping sex differences in brain and behavior: Lessons from cases of disorders of sex development.

PubMed

Bramble, Matthew S; Lipson, Allen; Vashist, Neerja; Vilain, Eric

2017-01-02

Sex differences in brain development and postnatal behavior are determined largely by genetic sex and in utero gonadal hormone secretions. In humans however, determining the weight that each of these factors contributes remains a challenge because social influences should also be considered. Cases of disorders of sex development (DSD) provide unique insight into how mutations in genes responsible for gonadal formation can perturb the subsequent developmental hormonal milieu and elicit changes in normal human brain maturation. Specific forms of DSDs such as complete androgen insensitivity syndrome (CAIS), congenital adrenal hyperplasia (CAH), and 5α-reductase deficiency syndrome have variable effects between males and females, and the developmental outcomes of such conditions are largely dependent on sex chromosome composition. Medical and psychological works focused on CAH, CAIS, and 5α-reductase deficiency have helped form the foundation for understanding the roles of genetic and hormonal factors necessary for guiding human brain development. Here we highlight how the three aforementioned DSDs contribute to brain and behavioral phenotypes that can uniquely affect 46,XY and 46,XX individuals in dramatically different fashions. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

DMRTA2 (DMRT5) is mutated in a novel cortical brain malformation.

PubMed

Urquhart, J E; Beaman, G; Byers, H; Roberts, N A; Chervinsky, E; O'Sullivan, J; Pilz, D; Fry, A; Williams, S G; Bhaskar, S S; Khayat, M; Simanovsky, N; Shachar, I B; Shalev, S A; Newman, W G

2016-06-01

Lissencephaly is a phenotypically and genetically heterogeneous group of cortical brain malformations due to abnormal neuronal migration. The identification of many causative genes has increased the understanding of normal brain development. A consanguineous family was ascertained with three siblings affected by a severe prenatal neurodevelopmental disorder characterised by fronto-parietal pachygyria, agenesis of the corpus callosum and progressive severe microcephaly. Autozygosity mapping and exome sequencing identified a homozygous novel single base pair deletion, c.1197delT in DMRTA2, predicted to result in a frameshift variant p.(Pro400Leufs*33). DMRTA2 encodes doublesex and mab-3-related transcription factor a2, a transcription factor key to the development of the dorsal telencephalon. Data from murine and zebrafish knockout models are consistent with the variant of DMTRA2 (DMRT5) as responsible for the cortical brain phenotype. Our study suggests that loss of function of DMRTA2 leads to a novel disorder of cortical development. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Peroxisomes in brain development and function☆

PubMed Central

Berger, Johannes; Dorninger, Fabian; Forss-Petter, Sonja; Kunze, Markus

2016-01-01

Peroxisomes contain numerous enzymatic activities that are important for mammalian physiology. Patients lacking either all peroxisomal functions or a single enzyme or transporter function typically develop severe neurological deficits, which originate from aberrant development of the brain, demyelination and loss of axonal integrity, neuroinflammation or other neurodegenerative processes. Whilst correlating peroxisomal properties with a compilation of pathologies observed in human patients and mouse models lacking all or individual peroxisomal functions, we discuss the importance of peroxisomal metabolites and tissue- and cell type-specific contributions to the observed brain pathologies. This enables us to deconstruct the local and systemic contribution of individual metabolic pathways to specific brain functions. We also review the recently discovered variability of pathological symptoms in cases with unexpectedly mild presentation of peroxisome biogenesis disorders. Finally, we explore the emerging evidence linking peroxisomes to more common neurological disorders such as Alzheimer’s disease, autism and amyotrophic lateral sclerosis. This article is part of a Special Issue entitled: Peroxisomes edited by Ralf Erdmann. PMID:26686055

Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms

PubMed Central

Bolton, Jessica L.; Bilbo, Staci D.

2014-01-01

Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly maternal obesity and high-fat diet consumption during gestation/lactation may “program” offspring longterm for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (eg, interleukin [IL]-6, 11-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (eg, serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment. PMID:25364282

The effects of vitamin D on brain development and adult brain function.

PubMed

Kesby, James P; Eyles, Darryl W; Burne, Thomas H J; McGrath, John J

2011-12-05

A role for vitamin D in brain development and function has been gaining support over the last decade. Multiple lines of evidence suggest that this vitamin is actually a neuroactive steroid that acts on brain development, leading to alterations in brain neurochemistry and adult brain function. Early deficiencies have been linked with neuropsychiatric disorders, such as schizophrenia, and adult deficiencies have been associated with a host of adverse brain outcomes, including Parkinson's disease, Alzheimer's disease, depression and cognitive decline. This review summarises the current state of research on the actions of vitamin D in the brain and the consequences of deficiencies in this vitamin. Furthermore, we discuss specific implications of vitamin D status on the neurotransmitter, dopamine. Copyright © 2011 Elsevier Ltd. All rights reserved.

Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders

PubMed Central

Autry, Anita E.

2012-01-01

Brain derived neurotrophic factor (BDNF) is the most prevalent growth factor in the central nervous system (CNS). It is essential for the development of the CNS and for neuronal plasticity. Because BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases. This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Rett syndrome, as well as other psychiatric and neurodevelopmental diseases. In addition, the review includes a discussion of the role of BDNF in the mechanism of action of pharmacological therapies currently used to treat these diseases, such antidepressants and antipsychotics. The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development. PMID:22407616

Characteristics of posttraumatic headache following mild traumatic brain injury in military personnel in Iran.

PubMed

Jouzdani, Saeid Rezaei; Ebrahimi, Ali; Rezaee, Maryam; Shishegar, Mehdi; Tavallaii, Abbas; Kaka, Gholamreza

2014-11-01

The primary goal of this study was to evaluate the incidence and characteristics of posttraumatic headache attributed to mild brain injury in military personnel in Iran within a prospective and observational study design. A prospective observational descriptive study was conducted with a cohort of military personnel under military education during a 6-month period at the Military Education Center in Isfahan, Iran. 322 military personnel under education were selected randomly and were given a 13-item mild brain injury questionnaire accompanied with affective disorders and headache questionnaires and were reevaluated after a 3-month interval. A total of 30 (9.3 %) of the 322 military personnel met criteria for a mild brain injury. Among them, 18 personnel (60 %) reported having headaches during the 3-month reevaluation. PTHs defined as headaches beginning within 1 week after a head trauma were present in 5.6 % of military personnel under study during 6 months. In total, 67 % of posttraumatic headaches (PTH) were classified as migrainous or possible migrainous features. Patients with affective disorders such as posttraumatic stress disorder and depression were at a higher risk for developing PTH following mild brain injury (p < 0.05). PTH did not relate to demographic factors such as age or type of trauma. Posttraumatic headache attributed to mild brain injury is a common disorder in military personnel. Migrainous features are predominant among them in comparison with the general population. PTH is not related to a type of trauma, but has association with affective disorders.

Microarray analysis of gene expression in the cyclooxygenase knockout mice - a connection to autism spectrum disorder.

PubMed

Rai-Bhogal, Ravneet; Ahmad, Eizaaz; Li, Hongyan; Crawford, Dorota A

2018-03-01

The cellular and molecular events that take place during brain development play an important role in governing function of the mature brain. Lipid-signalling molecules such as prostaglandin E 2 (PGE 2 ) play an important role in healthy brain development. Abnormalities along the COX-PGE 2 signalling pathway due to genetic or environmental causes have been linked to autism spectrum disorder (ASD). This study aims to evaluate the effect of altered COX-PGE 2 signalling on development and function of the prenatal brain using male mice lacking cyclooxygenase-1 and cyclooxygenase-2 (COX-1 -/- and COX-2 -/- ) as potential model systems of ASD. Microarray analysis was used to determine global changes in gene expression during embryonic days 16 (E16) and 19 (E19). Gene Ontology: Biological Process (GO:BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were implemented to identify affected developmental genes and cellular processes. We found that in both knockouts the brain at E16 had nearly twice as many differentially expressed genes, and affected biological pathways containing various ASD-associated genes important in neuronal function. Interestingly, using GeneMANIA and Cytoscape we also show that the ASD-risk genes identified in both COX-1 -/- and COX-2 -/- models belong to protein-interaction networks important for brain development despite of different cellular localization of these enzymes. Lastly, we identified eight genes that belong to the Wnt signalling pathways exclusively in the COX-2 -/- mice at E16. The level of PKA-phosphorylated β-catenin (S552), a major activator of the Wnt pathway, was increased in this model, suggesting crosstalk between the COX-2-PGE 2 and Wnt pathways during early brain development. Overall, these results provide further molecular insight into the contribution of the COX-PGE 2 pathways to ASD and demonstrate that COX-1 -/- and COX-2 -/- animals might be suitable new model systems for studying the disorders. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Movement disorders secondary to craniocerebral trauma.

PubMed

Krauss, Joachim K

2015-01-01

Over the past few decades it has been recognized that traumatic brain injury may result in various movement disorders. In survivors of severe head injury, post-traumatic movement disorders were reported in about 20%, and they persisted in about 10% of patients. The most frequent persisting movement disorder in this population is kinetic cerebellar outflow tremor in about 9%, followed by dystonia in about 4%. While tremor is associated most frequently with cerebellar or mesencephalic lesions, patients with dystonia frequently have basal ganglia or thalamic lesions. Moderate or mild traumatic brain injury only rarely causes persistent post-traumatic movement disorders. It appears that the frequency of post-traumatic movement disorders overall has been declining which most likely is secondary to improved treatment of brain injury. In patients with disabling post-traumatic movement disorders which are refractory to medical treatment, stereotactic neurosurgery can provide long-lasting benefit. While in the past the primary option for severe kinetic tremor was thalamotomy and for dystonia thalamotomy or pallidotomy, today deep brain stimulation has become the preferred treatment. Parkinsonism is a rare consequence of single head injury, but repeated head injury such as seen in boxing can result in chronic encephalopathy with parkinsonian features. While there is still controversy whether or not head injury is a risk factor for the development of Parkinson's disease, recent studies indicate that genetic susceptibility might be relevant. © 2015 Elsevier B.V. All rights reserved.

Autism, the superior temporal sulcus and social perception.

PubMed

Zilbovicius, Monica; Meresse, Isabelle; Chabane, Nadia; Brunelle, Francis; Samson, Yves; Boddaert, Nathalie

2006-07-01

The most common clinical sign of autism spectrum disorders (ASD) is social interaction impairment, which is associated with communication deficits and stereotyped behaviors. Based on recent brain-imaging results, our hypothesis is that abnormalities in the superior temporal sulcus (STS) are highly implicated in ASD. STS abnormalities are characterized by decreased gray matter concentration, rest hypoperfusion and abnormal activation during social tasks. STS anatomical and functional anomalies occurring during early brain development could constitute the first step in the cascade of neural dysfunction underlying ASD. We will focus this review on the STS, which has been highly implicated in social cognition. We will review recent data on the contribution of the STS to normal social cognition and review brain-imaging data implicating this area in ASD. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).

Alpha oscillations and their impairment in affective and post-traumatic stress disorders.

PubMed

Eidelman-Rothman, Moranne; Levy, Jonathan; Feldman, Ruth

2016-09-01

Affective and anxiety disorders are debilitating conditions characterized by impairments in cognitive and social functioning. Elucidating their neural underpinnings may assist in improving diagnosis and developing targeted interventions. Neural oscillations are fundamental for brain functioning. Specifically, oscillations in the alpha frequency range (alpha rhythms) are prevalent in the awake, conscious brain and play an important role in supporting perceptual, cognitive, and social processes. We review studies utilizing various alpha power measurements to assess abnormalities in brain functioning in affective and anxiety disorders as well as obsessive compulsive and post-traumatic stress disorders. Despite some inconsistencies, studies demonstrate associations between aberrant alpha patterns and these disorders both in response to specific cognitive and emotional tasks and during a resting state. We conclude by discussing methodological considerations and future directions, and underscore the need for much further research on the role of alpha functionality in social contexts. As social dysfunction accompanies most psychiatric conditions, research on alpha's involvement in social processes may provide a unique window into the neural mechanisms underlying these disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evolving knowledge of sex differences in brain structure, function, and chemistry.

PubMed

Cosgrove, Kelly P; Mazure, Carolyn M; Staley, Julie K

2007-10-15

Clinical and epidemiologic evidence demonstrates sex differences in the prevalence and course of various psychiatric disorders. Understanding sex-specific brain differences in healthy individuals is a critical first step toward understanding sex-specific expression of psychiatric disorders. Here, we evaluate evidence on sex differences in brain structure, chemistry, and function using imaging methodologies, including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), and structural magnetic resonance imaging (MRI) in mentally healthy individuals. MEDLINE searches of English-language literature (1980-November 2006) using the terms sex, gender, PET, SPECT, MRI, fMRI, morphometry, neurochemistry, and neurotransmission were performed to extract relevant sources. The literature suggests that while there are many similarities in brain structure, function, and neurotransmission in healthy men and women, there are important differences that distinguish the male from the female brain. Overall, brain volume is greater in men than women; yet, when controlling for total volume, women have a higher percentage of gray matter and men a higher percentage of white matter. Regional volume differences are less consistent. Global cerebral blood flow is higher in women than in men. Sex-specific differences in dopaminergic, serotonergic, and gamma-aminobutyric acid (GABA)ergic markers indicate that male and female brains are neurochemically distinct. Insight into the etiology of sex differences in the normal living human brain provides an important foundation to delineate the pathophysiological mechanisms underlying sex differences in neuropsychiatric disorders and to guide the development of sex-specific treatments for these devastating brain disorders.

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.

Memory and Brain Volume in Adults Prenatally Exposed to Alcohol

ERIC Educational Resources Information Center

Coles, Claire D.; Goldstein, Felicia C.; Lynch, Mary Ellen; Chen, Xiangchuan; Kable, Julie A.; Johnson, Katrina C.; Hu, Xiaoping

2011-01-01

The impact of prenatal alcohol exposure on memory and brain development was investigated in 92 African-American, young adults who were first identified in the prenatal period. Three groups (Control, n = 26; Alcohol-related Neurodevelopmental Disorder, n = 36; and Dysmorphic, n = 30) were imaged using structural MRI with brain volume calculated for…

Differential brain responses to cries of infants with autistic disorder and typical development: an fMRI study.

PubMed

Venuti, Paola; Caria, Andrea; Esposito, Gianluca; De Pisapia, Nicola; Bornstein, Marc H; de Falco, Simona

2012-01-01

This study used fMRI to measure brain activity during adult processing of cries of infants with autistic disorder (AD) compared to cries of typically developing (TD) infants. Using whole brain analysis, we found that cries of infants with AD compared to those of TD infants elicited enhanced activity in brain regions associated with verbal and prosodic processing, perhaps because altered acoustic patterns of AD cries render them especially difficult to interpret, and increased activity in brain regions associated with emotional processing, indicating that AD cries also elicit more negative feelings and may be perceived as more aversive and/or arousing. Perceived distress engendered by AD cries related to increased activation in brain regions associated with emotional processing. This study supports the hypothesis that cry is an early and meaningful anomaly displayed by children with AD. It could be that cries associated with AD alter parent-child interactions much earlier than the time that reliable AD diagnosis normally occurs. Copyright © 2012 Elsevier Ltd. All rights reserved.

Perinatal inflammation and adult psychopathology: From preclinical models to humans.

PubMed

Depino, Amaicha Mara

2018-05-01

Perinatal environment plays a crucial role in brain development and determines its function through life. Epidemiological studies and clinical reports link perinatal exposure to infection and/or immune activation to various psychiatric disorders. In addition, accumulating evidence from animal models shows that perinatal inflammation can affect various behaviors relevant to psychiatric disorders such as schizophrenia, autism, anxiety and depression. Remarkably, the effects on behavior and brain function do not always depend on the type of inflammatory stimulus or the perinatal age targeted, so diverse inflammatory events can have similar consequences on the brain. Moreover, other perinatal environmental factors that affect behavior (e.g. diet and stress) also elicit inflammatory responses. Understanding the interplay between perinatal environment and inflammation on brain development is required to identify the mechanisms through which perinatal inflammation affect brain function in the adult animal. Evidence for the role of the peripheral immune system and glia on perinatal programming of behavior is discussed in this review, along with recent evidence for the role of epigenetic mechanisms affecting gene expression in the brain. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mass spectrometry-based metabolomics: Targeting the crosstalk between gut microbiota and brain in neurodegenerative disorders.

PubMed

Luan, Hemi; Wang, Xian; Cai, Zongwei

2017-11-12

Metabolomics seeks to take a "snapshot" in a time of the levels, activities, regulation and interactions of all small molecule metabolites in response to a biological system with genetic or environmental changes. The emerging development in mass spectrometry technologies has shown promise in the discovery and quantitation of neuroactive small molecule metabolites associated with gut microbiota and brain. Significant progress has been made recently in the characterization of intermediate role of small molecule metabolites linked to neural development and neurodegenerative disorder, showing its potential in understanding the crosstalk between gut microbiota and the host brain. More evidence reveals that small molecule metabolites may play a critical role in mediating microbial effects on neurotransmission and disease development. Mass spectrometry-based metabolomics is uniquely suitable for obtaining the metabolic signals in bidirectional communication between gut microbiota and brain. In this review, we summarized major mass spectrometry technologies including liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and imaging mass spectrometry for metabolomics studies of neurodegenerative disorders. We also reviewed the recent advances in the identification of new metabolites by mass spectrometry and metabolic pathways involved in the connection of intestinal microbiota and brain. These metabolic pathways allowed the microbiota to impact the regular function of the brain, which can in turn affect the composition of microbiota via the neurotransmitter substances. The dysfunctional interaction of this crosstalk connects neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. The mass spectrometry-based metabolomics analysis provides information for targeting dysfunctional pathways of small molecule metabolites in the development of the neurodegenerative diseases, which may be valuable for the investigation of underlying mechanism of therapeutic strategies. © 2017 Wiley Periodicals, Inc.

Military-related traumatic brain injury and neurodegeneration

PubMed Central

McKee, Ann C.; Robinson, Meghan E.

2014-01-01

Mild traumatic brain injury (mTBI) includes concussion, subconcussion, and most exposures to explosive blast from improvised explosive devices. mTBI is the most common traumatic brain injury affecting military personnel; however, it is the most difficult to diagnose and the least well understood. It is also recognized that some mTBIs have persistent, and sometimes progressive, long-term debilitating effects. Increasing evidence suggests that a single traumatic brain injury can produce long-term gray and white matter atrophy, precipitate or accelerate age-related neurodegeneration, and increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease. In addition, repetitive mTBIs can provoke the development of a tauopathy, chronic traumatic encephalopathy. We found early changes of chronic traumatic encephalopathy in four young veterans of the Iraq and Afghanistan conflict who were exposed to explosive blast and in another young veteran who was repetitively concussed. Four of the five veterans with early-stage chronic traumatic encephalopathy were also diagnosed with posttraumatic stress disorder. Advanced chronic traumatic encephalopathy has been found in veterans who experienced repetitive neurotrauma while in service and in others who were accomplished athletes. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus; septal abnormalities; and abnormal deposits of hyperphosphorylated tau as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy has clinical and pathological features that overlap with postconcussion syndrome and posttraumatic stress disorder, suggesting that the three disorders might share some biological underpinnings. PMID:24924675

Military-related traumatic brain injury and neurodegeneration.

PubMed

McKee, Ann C; Robinson, Meghan E

2014-06-01

Mild traumatic brain injury (mTBI) includes concussion, subconcussion, and most exposures to explosive blast from improvised explosive devices. mTBI is the most common traumatic brain injury affecting military personnel; however, it is the most difficult to diagnose and the least well understood. It is also recognized that some mTBIs have persistent, and sometimes progressive, long-term debilitating effects. Increasing evidence suggests that a single traumatic brain injury can produce long-term gray and white matter atrophy, precipitate or accelerate age-related neurodegeneration, and increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease. In addition, repetitive mTBIs can provoke the development of a tauopathy, chronic traumatic encephalopathy. We found early changes of chronic traumatic encephalopathy in four young veterans of the Iraq and Afghanistan conflict who were exposed to explosive blast and in another young veteran who was repetitively concussed. Four of the five veterans with early-stage chronic traumatic encephalopathy were also diagnosed with posttraumatic stress disorder. Advanced chronic traumatic encephalopathy has been found in veterans who experienced repetitive neurotrauma while in service and in others who were accomplished athletes. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus; septal abnormalities; and abnormal deposits of hyperphosphorylated tau as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy has clinical and pathological features that overlap with postconcussion syndrome and posttraumatic stress disorder, suggesting that the three disorders might share some biological underpinnings. Copyright © 2014. Published by Elsevier Inc.

[Circadian rhythm disruption and human development].

PubMed

Kohyama, Jun

2013-12-01

Ontogenetic developments of rest-activity, sleep-wakefulness, temperature and several hormone rhythms in humans were reviewed. The reported effects of environment on these alterations were also summarized. Then, disorders or conditions which often encounter during early stage of life and reveal circadian rhythm disruptions were described. These disorders or conditions included severe brain damage, visual disturbance, developmental disorders(autistic spectrum disorder and attention deficit/hyperactivity disorder), Rett syndrome, Angelman syndrome, Smith-Magenis syndrome, epilepsy, Yonaki, and inadequate sleep hygiene. Finally, it was emphasized that we should pay special attention on the development of youngsters who showed sleep disturbance during early stage of life with special reference to the later occurrence of developmental disorders.

The Neurobiology of Autism: Theoretical Applications

ERIC Educational Resources Information Center

Schroeder, Jessica H.; Desrocher, Mary; Bebko, James M.; Cappadocia, M. Catherine

2010-01-01

Autism spectrum disorders (ASD) are complex neurological disorders characterized by heterogeneity in skills and impairments. A variety of models have been developed to describe the disorders and a wide range of brain processes have been implicated. This review attempts to integrate some of the consistent neurological findings in the research with…

Prefrontal Dysfunction in Attention-Deficit/Hyperactivity Disorder as Measured by Near-Infrared Spectroscopy

ERIC Educational Resources Information Center

Negoro, Hideki; Sawada, Masayuki; Iida, Junzo; Ota, Toyosaku; Tanaka, Shohei; Kishimoto, Toshifumi

2010-01-01

Recent developments in near-infrared spectroscopy (NIRS) have enabled non-invasive clarification of brain functions in psychiatric disorders with measurement of hemoglobin concentrations as cerebral blood volume. Twenty medication-naive children with attention-deficit/hyperactivity disorder (ADHD) and 20 age- and sex-matched healthy control…

The autistic brain in the context of normal neurodevelopment.

PubMed

Ziats, Mark N; Edmonson, Catherine; Rennert, Owen M

2015-01-01

The etiology of autism spectrum disorders (ASDs) is complex and largely unclear. Among various lines of inquiry, many have suggested convergence onto disruptions in both neural circuitry and immune regulation/glial cell function pathways. However, the interpretation of the relationship between these two putative mechanisms has largely focused on the role of exogenous factors and insults, such as maternal infection, in activating immune pathways that in turn result in neural network abnormalities. Yet, given recent insights into our understanding of human neurodevelopment, and in particular the critical role of glia and the immune system in normal brain development, it is important to consider these putative pathological processes in their appropriate normal neurodevelopmental context. In this review, we explore the hypothesis that the autistic brain cellular phenotype likely represents intrinsic abnormalities of glial/immune processes constitutively operant in normal brain development that result in the observed neural network dysfunction. We review recent studies demonstrating the intercalated role of neural circuit development, the immune system, and glial cells in the normal developing brain, and integrate them with studies demonstrating pathological alterations in these processes in autism. By discussing known abnormalities in the autistic brain in the context of normal brain development, we explore the hypothesis that the glial/immune component of ASD may instead be related to intrinsic exaggerated/abnormal constitutive neurodevelopmental processes such as network pruning. Moreover, this hypothesis may be relevant to other neurodevelopmental disorders that share genetic, pathologic, and clinical features with autism.

Long-term influence of normal variation in neonatal characteristics on human brain development

PubMed Central

Walhovd, Kristine B.; Fjell, Anders M.; Brown, Timothy T.; Kuperman, Joshua M.; Chung, Yoonho; Hagler, Donald J.; Roddey, J. Cooper; Erhart, Matthew; McCabe, Connor; Akshoomoff, Natacha; Amaral, David G.; Bloss, Cinnamon S.; Libiger, Ondrej; Schork, Nicholas J.; Darst, Burcu F.; Casey, B. J.; Chang, Linda; Ernst, Thomas M.; Frazier, Jean; Gruen, Jeffrey R.; Kaufmann, Walter E.; Murray, Sarah S.; van Zijl, Peter; Mostofsky, Stewart; Dale, Anders M.; Jernigan, Terry L.; McCabe, Connor; Chang, Linda; Akshoomoff, Natacha; Newman, Erik; Dale, Anders M.; Ernst, Thomas; Dale, Anders M.; Van Zijl, Peter; Kuperman, Joshua; Murray, Sarah; Bloss, Cinnamon; Schork, Nicholas J.; Appelbaum, Mark; Gamst, Anthony; Thompson, Wesley; Bartsch, Hauke; Jernigan, Terry L.; Dale, Anders M.; Akshoomoff, Natacha; Chang, Linda; Ernst, Thomas; Keating, Brian; Amaral, David; Sowell, Elizabeth; Kaufmann, Walter; Van Zijl, Peter; Mostofsky, Stewart; Casey, B.J.; Ruberry, Erika J.; Powers, Alisa; Rosen, Bruce; Kenet, Tal; Frazier, Jean; Kennedy, David; Gruen, Jeffrey

2012-01-01

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences. PMID:23169628

Long-term influence of normal variation in neonatal characteristics on human brain development.

PubMed

Walhovd, Kristine B; Fjell, Anders M; Brown, Timothy T; Kuperman, Joshua M; Chung, Yoonho; Hagler, Donald J; Roddey, J Cooper; Erhart, Matthew; McCabe, Connor; Akshoomoff, Natacha; Amaral, David G; Bloss, Cinnamon S; Libiger, Ondrej; Schork, Nicholas J; Darst, Burcu F; Casey, B J; Chang, Linda; Ernst, Thomas M; Frazier, Jean; Gruen, Jeffrey R; Kaufmann, Walter E; Murray, Sarah S; van Zijl, Peter; Mostofsky, Stewart; Dale, Anders M

2012-12-04

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences.

Primary Cortical Folding in the Human Newborn: An Early Marker of Later Functional Development

ERIC Educational Resources Information Center

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

2008-01-01

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…

Neuronopathic lysosomal storage disorders: Approaches to treat the central nervous system.

PubMed

Scarpa, Maurizio; Bellettato, Cinzia Maria; Lampe, Christina; Begley, David J

2015-03-01

Pharmacological research has always focused on developing new therapeutic strategies capable of modifying a disease's natural history and improving patients' quality of life. Despite recent advances within the fields of medicine and biology, some diseases still represent a major challenge for successful therapy. Neuronopathic lysosomal storage disorders, in particular, have high rates of morbidity and mortality and a devastating socio-economic effect. Many of the available therapies, such as enzyme replacement therapy, can reverse the natural history of the disease in peripheral organs but, unfortunately, are still unable to reach the central nervous system effectively because they cannot cross the blood-brain barrier that surrounds and protects the brain. Moreover, many lysosomal storage disorders are characterized by a number of blood-brain barrier dysfunctions, which may further contribute to disease neuropathology and accelerate neuronal cell death. These issues, and their context in the development of new therapeutic strategies, will be discussed in detail in this chapter. Copyright © 2014 Elsevier Ltd. All rights reserved.

Ambra1 Shapes Hippocampal Inhibition/Excitation Balance: Role in Neurodevelopmental Disorders.

PubMed

Nobili, Annalisa; Krashia, Paraskevi; Cordella, Alberto; La Barbera, Livia; Dell'Acqua, Maria Concetta; Caruso, Angela; Pignataro, Annabella; Marino, Ramona; Sciarra, Francesca; Biamonte, Filippo; Scattoni, Maria Luisa; Ammassari-Teule, Martine; Cecconi, Francesco; Berretta, Nicola; Keller, Flavio; Mercuri, Nicola Biagio; D'Amelio, Marcello

2018-02-27

Imbalances between excitatory and inhibitory synaptic transmission cause brain network dysfunction and are central to the pathogenesis of neurodevelopmental disorders. Parvalbumin interneurons are highly implicated in this imbalance. Here, we probed the social behavior and hippocampal function of mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene crucial for brain development. We show that heterozygous Ambra1 mice (Ambra +/- ) are characterized by loss of hippocampal parvalbumin interneurons, decreases in the inhibition/excitation ratio, and altered social behaviors that are solely restricted to the female gender. Loss of parvalbumin interneurons in Ambra1 +/- females is further linked to reductions of the inhibitory drive onto principal neurons and alterations in network oscillatory activity, CA1 synaptic plasticity, and pyramidal neuron spine density. Parvalbumin interneuron loss is underlined by increased apoptosis during the embryonic development of progenitor neurons in the medial ganglionic eminence. Together, these findings identify an Ambra1-dependent mechanism that drives inhibition/excitation imbalance in the hippocampus, contributing to abnormal brain activity reminiscent of neurodevelopmental disorders.

White Matter and Development in Children with an Autism Spectrum Disorder

ERIC Educational Resources Information Center

Mak-Fan, Kathleen M.; Morris, Drew; Vidal, Julie; Anagnostou, Evdokia; Roberts, Wendy; Taylor, Margot J.

2013-01-01

Recent research suggests that brain development follows an abnormal trajectory in children with autism spectrum disorders (ASD). The current study examined changes in diffusivity with age within defined white matter tracts in a group of typically developing children and a group of children with an ASD, aged 6 to 14 years. Age by group interactions…

Developing Master Keys to Brain Pathology, Cancer and Aging from the Structural Biology of Proteins Controlling Reactive Oxygen Species and DNA Repair

PubMed Central

Perry, J. Jefferson P.; Fan, Li; Tainer, John A.

2007-01-01

This review is focused on proteins with key roles in pathways controlling either reactive oxygen species or DNA damage responses, both of which are essential for preserving the nervous system. An imbalance of reactive oxygen species or inappropriate DNA damage response likely causes mutational or cytotoxic outcomes, which may lead to cancer and/or aging phenotypes. Moreover, individuals with hereditary disorders in proteins of these cellular pathways have significant neurological abnormalities. Mutations in a superoxide dismutase, which removes oxygen free radicals, may cause the neurodegenerative disease amyotrophic lateral sclerosis. Additionally, DNA repair disorders that affect the brain to varying extents include ataxia-telangiectasia-like disorder, Cockayne syndrome or Werner syndrome. Here, we highlight recent advances gained through structural biochemistry studies on enzymes linked to these disorders and other related enzymes acting within the same cellular pathways. We describe the current understanding of how these vital proteins coordinate chemical steps and integrate cellular signaling and response events. Significantly, these structural studies may provide a set of master keys to developing a unified understanding of the survival mechanisms utilized after insults by reactive oxygen species and genotoxic agents, and also provide a basis for developing an informed intervention in brain tumor and neurodegenerative disease progression. PMID:17174478

Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging

PubMed Central

Pike, Victor W.

2017-01-01

The development of reversibly binding radioligands for imaging brain proteins in vivo, such as enzymes, neurotransmitter transporters, receptors and ion channels, with positron emission tomography (PET) is keenly sought for biomedical studies of neuropsychiatric disorders and for drug discovery and development, but is recognized as being highly challenging at the medicinal chemistry level. This article aims to compile and discuss the main considerations to be taken into account by chemists embarking on programs of radioligand development for PET imaging of brain protein targets. PMID:27087244

Structural MRI biomarkers of shared pathogenesis in autism spectrum disorder and epilepsy.

PubMed

Blackmon, Karen

2015-06-01

Etiological factors that contribute to a high comorbidity between autism spectrum disorder (ASD) and epilepsy are the subject of much debate. Does epilepsy cause ASD or are there common underlying brain abnormalities that increase the risk of developing both disorders? This review summarizes evidence from quantitative MRI studies to suggest that abnormalities of brain structure are not necessarily the consequence of ASD and epilepsy but are antecedent to disease expression. Abnormal gray and white matter volumes are present prior to onset of ASD and evident at the time of onset in pediatric epilepsy. Aberrant brain growth trajectories are also common in both disorders, as evidenced by blunted gray matter maturation and white matter maturation. Although the etiological factors that explain these abnormalities are unclear, high heritability estimates for gray matter volume and white matter microstructure demonstrate that genetic factors assert a strong influence on brain structure. In addition, histopathological studies of ASD and epilepsy brain tissue reveal elevated rates of malformations of cortical development (MCDs), such as focal cortical dysplasia and heterotopias, which supports disruption of neuronal migration as a contributing factor. Although MCDs are not always visible on MRI with conventional radiological analysis, quantitative MRI detection methods show high sensitivity to subtle malformations in epilepsy and can be potentially applied to MCD detection in ASD. Such an approach is critical for establishing quantitative neuroanatomic endophenotypes that can be used in genetic research. In the context of emerging drug treatments for seizures and autism symptoms, such as rapamycin and rapalogs, in vivo neuroimaging markers of subtle structural brain abnormalities could improve sample stratification in human clinical trials and potentially extend the range of patients that might benefit from treatment. This article is part of a Special Issue entitled "Autism and Epilepsy". Copyright © 2015 Elsevier Inc. All rights reserved.

Project TENDR: Targeting Environmental Neuro-Developmental Risks The TENDR Consensus Statement

PubMed Central

Bennett, Deborah; Bellinger, David C.; Birnbaum, Linda S.; Bradman, Asa; Chen, Aimin; Cory-Slechta, Deborah A.; Engel, Stephanie M.; Fallin, M. Daniele; Halladay, Alycia; Hauser, Russ; Hertz-Picciotto, Irva; Kwiatkowski, Carol F.; Lanphear, Bruce P.; Marquez, Emily; Marty, Melanie; McPartland, Jennifer; Newschaffer, Craig J.; Payne-Sturges, Devon; Patisaul, Heather B.; Perera, Frederica P.; Ritz, Beate; Sass, Jennifer; Schantz, Susan L.; Webster, Thomas F.; Whyatt, Robin M.; Woodruff, Tracey J.; Zoeller, R. Thomas; Anderko, Laura; Campbell, Carla; Conry, Jeanne A.; DeNicola, Nathaniel; Gould, Robert M.; Hirtz, Deborah; Huffling, Katie; Landrigan, Philip J.; Lavin, Arthur; Miller, Mark; Mitchell, Mark A.; Rubin, Leslie; Schettler, Ted; Tran, Ho Luong; Acosta, Annie; Brody, Charlotte; Miller, Elise; Miller, Pamela; Swanson, Maureen; Witherspoon, Nsedu Obot

2016-01-01

Summary: Children in America today are at an unacceptably high risk of developing neurodevelopmental disorders that affect the brain and nervous system including autism, attention deficit hyperactivity disorder, intellectual disabilities, and other learning and behavioral disabilities. These are complex disorders with multiple causes—genetic, social, and environmental. The contribution of toxic chemicals to these disorders can be prevented. Approach: Leading scientific and medical experts, along with children’s health advocates, came together in 2015 under the auspices of Project TENDR: Targeting Environmental Neuro-Developmental Risks to issue a call to action to reduce widespread exposures to chemicals that interfere with fetal and children’s brain development. Based on the available scientific evidence, the TENDR authors have identified prime examples of toxic chemicals and pollutants that increase children’s risks for neurodevelopmental disorders. These include chemicals that are used extensively in consumer products and that have become widespread in the environment. Some are chemicals to which children and pregnant women are regularly exposed, and they are detected in the bodies of virtually all Americans in national surveys conducted by the U.S. Centers for Disease Control and Prevention. The vast majority of chemicals in industrial and consumer products undergo almost no testing for developmental neurotoxicity or other health effects. Conclusion: Based on these findings, we assert that the current system in the United States for evaluating scientific evidence and making health-based decisions about environmental chemicals is fundamentally broken. To help reduce the unacceptably high prevalence of neurodevelopmental disorders in our children, we must eliminate or significantly reduce exposures to chemicals that contribute to these conditions. We must adopt a new framework for assessing chemicals that have the potential to disrupt brain development and prevent the use of those that may pose a risk. This consensus statement lays the foundation for developing recommendations to monitor, assess, and reduce exposures to neurotoxic chemicals. These measures are urgently needed if we are to protect healthy brain development so that current and future generations can reach their fullest potential. PMID:27479987

North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2

ClinicalTrials.gov

2018-06-06

Epilepsy; Seizure; Neuromuscular Diseases; Brain Malformation; Intellectual Disability; Autism Spectrum Disorder; Hypotonia; Inborn Errors of Metabolism; Movement Disorders; Genetic Disease; Development Delay; Chromosome Abnormality; Hearing Loss; Dysmorphic Features; Skeletal Dysplasia; Congenital Abnormality; Microcephaly; Macrocephaly

Psychedelics: Where we are now, why we got here, what we must do.

PubMed

Belouin, Sean J; Henningfield, Jack E

2018-02-21

The purpose of this commentary is to provide an introduction to this special issue of Neuropharmacology with a historical perspective of psychedelic drug research, their use in psychiatric disorders, research-restricting regulatory controls, and their recent emergence as potential breakthrough therapies for several brain-related disorders. It begins with the discovery of lysergic acid diethylamide (LSD) and its promising development as a treatment for several types of mental illnesses during the 1940s. This was followed by its abuse and stigmatization in the 1960s that ultimately led to the placement of LSD and other psychedelic drugs into the most restrictively regulated drug schedule of the United States Controlled Substances Act (Schedule I) in 1970 and its international counterparts. These regulatory controls severely constrained development of psychedelic substances and their potential for clinical research in psychiatric disorders. Despite the limitations, there was continued research into brain mechanisms of action for psychedelic drugs with potential clinical applications which began during the 1990s and early 2000s. Finding pathways to accelerate clinical research in psychedelic drug development is supported by the growing body of research findings that are documented throughout this special issue of Neuropharmacology. Accumulated research to date suggests psychedelic drug assisted psychotherapy may emerge as a potential breakthrough treatment for several types of mental illnesses including depression, anxiety, post-traumatic stress disorder, and addiction that are refractory to current evidenced based therapies. This research equally shows promise in advancing the understanding of the brain, brain related functioning, and the consequential effects of untreated brain related diseases that have been implicated in causing and/or exacerbating numerous physical disease state conditions. The authors conclude that more must be done to effectively address mental illnesses and brain related diseases which have become so pervasive, destructive, and whose treatments are becoming increasingly resistant to current evidenced based therapies. Published by Elsevier Ltd.

Toxoplasma gondii-A Gastrointestinal Pathogen Associated with Human Brain Diseases.

PubMed

Severance, E G; Xiao, J; Jones-Brando, L; Sabunciyan, S; Li, Y; Pletnikov, M; Prandovszky, E; Yolken, R

2016-01-01

Serious psychiatric disorders such as schizophrenia, bipolar disorder, and major depression are important causes of mortality and morbidity worldwide. While these are primarily diseases involving altered brain functioning, numerous studies have documented increased rates of gastrointestinal inflammation and dysfunction in many individuals with these disorders. Toxoplasma gondii is an apicomplexan protozoan intracellular parasite with a widespread distribution in both developed and developing countries. Toxoplasma organisms enter the ecosystem through the shedding of oocysts by Toxoplasma-infected felines. In almost all cases of postnatal human infection, Toxoplasma enters its hosts through the intestinal tract either by the ingestion of oocysts or by the consumption of meat from food animals which themselves were infected by Toxoplasma oocysts. It had previously been thought that most cases of Toxoplasma infection in immune competent children and adults were inapparent and asymptomatic. However, recent studies cast doubt on this concept as exposure to Toxoplasma has been associated with a range of acute and chronic symptoms. Of particular note has been the finding of an increased rate of a range of neurological and psychiatric disorders associated with serological evidence of Toxoplasma exposure. A role of Toxoplasma infection in brain diseases is also supported by the consistent finding of altered cognition and behavior in animal models of infections. Much of the attention relating to the role of Toxoplasma infection in neuropsychiatric disorders has focused on the brain, where Toxoplasma tissue cysts can persist for extended periods of time. However, recent discoveries relating to the role of the gastrointestinal tract in cognition and behavior suggest that Toxoplasma may also increase susceptibility to human brain diseases through immune activation, particularly involving the gastrointestinal mucosa. The study of the pathways relating to the pathobiology and immunology of Toxoplasma infection may provide insights into the pathogenesis of a range of human neuropsychiatric disorders as well as into cognitive functioning in otherwise healthy individuals. © 2016 Elsevier Inc. All rights reserved.

Implications of Prenatal Steroid Perturbations for Neurodevelopment, Behavior, and Autism

PubMed Central

Martien, Katherine M.; Gagnidze, Khatuna; Pfaff, Donald

2014-01-01

The prenatal brain develops under the influence of an ever-changing hormonal milieu that includes endogenous fetal gonadal and adrenal hormones, placental and maternal hormones, and exogenous substances with hormonal activity that can cross the placental barrier. This review discusses the influences of endogenous fetal and maternal hormones on normal brain development and potential consequences of pathophysiological hormonal perturbations to the developing brain, with particular reference to autism. We also consider the effects of hormonal pharmaceuticals used for assisted reproduction, the maintenance of pregnancy, the prevention of congenital adrenal hypertrophy, and hormonal contraceptives continued into an unanticipated pregnancy, among others. These treatments, although in some instances life-saving, may have unintended consequences on the developing fetuses. Additional concern is raised by fetal exposures to endocrine-disrupting chemicals encountered universally by pregnant women from food/water containers, contaminated food, household chemicals, and other sources. What are the potential outcomes of prenatal steroid perturbations on neurodevelopmental and behavioral disorders, including autism-spectrum disorders? Our purposes here are 1) to summarize some consequences of steroid exposures during pregnancy for the development of brain and behavior in the offspring; 2) to summarize what is known about the relationships between exposures and behavior, including autism spectrum disorders; 3) to discuss the molecular underpinnings of such effects, especially molecular epigenetic mechanisms of prenatal steroid manipulations, a field that may explain effects of direct exposures, and even transgenerational effects; and 4) for all of these, to add cautionary notes about their interpretation in the name of scientific rigor. PMID:25211453

Implications of prenatal steroid perturbations for neurodevelopment, behavior, and autism.

PubMed

Gore, Andrea C; Martien, Katherine M; Gagnidze, Khatuna; Pfaff, Donald

2014-12-01

The prenatal brain develops under the influence of an ever-changing hormonal milieu that includes endogenous fetal gonadal and adrenal hormones, placental and maternal hormones, and exogenous substances with hormonal activity that can cross the placental barrier. This review discusses the influences of endogenous fetal and maternal hormones on normal brain development and potential consequences of pathophysiological hormonal perturbations to the developing brain, with particular reference to autism. We also consider the effects of hormonal pharmaceuticals used for assisted reproduction, the maintenance of pregnancy, the prevention of congenital adrenal hypertrophy, and hormonal contraceptives continued into an unanticipated pregnancy, among others. These treatments, although in some instances life-saving, may have unintended consequences on the developing fetuses. Additional concern is raised by fetal exposures to endocrine-disrupting chemicals encountered universally by pregnant women from food/water containers, contaminated food, household chemicals, and other sources. What are the potential outcomes of prenatal steroid perturbations on neurodevelopmental and behavioral disorders, including autism-spectrum disorders? Our purposes here are 1) to summarize some consequences of steroid exposures during pregnancy for the development of brain and behavior in the offspring; 2) to summarize what is known about the relationships between exposures and behavior, including autism spectrum disorders; 3) to discuss the molecular underpinnings of such effects, especially molecular epigenetic mechanisms of prenatal steroid manipulations, a field that may explain effects of direct exposures, and even transgenerational effects; and 4) for all of these, to add cautionary notes about their interpretation in the name of scientific rigor.

Translational Approaches for Studying Neurodevelopmental Disorders Utilizing in Vivo Proton (+H) Magnetic Resonance Spectroscopic Imaging in Rats

NASA Technical Reports Server (NTRS)

Ronca, April E.

2014-01-01

Intrauterine complications have been implicated in the etiology of neuripsychiatric disorders including schizophrenia, autism and ADHD. This presentation will describe new translational studies derived from in vivo magnetic resonance imaging of developing and adult brain following perinatal asphyxia (PA). Our findings reveal significant effects of PA on neurometabolic profiles at one week of age, and significant relationships between early metabolites and later life phenotypes including behavior and brain morphometry

Mouse IDGenes: a reference database for genetic interactions in the developing mouse brain

PubMed Central

Matthes, Michaela; Preusse, Martin; Zhang, Jingzhong; Schechter, Julia; Mayer, Daniela; Lentes, Bernd; Theis, Fabian; Prakash, Nilima; Wurst, Wolfgang; Trümbach, Dietrich

2014-01-01

The study of developmental processes in the mouse and other vertebrates includes the understanding of patterning along the anterior–posterior, dorsal–ventral and medial– lateral axis. Specifically, neural development is also of great clinical relevance because several human neuropsychiatric disorders such as schizophrenia, autism disorders or drug addiction and also brain malformations are thought to have neurodevelopmental origins, i.e. pathogenesis initiates during childhood and adolescence. Impacts during early neurodevelopment might also predispose to late-onset neurodegenerative disorders, such as Parkinson’s disease. The neural tube develops from its precursor tissue, the neural plate, in a patterning process that is determined by compartmentalization into morphogenetic units, the action of local signaling centers and a well-defined and locally restricted expression of genes and their interactions. While public databases provide gene expression data with spatio-temporal resolution, they usually neglect the genetic interactions that govern neural development. Here, we introduce Mouse IDGenes, a reference database for genetic interactions in the developing mouse brain. The database is highly curated and offers detailed information about gene expressions and the genetic interactions at the developing mid-/hindbrain boundary. To showcase the predictive power of interaction data, we infer new Wnt/β-catenin target genes by machine learning and validate one of them experimentally. The database is updated regularly. Moreover, it can easily be extended by the research community. Mouse IDGenes will contribute as an important resource to the research on mouse brain development, not exclusively by offering data retrieval, but also by allowing data input. Database URL: http://mouseidgenes.helmholtz-muenchen.de. PMID:25145340

Mouse IDGenes: a reference database for genetic interactions in the developing mouse brain.

PubMed

Matthes, Michaela; Preusse, Martin; Zhang, Jingzhong; Schechter, Julia; Mayer, Daniela; Lentes, Bernd; Theis, Fabian; Prakash, Nilima; Wurst, Wolfgang; Trümbach, Dietrich

2014-01-01

The study of developmental processes in the mouse and other vertebrates includes the understanding of patterning along the anterior-posterior, dorsal-ventral and medial- lateral axis. Specifically, neural development is also of great clinical relevance because several human neuropsychiatric disorders such as schizophrenia, autism disorders or drug addiction and also brain malformations are thought to have neurodevelopmental origins, i.e. pathogenesis initiates during childhood and adolescence. Impacts during early neurodevelopment might also predispose to late-onset neurodegenerative disorders, such as Parkinson's disease. The neural tube develops from its precursor tissue, the neural plate, in a patterning process that is determined by compartmentalization into morphogenetic units, the action of local signaling centers and a well-defined and locally restricted expression of genes and their interactions. While public databases provide gene expression data with spatio-temporal resolution, they usually neglect the genetic interactions that govern neural development. Here, we introduce Mouse IDGenes, a reference database for genetic interactions in the developing mouse brain. The database is highly curated and offers detailed information about gene expressions and the genetic interactions at the developing mid-/hindbrain boundary. To showcase the predictive power of interaction data, we infer new Wnt/β-catenin target genes by machine learning and validate one of them experimentally. The database is updated regularly. Moreover, it can easily be extended by the research community. Mouse IDGenes will contribute as an important resource to the research on mouse brain development, not exclusively by offering data retrieval, but also by allowing data input. http://mouseidgenes.helmholtz-muenchen.de. © The Author(s) 2014. Published by Oxford University Press.

Advances in the understanding of headache.

PubMed

Goadsby, Peter J

2005-01-01

Primary headache disorders account for a substantial part of the morbidity seen in medical practice and so advances in their understanding and management are of general importance. The classification of headache disorders has recently been revised, and the importance of frequent migraine, chronic (transformed) migraine and some important, albeit rarer, conditions that were previously not included has been recognized. Identification of the first genes for a migraine syndrome, namely familial hemiplegic migraine, and their classification as channelopathies opens up new understanding of these disorders and their possible pathophysiology. Functional brain imaging of migraine and cluster headache has placed the pathophysiology of these disorders firmly and clearly in the brain. As our understanding of migraine and related syndromes has increased, new therapies have been developed which reduce the significant disability associated with these important neurological disorders.

BDNF in fragile X syndrome.

PubMed

Castrén, Maija L; Castrén, Eero

2014-01-01

Fragile X syndrome (FXS) is a monogenic disorder that is caused by the absence of FMR1 protein (FMRP). FXS serves as an excellent model disorder for studies investigating disturbed molecular mechanisms and synapse function underlying cognitive impairment, autism, and behavioral disturbance. Abnormalities in dendritic spines and synaptic transmission in the brain of FXS individuals and mouse models for FXS indicate perturbations in the development, maintenance, and plasticity of neuronal network connectivity. However, numerous alterations are found during the early development in FXS, including abnormal differentiation of neural progenitors and impaired migration of newly born neurons. Several aspects of FMRP function are modulated by brain-derived neurotrophic factor (BDNF) signaling. Here, we review the evidence of the role for BDNF in the developing and adult FXS brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects of omega-3 polyunsaturated fatty acids on human brain morphology and function: What is the evidence?

PubMed

Bos, Dienke J; van Montfort, Simone J T; Oranje, Bob; Durston, Sarah; Smeets, Paul A M

2016-03-01

Public opinion and media coverage suggest that there are benefits of long-chain ω-3 polyunsaturated fatty acid (LC-PUFA) intake on brain functioning. However, it is an open question whether this is indeed the case. Therefore, we reviewed the evidence for effects of ω-3 LC-PUFA on human brain morphology and function. We included studies on (1) naturalistic long-term ω-3 LC-PUFA intake during life (2) the effects of short-term ω-3 LC-PUFA supplementation in healthy subjects and (3) the effects of ω-3 LC-PUFA supplementation as alternative or add-on treatment for psychiatric or neurological disorders. To date, 24 studies have been published on the effect of ω-3 LC-PUFA on brain function and structure. Findings from naturalistic studies and clinical trials in healthy individuals indicate that ω-3 LC-PUFA intake may be associated with increased functional activation of the prefrontal cortex in children, and greater gray matter volume and white matter integrity during aging. However, most naturalistic studies were cross-sectional or did not find any effect on cognition. As such, it is hard to estimate the magnitude of any beneficial effects. Furthermore, there is only limited evidence to support that ω-3 LC-PUFA supplementation is beneficial in brain disorders, such as Alzheimer's Disease, Attention Deficit/Hyperactivity Disorder, Major Depressive Disorder and schizophrenia. Overall, the literature suggests that sensitivity to supplementation may vary over development, and as a consequence of brain disorders. The biological mechanisms underlying any (beneficial) effects ω-3 LC-PUFAs on the brain are currently unknown and need to be investigated. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

ALL OUR SONS: THE DEVELOPMENTAL NEUROBIOLOGY AND NEUROENDOCRINOLOGY OF BOYS AT RISK.

PubMed

Schore, Allan N

2017-01-01

Why are boys at risk? To address this question, I use the perspective of regulation theory to offer a model of the deeper psychoneurobiological mechanisms that underlie the vulnerability of the developing male. The central thesis of this work dictates that significant gender differences are seen between male and female social and emotional functions in the earliest stages of development, and that these result from not only differences in sex hormones and social experiences but also in rates of male and female brain maturation, specifically in the early developing right brain. I present interdisciplinary research which indicates that the stress-regulating circuits of the male brain mature more slowly than those of the female in the prenatal, perinatal, and postnatal critical periods, and that this differential structural maturation is reflected in normal gender differences in right-brain attachment functions. Due to this maturational delay, developing males also are more vulnerable over a longer period of time to stressors in the social environment (attachment trauma) and toxins in the physical environment (endocrine disruptors) that negatively impact right-brain development. In terms of differences in gender-related psychopathology, I describe the early developmental neuroendocrinological and neurobiological mechanisms that are involved in the increased vulnerability of males to autism, early onset schizophrenia, attention deficit hyperactivity disorder, and conduct disorders as well as the epigenetic mechanisms that can account for the recent widespread increase of these disorders in U.S. culture. I also offer a clinical formulation of early assessments of boys at risk, discuss the impact of early childcare on male psychopathogenesis, and end with a neurobiological model of optimal adult male socioemotional functions. © 2017 Michigan Association for Infant Mental Health.

An Australian Brain Bank: a critical investment with a high return!

PubMed

Sheedy, D; Garrick, T; Dedova, I; Hunt, C; Miller, R; Sundqvist, N; Harper, C

2008-09-01

Research into neuropsychiatric disorders, including alcohol-related problems, is limited in part by the lack of appropriate animal models. However, the development of new technologies in pathology and molecular biology means that many more questions can be addressed using appropriately stored human brain tissues. The New South Wales Tissue Resource Centre (TRC) in the University of Sydney (Australia) is a human brain bank that can provide tissues to the neuroscience research community studying alcohol-related brain disorders, schizophrenia, depression and bipolar disorders. Carefully standardised operational protocols and integrated information systems means that the TRC can provide high quality, accurately characterised, tissues for research. A recent initiative, the pre-mortem donor program called "Using our Brains", encourages individuals without neuropsychiatric illness to register as control donors, a critical group for all research. Community support for this program is strong with over 2,000 people registering their interest. Discussed herein are the protocols pertaining to this multifaceted facility and the benefits of investment, both scientific and financial, to neuroscience researchers and the community at large.

Brain donation in psychiatry: results of a Dutch prospective donor program among psychiatric cohort participants.

PubMed

de Lange, Geertje M; Rademaker, Marleen; Boks, Marco P; Palmen, Saskia J M C

2017-10-20

Human brain tissue is crucial to study the molecular and cellular basis of psychiatric disorders. However, the current availability of human brain tissue is inadequate. Therefore, the Netherlands Brain Bank initiated a program in which almost 4.000 participants of 15 large Dutch psychiatric research cohorts were asked to register as prospective brain donors. We approached patients with schizophrenia, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder, families with a child with autism or Attention Deficit Hyperactivity Disorder, healthy relatives and healthy unrelated controls, either face-to-face or by post. We investigated whether diagnosis, method of approach, age, and gender were related to the likelihood of brain-donor registration. We found a striking difference in registration efficiency between the diagnosis groups. Patients with bipolar disorder and healthy relatives registered most often (25% respectively 17%), followed by unrelated controls (8%) and patients with major depressive disorder, post-traumatic stress disorder, and obsessive-compulsive disorder (9%, 6% resp. 5%). A face-to-face approach was 1.3 times more effective than a postal approach and the likelihood of registering as brain donor significantly increased with age. Gender did not make a difference. Between 2013 and 2016, our prospective brain-donor program for psychiatry resulted in an almost eightfold increase (from 149 to 1149) in the number of registered psychiatric patients at the Netherlands Brain Bank. Based on our results we recommend, when starting a prospective brain donor program in psychiatric patients, to focus on face to face recruitment of people in their sixties or older.

The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders

PubMed Central

Kundakovic, Marija; Jaric, Ivana

2017-01-01

Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf). These epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. Although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. An extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders. PMID:28335457

Infant Brain Development and Vulnerability to Later Internalizing Difficulties: The Generation R Study

ERIC Educational Resources Information Center

Herba, Catherine M.; Roza, Sabine J.; Govaert, Paul; van Rossum, Joram; Hofman, Albert; Jaddoe, Vincent; Verhulst, Frank C.; Tiemeier, Henning

2010-01-01

Objective: Although clinical studies have demonstrated smaller subcortical volumes in structures such as the amygdala, hippocampus, caudate nucleus, and thalamus in adults and adolescents with depressive disorders and anxiety, no study has assessed such structures in babies, long before the development of the disorders. This study examined whether…

Neural markers of social and monetary rewards in children with Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder.

PubMed

Gonzalez-Gadea, Maria Luz; Sigman, Mariano; Rattazzi, Alexia; Lavin, Claudio; Rivera-Rei, Alvaro; Marino, Julian; Manes, Facundo; Ibanez, Agustin

2016-07-28

Recent theories of decision making propose a shared value-related brain mechanism for encoding monetary and social rewards. We tested this model in children with Attention-Deficit/Hyperactivity Disorder (ADHD), children with Autism Spectrum Disorder (ASD) and control children. We monitored participants' brain dynamics using high density-electroencephalography while they played a monetary and social reward tasks. Control children exhibited a feedback Error-Related Negativity (fERN) modulation and Anterior Cingulate Cortex (ACC) source activation during both tasks. Remarkably, although cooperation resulted in greater losses for the participants, the betrayal options generated greater fERN responses. ADHD subjects exhibited an absence of fERN modulation and reduced ACC activation during both tasks. ASD subjects exhibited normal fERN modulation during monetary choices and inverted fERN/ACC responses in social options than did controls. These results suggest that in neurotypicals, monetary losses and observed disloyal social decisions induced similar activity in the brain value system. In ADHD children, difficulties in reward processing affected early brain signatures of monetary and social decisions. Conversely, ASD children showed intact neural markers of value-related monetary mechanisms, but no brain modulation by prosociality in the social task. These results offer insight into the typical and atypical developments of neural correlates of monetary and social reward processing.

5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders

PubMed Central

Ciranna, Lucia; Catania, Maria Vincenza

2014-01-01

Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD. PMID:25221471

Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI.

PubMed

Prasad, Kedar N; Bondy, Stephen C

2015-03-02

Post-traumatic stress disorder (PTSD) is a complex mental disorder with psychological and emotional components, caused by exposure to single or repeated extreme traumatic events found in war, terrorist attacks, natural or man-caused disasters, and by violent personal assaults and accidents. Mild traumatic brain injury (TBI) occurs when the brain is violently rocked back and forth within the skull following a blow to the head or neck as in contact sports, or when in close proximity to a blast pressure wave following detonation of explosives in the battlefield. Penetrating TBI occurs when an object penetrates the skull and damages the brain, and is caused by vehicle crashes, gunshot wound to the head, and exposure to solid fragments in the proximity of explosions, and other combat-related head injuries. Despite clinical studies and improved understanding of the mechanisms of cellular damage, prevention and treatment strategies for patients with PTSD and TBI remain unsatisfactory. To develop an improved plan for treating and impeding progression of PTSD and TBI, it is important to identify underlying biochemical changes that may play key role in the initiation and progression of these disorders. This review identifies three common biochemical events, namely oxidative stress, chronic inflammation and excitotoxicity that participate in the initiation and progression of these conditions. While these features are separately discussed, in many instances, they overlap. This review also addresses the goal of developing novel treatments and drug regimens, aimed at combating this triad of events common to, and underlying, injury to the brain. Copyright © 2014 Elsevier B.V. All rights reserved.

Measurement and Analysis of Olfactory Responses with the Aim of Establishing an Objective Diagnostic Method for Central Olfactory Disorders

NASA Astrophysics Data System (ADS)

Uno, Tominori; Wang, Li-Qun; Miwakeichi, Fumikazu; Tonoike, Mitsuo; Kaneda, Teruo

In order to establish a new diagnostic method for central olfactory disorders and to identify objective indicators, we measured and analyzed brain activities in the parahippocampal gyrus and uncus, region of responsibility for central olfactory disorders. The relationship between olfactory stimulation and brain response at region of responsibility can be examined in terms of fitted responses (FR). FR in these regions may be individual indicators of changes in brain olfactory responses. In the present study, in order to non-invasively and objectively measure olfactory responses, an odor oddball task was conducted on four healthy volunteers using functional magnetic resonance imaging (fMRI) and a odorant stimulator with blast-method. The results showed favorable FR and activation in the parahippocampal gyrus or uncus in all subjects. In some subjects, both the parahippocampal gyrus and uncus were activated. Furthermore, activation was also confirmed in the cingulate gyrus, middle frontal gyrus, precentral gyrus, postcentral gyrus, superior temporal gyrus and insula. The hippocampus and uncus are known to be involved in the olfactory disorders associated with early-stage Alzheimer's disease and other olfactory disorders. In the future, it will be necessary to further develop the present measurement and analysis method to clarify the relationship between central olfactory disorders and brain activities and establish objective indicators that are useful for diagnosis.

Interaction between BDNF rs6265 Met allele and low family cohesion is associated with smaller left hippocampal volume in pediatric bipolar disorder.

PubMed

Zeni, Cristian Patrick; Mwangi, Benson; Cao, Bo; Hasan, Khader M; Walss-Bass, Consuelo; Zunta-Soares, Giovana; Soares, Jair C

2016-01-01

Genetic and environmental factors are implicated in the onset and evolution of pediatric bipolar disorder, and may be associated to structural brain abnormalities. The aim of our study was to assess the impact of the interaction between the Brain-Derived Neurotrophic Factor (BDNF) rs6265 polymorphism and family functioning on hippocampal volumes of children and adolescents with bipolar disorder, and typically-developing controls. We evaluated the family functioning cohesion subscale using the Family Environment Scale-Revised, genotyped the BDNF rs6265 polymorphism, and performed structural brain imaging in 29 children and adolescents with bipolar disorder, and 22 healthy controls. We did not find significant differences between patients with BD or controls in left or right hippocampus volume (p=0.44, and p=0.71, respectively). However, we detected a significant interaction between low scores on the cohesion subscale and the presence of the Met allele at BNDF on left hippocampal volume of patients with bipolar disorder (F=3.4, p=0.043). None of the factors independently (BDNF Val66Met, cohesion scores) was significantly associated with hippocampal volume differences. small sample size, cross-sectional study. These results may lead to a better understanding of the impact of the interaction between genes and environment factors on brain structures associated to bipolar disorder and its manifestations. Copyright © 2015 Elsevier B.V. All rights reserved.

Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior.

PubMed

Patrick, Rhonda P; Ames, Bruce N

2015-06-01

Serotonin regulates a wide variety of brain functions and behaviors. Here, we synthesize previous findings that serotonin regulates executive function, sensory gating, and social behavior and that attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior all share in common defects in these functions. It has remained unclear why supplementation with omega-3 fatty acids and vitamin D improve cognitive function and behavior in these brain disorders. Here, we propose mechanisms by which serotonin synthesis, release, and function in the brain are modulated by vitamin D and the 2 marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D hormone. Inadequate levels of vitamin D (∼70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal. We propose mechanisms by which EPA increases serotonin release from presynaptic neurons by reducing E2 series prostaglandins and DHA influences serotonin receptor action by increasing cell membrane fluidity in postsynaptic neurons. We propose a model whereby insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression. This model suggests that optimizing vitamin D and marine omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction. © FASEB.

Neuroimaging is a novel tool to understand the impact of environmental chemicals on neurodevelopment.

PubMed

Horton, Megan K; Margolis, Amy E; Tang, Cheuk; Wright, Robert

2014-04-01

The prevalence of childhood neurodevelopmental disorders has been increasing over the last several decades. Prenatal and early childhood exposure to environmental toxicants is increasingly recognized as contributing to the growing rate of neurodevelopmental disorders. Very little information is known about the mechanistic processes by which environmental chemicals alter brain development. We review the recent advances in brain imaging modalities and discuss their application in epidemiologic studies of prenatal and early childhood exposure to environmental toxicants. Neuroimaging techniques (volumetric and functional MRI, diffusor tensor imaging, and magnetic resonance spectroscopy) have opened unprecedented access to study the developing human brain. These techniques are noninvasive and free of ionization radiation making them suitable for research applications in children. Using these techniques, we now understand much about structural and functional patterns in the typically developing brain. This knowledge allows us to investigate how prenatal exposure to environmental toxicants may alter the typical developmental trajectory. MRI is a powerful tool that allows in-vivo visualization of brain structure and function. Used in epidemiologic studies of environmental exposure, it offers the promise to causally link exposure with behavioral and cognitive manifestations and ultimately to inform programs to reduce exposure and mitigate adverse effects of exposure.

Genes, Brain Development and Psychiatric Phenotypes in Velo-Cardio-Facial Syndrome

ERIC Educational Resources Information Center

Gothelf, Doron; Schaer, Marie; Eliez, Stephan

2008-01-01

Velo-cardio-facial syndrome (VCFS) has been in the focus of intensive research over the last 15 years. The syndrome represents a homogeneous model for studying the effect of a decreased dosage of genes on the development of brain structure and function and, consequently, on the emergence of schizophrenia-like psychotic disorder. In this review, we…

Narratives Reflecting the Lived Experiences of People with Brain Disorders: Common Psychosocial Difficulties and Determinants

PubMed Central

Hartley, Sally; McArthur, Maggie; Coenen, Michaela; Cabello, Maria; Covelli, Venusia; Roszczynska-Michta, Joanna; Pitkänen, Tuuli; Bickenbach, Jerome; Cieza, Alarcos

2014-01-01

Background People with brain disorders - defined as both, mental disorders and neurological disorders experience a wide range of psychosocial difficulties (PSDs) (e.g., concentrating, maintaining energy levels, and maintaining relationships). Research evidence is required to show that these PSDs are common across brain disorders. Objectives To explore and gain deeper understanding of the experiences of people with seven brain disorders (alcohol dependency, depression, epilepsy, multiple sclerosis, Parkinson’s disease, schizophrenia, stroke). It examines the common PSDs and their influencing factors. Methods Seventy seven qualitative studies identified in a systematic literature review and qualitative data derived from six focus groups are used to generate first-person narratives representing seven brain disorders. A theory-driven thematic analysis of these narratives identifies the PSDs and their influencing factors for comparison between the seven disorders. Results First-person narratives illustrate realities for people with brain disorders facilitating a deeper understanding of their every-day life experiences. Thematic analysis serves to highlight the commonalities, both of PSDs, such as loneliness, anger, uncertainty about the future and problems with work activities, and their determinants, such as work opportunities, trusting relationships and access to self-help groups. Conclusions The strength of the methodology and the narratives is that they provide the opportunity for the reader to empathise with people with brain disorders and facilitate deeper levels of understanding of the complexity of the relationship of PSDs, determinants and facilitators. The latter reflect positive aspects of the lives of people with brain disorders. The result that many PSDs and their influencing factors are common to people with different brain disorders opens up the door to the possibility of using cross-cutting interventions involving different sectors. This strengthens the message that ‘a great deal can be done’ to improve the lived experience of persons with brain disorders when medical interventions are exhausted. PMID:24805128

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

Neuroimaging in Posttraumatic Stress Disorder and Other Stress-related Disorders

PubMed Central

Bremner, J. Douglas

2009-01-01

Synopsis Traumatic stress has a broad range of effects on the brain. Brain areas implicated in the stress response include the amygdala, hippocampus, and prefrontal cortex. Studies in patients with posttraumatic stress disorder (PTSD) and other psychiatric disorders related to stress have replicated findings in animal studies by finding alterations in these brain areas. Brain regions implicated in PTSD also play an important role in memory function, highlighting the important interplay between memory and the traumatic stress response. Abnormalities in these brain areas are hypothesized to underlie symptoms of PTSD and other stress-related psychiatric disorders. PMID:17983968

The effect of nanoparticle size on the ability to cross the blood-brain barrier: an in vivo study.

PubMed

Betzer, Oshra; Shilo, Malka; Opochinsky, Renana; Barnoy, Eran; Motiei, Menachem; Okun, Eitan; Yadid, Gal; Popovtzer, Rachela

2017-07-01

Our goal was to develop an efficient nanoparticle-based system that can overcome the restrictive mechanism of the blood-brain barrier (BBB) by targeting insulin receptors and would thus enable drug delivery to the brain. Insulin-coated gold nanoparticles (INS-GNPs) were synthesized to serve as a BBB transport system. The effect of nanoparticle size (20, 50 and 70 nm) on their ability to cross the BBB was quantitatively investigated in Balb/C mice. The most widespread biodistribution and highest accumulation within the brain were observed using 20 nm INS-GNPs, 2 h post injection. In vivo CT imaging revealed that particles migrated to specific brain regions, which are involved in neurodegenerative and neuropsychiatric disorders. These findings promote the optimization of nanovehicles for transport of drugs through the BBB. The insulin coating of the particles enabled targeting of specific brain regions, suggesting the potential use of INS-GNPs for delivery of various treatments for brain-related disorders.

Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders.

PubMed

O'Donnell, Cian; Gonçalves, J Tiago; Portera-Cailliau, Carlos; Sejnowski, Terrence J

2017-10-11

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here, we combined computational simulations with analysis of in vivo two-photon Ca 2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: (1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; (2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; (3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher dimensional models that can better capture the multidimensional computational functions of neural circuits.

Precise and accurate assay of pregnenolone and five other neurosteroids in monkey brain tissue by LC-MS/MS.

PubMed

Dury, Alain Y; Ke, Yuyong; Labrie, Fernand

2016-09-01

A series of steroids present in the brain have been named "neurosteroids" following the possibility of their role in the central nervous system impairments such as anxiety disorders, depression, premenstrual dysphoric disorder (PMDD), addiction, or even neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Study of their potential role requires a sensitive and accurate assay of their concentration in the monkey brain, the closest model to the human. We have thus developed a robust, precise and accurate liquid chromatography-tandem mass spectrometry method for the assay of pregnenolone, pregnanolone, epipregnanolone, allopregnanolone, epiallopregnanolone, and androsterone in the cynomolgus monkey brain. The extraction method includes a thorough sample cleanup using protein precipitation and phospholipid removal, followed by hexane liquid-liquid extraction and a Girard T ketone-specific derivatization. This method opens the possibility of investigating the potential implication of these six steroids in the most suitable animal model for neurosteroid-related research. Copyright © 2016 Elsevier Inc. All rights reserved.

Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders

PubMed Central

Gonçalves, J Tiago; Portera-Cailliau, Carlos

2017-01-01

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here, we combined computational simulations with analysis of in vivo two-photon Ca2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: (1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; (2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; (3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher dimensional models that can better capture the multidimensional computational functions of neural circuits. PMID:29019321

Progressive gender differences of structural brain networks in healthy adults: a longitudinal, diffusion tensor imaging study.

PubMed

Sun, Yu; Lee, Renick; Chen, Yu; Collinson, Simon; Thakor, Nitish; Bezerianos, Anastasios; Sim, Kang

2015-01-01

Sexual dimorphism in the brain maturation during childhood and adolescence has been repeatedly documented, which may underlie the differences in behaviors and cognitive performance. However, our understanding of how gender modulates the development of structural connectome in healthy adults is still not entirely clear. Here we utilized graph theoretical analysis of longitudinal diffusion tensor imaging data over a five-year period to investigate the progressive gender differences of brain network topology. The brain networks of both genders showed prominent economical "small-world" architecture (high local clustering and short paths between nodes). Additional analysis revealed a more economical "small-world" architecture in females as well as a greater global efficiency in males regardless of scan time point. At the regional level, both increased and decreased efficiency were found across the cerebral cortex for both males and females, indicating a compensation mechanism of cortical network reorganization over time. Furthermore, we found that weighted clustering coefficient exhibited significant gender-time interactions, implying different development trends between males and females. Moreover, several specific brain regions (e.g., insula, superior temporal gyrus, cuneus, putamen, and parahippocampal gyrus) exhibited different development trajectories between males and females. Our findings further prove the presence of sexual dimorphism in brain structures that may underlie gender differences in behavioral and cognitive functioning. The sex-specific progress trajectories in brain connectome revealed in this work provide an important foundation to delineate the gender related pathophysiological mechanisms in various neuropsychiatric disorders, which may potentially guide the development of sex-specific treatments for these devastating brain disorders.

Insulin Action in Brain Regulates Systemic Metabolism and Brain Function

PubMed Central

Kleinridders, André; Ferris, Heather A.; Cai, Weikang

2014-01-01

Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in the brain leads to impairment of neuronal function and synaptogenesis. In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease. Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases. PMID:24931034

Linking traumatic brain injury to chronic traumatic encephalopathy: identification of potential mechanisms leading to neurofibrillary tangle development.

PubMed

Lucke-Wold, Brandon Peter; Turner, Ryan Coddington; Logsdon, Aric Flint; Bailes, Julian Edwin; Huber, Jason Delwyn; Rosen, Charles Lee

2014-07-01

Significant attention has recently been drawn to the potential link between head trauma and the development of neurodegenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sports-related concussions in athletes and blast-induced traumatic brain injury in soldiers elevates the risk for future development of chronic neurodegenerative diseases such as CTE. CTE is a progressive disease distinguished by characteristic tau neurofibrillary tangles (NFTs) and, occasionally, transactive response DNA binding protein 43 (TDP43) oligomers, both of which have a predilection for perivascular and subcortical areas near reactive astrocytes and microglia. The disease is currently only diagnosed postmortem by neuropathological identification of NFTs. A recent workshop sponsored by National Institute of Neurological Disorders and Stroke emphasized the need for premortem diagnosis, to better understand disease pathophysiology and to develop targeted treatments. In order to accomplish this objective, it is necessary to discover the mechanistic link between acute neurotrauma and the development of chronic neurodegenerative and neuropsychiatric disorders such as CTE. In this review, we briefly summarize what is currently known about CTE development and pathophysiology, and subsequently discuss injury-induced pathways that warrant further investigation. Understanding the mechanistic link between acute brain injury and chronic neurodegeneration will facilitate the development of appropriate diagnostic and therapeutic options for CTE and other related disorders.

The Influence of Adipose Tissue on Brain Development, Cognition, and Risk of Neurodegenerative Disorders.

PubMed

Letra, Liliana; Santana, Isabel

2017-01-01

The brain is a highly metabolic organ and thus especially vulnerable to changes in peripheral metabolism, including those induced by obesity-associated adipose tissue dysfunction. In this context, it is likely that the development and maturation of neurocognitive circuits may also be affected and modulated by metabolic environmental factors, beginning in utero. It is currently recognized that maternal obesity, either pre-gestational or gestational, negatively influences fetal brain development and elevates the risk of cognitive impairment and neuropsychiatric disorders in the offspring. During infancy and adolescence, obesity remains a limiting factor for healthy neurodevelopment, especially affecting executive functions but also attention, visuospatial ability, and motor skills. In middle age, obesity seems to induce an accelerated brain aging and thus may increase the risk of age-related neurodegenerative diseases such as Alzheimer's disease. In this chapter we review and discuss experimental and clinical evidence focusing on the influence of adipose tissue dysfunction on neurodevelopment and cognition across lifespan, as well as some possible mechanistic links, namely the role of the most well studied adipokines.

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.

The neuropathology of traumatic brain injury.

PubMed

Mckee, Ann C; Daneshvar, Daniel H

2015-01-01

Traumatic brain injury, a leading cause of mortality and morbidity, is divided into three grades of severity: mild, moderate, and severe, based on the Glasgow Coma Scale, the loss of consciousness, and the development of post-traumatic amnesia. Although mild traumatic brain injury, including concussion and subconcussion, is by far the most common, it is also the most difficult to diagnose and the least well understood. Proper recognition, management, and treatment of acute concussion and mild traumatic brain injury are the fundamentals of an emerging clinical discipline. It is also becoming increasingly clear that some mild traumatic brain injuries have persistent, and sometimes progressive, long-term debilitating effects. Evidence indicates that a single traumatic brain injury can precipitate or accelerate multiple age-related neurodegenerations, increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease, and that repetitive mild traumatic brain injuries can provoke the development of a tauopathy, chronic traumatic encephalopathy. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus, septal abnormalities, and abnormal deposits of hyperphosphorylated tau (τ) as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy frequently occurs as a sole diagnosis, but may be associated with other neurodegenerative disorders, including Alzheimer's disease, Lewy body disease, and motor neuron disease. Currently, chronic traumatic encephalopathy can be diagnosed only at autopsy; however, promising efforts to develop imaging, spinal fluid, and peripheral blood biomarkers are underway to diagnose and monitor the course of disease in living subjects. © 2015 Elsevier B.V. All rights reserved.

Addressing the Complexity of Tourette's Syndrome through the Use of Animal Models

PubMed Central

Nespoli, Ester; Rizzo, Francesca; Boeckers, Tobias M.; Hengerer, Bastian; Ludolph, Andrea G.

2016-01-01

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by fluctuating motor and vocal tics, usually preceded by sensory premonitions, called premonitory urges. Besides tics, the vast majority—up to 90%—of TS patients suffer from psychiatric comorbidities, mainly attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The etiology of TS remains elusive. Genetics is believed to play an important role, but it is clear that other factors contribute to TS, possibly altering brain functioning and architecture during a sensitive phase of neural development. Clinical brain imaging and genetic studies have contributed to elucidate TS pathophysiology and disease mechanisms; however, TS disease etiology still is poorly understood. Findings from genetic studies led to the development of genetic animal models, but they poorly reflect the pathophysiology of TS. Addressing the role of neurotransmission, brain regions, and brain circuits in TS disease pathomechanisms is another focus area for preclinical TS model development. We are now in an interesting moment in time when numerous innovative animal models are continuously brought to the attention of the public. Due to the diverse and largely unknown etiology of TS, there is no single preclinical model featuring all different aspects of TS symptomatology. TS has been dissected into its key symptomst hat have been investigated separately, in line with the Research Domain Criteria concept. The different rationales used to develop the respective animal models are critically reviewed, to discuss the potential of the contribution of animal models to elucidate TS disease mechanisms. PMID:27092043

Canonical TGF-β Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression.

PubMed

Nakashima, Hideyuki; Tsujimura, Keita; Irie, Koichiro; Ishizu, Masataka; Pan, Miao; Kameda, Tomonori; Nakashima, Kinichi

2018-05-16

Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-β (TGF-β) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-β family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG-interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF-β family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-β receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-β signaling is involved in the pathogenesis of neurodevelopmental diseases. SIGNIFICANCE STATEMENT Canonical transforming growth factor-β (TGF-β) signaling plays a crucial role in multiple organ development, including brain, and mutations in components of the signaling pathway associated with several human developmental disorders. In this study, we found that Smads/TG-interacting factor-dependent canonical TGF-β signaling regulates neuronal morphogenesis through the suppression of collapsin response mediator protein-2 (CRMP2) expression during brain development, and that function of this signaling is evolutionarily conserved in the mammalian brain. Mutations in canonical TGF-β signaling factors identified in patients with neurodevelopmental disorders disrupt the morphological development of neurons. Thus, our results suggest that proper control of TGF-β/Smads/CRMP2 signaling pathways is critical for the precise execution of neuronal morphogenesis, whose impairment eventually results in neurodevelopmental disorders. Copyright © 2018 the authors 0270-6474/18/384791-20$15.00/0.

Use of the emotional Stroop to assess psychological trauma following traumatic brain injury.

PubMed

Coates, Richard C

2008-04-01

A modified Stroop task was used to investigate the hypothesis that implicit memory may be a possible mechanism for the development of acute stress disorder (ASD) in patients who have suffered a closed head injury. Three groups of hospital patients were compared within 1 month post-trauma: road traffic accident (RTA) patients with a brain injury (n = 15), RTA patients without a brain injury (n = 13) and a control group of orthopaedic and plastics patients (n = 15). Participants named colours of five types of words: RTA-related words, words related to hospitalization, obsessive-compulsive disorder (OCD) words, positive words and neutral words. Participants were also administered the Acute Stress Disorder Interview and the State-Trait Anxiety Inventory. Both RTA patients with and without a brain injury demonstrated significant interference on words related to an RTA. Significant interference was unexpectedly observed for OCD words in RTA patients. Control patients did not display significant interference effects. Findings suggested that patients, both with and without explicit recall for an RTA, responded similarly on a task involving implicit memory for trauma. Possible implications for ASD and Post-traumatic Stress Disorder are discussed.

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.

Early Life Stressors and Genetic Influences on the Development of Bipolar Disorder: The Roles of Childhood Abuse and Brain-Derived Neurotrophic Factor

ERIC Educational Resources Information Center

Liu, Richard T.

2010-01-01

Objectives: Although there is increasing research exploring the psychosocial influences and biological underpinnings of bipolar disorder, relatively few studies have specifically examined the interplay between these factors in the development of this illness. Social-biological models within a developmental psychopathology perspective are necessary…

Transient Maternal Hypothyroidism Alters Neural Progenitor Expression Resulting in Abnormal Brain Development

EPA Science Inventory

Heterotopias are a birth defect of the brain, and have varying etiologies in humans. They are characterized as clusters of mislocalized neurons, and are associated with disorders such as autism, epilepsy, and learning disabilities. We have previously characterized the robust pene...

Transient Maternal Hypothyroidism Alters Neural Progenitors Resulting in Abnormal Brain Development

EPA Science Inventory

Heterotopias are a birth defect of the brain and have varying etiologies in humans. They are characterized as clusters of mislocalized neurons and are associated with disorders such as autism, epilepsy, and learning disabilities. We have previously characterized the robust penetr...

Brain Plasticity and Disease: A Matter of Inhibition

PubMed Central

Baroncelli, Laura; Braschi, Chiara; Spolidoro, Maria; Begenisic, Tatjana; Maffei, Lamberto; Sale, Alessandro

2011-01-01

One major goal in Neuroscience is the development of strategies promoting neural plasticity in the adult central nervous system, when functional recovery from brain disease and injury is limited. New evidence has underscored a pivotal role for cortical inhibitory circuitries in regulating plasticity both during development and in adulthood. This paper summarizes recent findings showing that the inhibition-excitation balance controls adult brain plasticity and is at the core of the pathogenesis of neurodevelopmental disorders like autism, Down syndrome, and Rett syndrome. PMID:21766040

Brain metabolic stress and neuroinflammation at the basis of cognitive impairment in Alzheimer’s disease

PubMed Central

De Felice, Fernanda G.; Lourenco, Mychael V.

2015-01-01

Brain metabolic dysfunction is known to influence brain activity in several neurological disorders, including Alzheimer’s disease (AD). In fact, deregulation of neuronal metabolism has been postulated to play a key role leading to the clinical outcomes observed in AD. Besides deficits in glucose utilization in AD patients, recent evidence has implicated neuroinflammation and endoplasmic reticulum (ER) stress as components of a novel form of brain metabolic stress that develop in AD and other neurological disorders. Here we review findings supporting this novel paradigm and further discuss how these mechanisms seem to participate in synapse and cognitive impairments that are germane to AD. These deleterious processes resemble pathways that act in peripheral tissues leading to insulin resistance and glucose intolerance, in an intriguing molecular connection linking AD to diabetes. The discovery of detailed mechanisms leading to neuronal metabolic stress may be a key step that will allow the understanding how cognitive impairment develops in AD, thereby offering new avenues for effective disease prevention and therapeutic targeting. PMID:26042036

Different Aberrant Mentalizing Networks in Males and Females with Autism Spectrum Disorders: Evidence from Resting-State Functional Magnetic Resonance Imaging

ERIC Educational Resources Information Center

Yang, Jie; Lee, Jonathan

2018-01-01

Previous studies have found that individuals with autism spectrum disorders show impairments in mentalizing processes and aberrant brain activity compared with typically developing participants. However, the findings are mainly from male participants and the aberrant effects in autism spectrum disorder females and sex differences are still…

Neuroanatomy of conversion disorder: towards a network approach.

PubMed

Conejero, Ismael; Thouvenot, Eric; Abbar, Mocrane; Mouchabac, Stéphane; Courtet, Philippe; Olié, Emilie

2018-06-27

The pathophysiology of conversion disorder is not well understood, although studies using functional brain imaging in patients with motor and sensory symptoms are progressively increasing. We conducted a systematic review of the literature with the aim of summarising the available data on the neuroanatomical features of this disorder. We also propose a general model of the neurobiological disturbance in motor conversion disorder. We systematically searched articles in Medline using the Medical Subject Headings terms '(conversion disorder or hysterical motor disorder) and (neuropsychology or cognition) or (functional magnetic resonance imaging or positron emission tomography or neuroimaging) or (genetics or polymorphisms or epigenetics) or (biomarkers or biology)', following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two authors independently reviewed the retrieved records and abstracts, assessed the exhaustiveness of data abstraction, and confirmed the quality rating. Analysis of the available literature data shows that multiple specialised brain networks (self-agency, action monitoring, salience system, and memory suppression) influence action selection and modulate supplementary motor area activation. Some findings suggest that conceptualisation of movement and motor intention is preserved in patients with limb weakness. More studies are needed to fully understand the brain alterations in conversion disorders and pave the way for the development of effective therapeutic strategies.

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.

May the Force Be With You: The Light and Dark Sides of the Microbiota-Gut-Brain Axis in Neuropsychiatry.

PubMed

Sherwin, Eoin; Sandhu, Kiran V; Dinan, Timothy G; Cryan, John F

2016-11-01

The role of the gut microbiota in health and disease is becoming increasingly recognized. The microbiota-gut-brain axis is a bi-directional pathway between the brain and the gastrointestinal system. The bacterial commensals in our gut can signal to the brain through a variety of mechanisms, which are slowly being resolved. These include the vagus nerve, immune mediators and microbial metabolites, which influence central processes such as neurotransmission and behaviour. Dysregulation in the composition of the gut microbiota has been identified in several neuropsychiatric disorders, such as autism, schizophrenia and depression. Moreover, preclinical studies suggest that they may be the driving force behind the behavioural abnormalities observed in these conditions. Understanding how bacterial commensals are involved in regulating brain function may lead to novel strategies for development of microbiota-based therapies for these neuropsychiatric disorders.

Relationship between diet, the gut microbiota, and brain function.

PubMed

Tengeler, Anouk C; Kozicz, Tamas; Kiliaan, Amanda J

2018-04-28

The human intestinal microbiota, comprising trillions of microorganisms, exerts a substantial effect on the host. The microbiota plays essential roles in the function and development of several physiological processes, including those in the brain. A disruption in the microbial composition of the gut has been associated with many metabolic, inflammatory, neurodevelopmental, and neurodegenerative disorders. Nutrition is one of several key factors that shape the microbial composition during infancy and throughout life, thereby affecting brain structure and function. This review examines the effect of the gut microbiota on brain function. The ability of external factors, such as diet, to influence the microbial composition implies a certain vulnerability of the gut microbiota. However, it also offers a potential therapeutic strategy for ameliorating symptoms of mental and physical disorders. Therefore, this review examines the potential effect of nutritional components on gut microbial composition and brain function.

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

PubMed Central

Stankiewicz, James; Panter, Scott S; Neema, Mohit; Arora, Ashish; Batt, Courtney; Bakshi, Rohit

2007-01-01

Summary Iron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurologic disorders including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathologic processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development. PMID:17599703

Sleep Disorders Associated With Alzheimer's Disease: A Perspective

PubMed Central

Brzecka, Anna; Leszek, Jerzy; Ashraf, Ghulam Md; Ejma, Maria; Ávila-Rodriguez, Marco F.; Yarla, Nagendra S.; Tarasov, Vadim V.; Chubarev, Vladimir N.; Samsonova, Anna N.; Barreto, George E.; Aliev, Gjumrakch

2018-01-01

Sleep disturbances, as well as sleep-wake rhythm disturbances, are typical symptoms of Alzheimer's disease (AD) that may precede the other clinical signs of this neurodegenerative disease. Here, we describe clinical features of sleep disorders in AD and the relation between sleep disorders and both cognitive impairment and poor prognosis of the disease. There are difficulties of the diagnosis of sleep disorders based on sleep questionnaires, polysomnography or actigraphy in the AD patients. Typical disturbances of the neurophysiological sleep architecture in the course of the AD include deep sleep and paradoxical sleep deprivation. Among sleep disorders occurring in patients with AD, the most frequent disorders are sleep breathing disorders and restless legs syndrome. Sleep disorders may influence circadian fluctuations of the concentrations of amyloid-β in the interstitial brain fluid and in the cerebrovascular fluid related to the glymphatic brain system and production of the amyloid-β. There is accumulating evidence suggesting that disordered sleep contributes to cognitive decline and the development of AD pathology. In this mini-review, we highlight and discuss the association between sleep disorders and AD. PMID:29904334

Targeting the brain--surmounting or bypassing the blood-brain barrier.

PubMed

Potschka, Heidrun

2010-01-01

The constituents of the blood-brain barrier, including its efflux transporter system, can efficiently limit brain penetration of potential CNS therapeutics. Effective extrusion from the brain by transporters is a frequent reason for the pharmaceutical industry to exclude novel compounds from further development for CNS therapeutics. Moreover, high transporter expression levels that are present in individual patients or may be generally associated with the pathophysiology seem to be a major cause of therapeutic failure in a variety of CNS diseases including brain tumors, epilepsy, brain HIV infection, and psychiatric disorders. Increasing knowledge of the structure and function of the blood-brain barrier creates a basis for the development of strategies which aim to enhance brain uptake of beneficial pharmaceutical compounds. The different strategies discussed in this review aim to modulate blood-brain barrier function or to bypass constituents of the blood-brain barrier.

Targeting therapeutics across the blood brain barrier (BBB), prerequisite towards thrombolytic therapy for cerebrovascular disorders-an overview and advancements.

PubMed

Pulicherla, K K; Verma, Mahendra Kumar

2015-04-01

Cerebral tissues possess highly selective and dynamic protection known as blood brain barrier (BBB) that regulates brain homeostasis and provides protection against invading pathogens and various chemicals including drug molecules. Such natural protection strictly monitors entry of drug molecules often required for the management of several diseases and disorders including cerebral vascular and neurological disorders. However, in recent times, the ischemic cerebrovascular disease and clinical manifestation of acute arterial thrombosis are the most common causes of mortality and morbidity worldwide. The management of cerebral Ischemia requires immediate infusion of external thrombolytic into systemic circulation and must cross the blood brain barrier. The major challenge with available thrombolytic is their poor affinity towards the blood brain barrier and cerebral tissue subsequently. In the clinical practice, a high dose of thrombolytic often prescribed to deliver drugs across the blood brain barrier which results in drug dependent toxicity leading to damage of neuronal tissues. In recent times, more emphasis was given to utilize blood brain barrier transport mechanism to deliver drugs in neuronal tissue. The blood brain barrier expresses a series of receptor on membrane became an ideal target for selective drug delivery. In this review, the author has given more emphasis molecular biology of receptor on blood brain barrier and their potential as a carrier for drug molecules to cerebral tissues. Further, the use of nanoscale design and real-time monitoring for developed therapeutic to encounter drug dependent toxicity has been reviewed in this study.

[Can music therapy for patients with neurological disorders?].

PubMed

Myskja, Audun

2004-12-16

Recent developments in brain research and in the field of music therapy have led to the development of music-based methods specifically aimed at relieving symptoms of Parkinson's disease and other neurologic disorders. Rhythmic auditory stimulation uses external rhythmic auditory cues from song, music or metronome to aid patients improving their walking functioning and has been shown to be effective both within sessions and as a result of training over time. Melodic intonation therapy and related vocal techniques can improve expressive dysphasia and aid rehabilitation of neurologic disorders, particularly Parkinson's disease, stroke and developmental disorders.

Organoid technology for brain and therapeutics research.

PubMed

Wang, Zhi; Wang, Shu-Na; Xu, Tian-Ying; Miao, Zhu-Wei; Su, Ding-Feng; Miao, Chao-Yu

2017-10-01

Brain is one of the most complex organs in human. The current brain research is mainly based on the animal models and traditional cell culture. However, the inherent species differences between humans and animals as well as the gap between organ level and cell level make it difficult to study human brain development and associated disorders through traditional technologies. Recently, the brain organoids derived from pluripotent stem cells have been reported to recapitulate many key features of human brain in vivo, for example recapitulating the zone of putative outer radial glia cells. Brain organoids offer a new platform for scientists to study brain development, neurological diseases, drug discovery and personalized medicine, regenerative medicine, and so on. Here, we discuss the progress, applications, advantages, limitations, and prospects of brain organoid technology in neurosciences and related therapeutics. © 2017 John Wiley & Sons Ltd.

A chronological expression profile of gene activity during embryonic mouse brain development.

PubMed

Goggolidou, P; Soneji, S; Powles-Glover, N; Williams, D; Sethi, S; Baban, D; Simon, M M; Ragoussis, I; Norris, D P

2013-12-01

The brain is a functionally complex organ, the patterning and development of which are key to adult health. To help elucidate the genetic networks underlying mammalian brain patterning, we conducted detailed transcriptional profiling during embryonic development of the mouse brain. A total of 2,400 genes were identified as showing differential expression between three developmental stages. Analysis of the data identified nine gene clusters to demonstrate analogous expression profiles. A significant group of novel genes of as yet undiscovered biological function were detected as being potentially relevant to brain development and function, in addition to genes that have previously identified roles in the brain. Furthermore, analysis for genes that display asymmetric expression between the left and right brain hemispheres during development revealed 35 genes as putatively asymmetric from a combined data set. Our data constitute a valuable new resource for neuroscience and neurodevelopment, exposing possible functional associations between genes, including novel loci, and encouraging their further investigation in human neurological and behavioural disorders.

Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders

PubMed Central

Nakazawa, Takanobu; Hashimoto, Ryota; Sakoori, Kazuto; Sugaya, Yuki; Tanimura, Asami; Hashimotodani, Yuki; Ohi, Kazutaka; Yamamori, Hidenaga; Yasuda, Yuka; Umeda-Yano, Satomi; Kiyama, Yuji; Konno, Kohtarou; Inoue, Takeshi; Yokoyama, Kazumasa; Inoue, Takafumi; Numata, Shusuke; Ohnuma, Tohru; Iwata, Nakao; Ozaki, Norio; Hashimoto, Hitoshi; Watanabe, Masahiko; Manabe, Toshiya; Yamamoto, Tadashi; Takeda, Masatoshi; Kano, Masanobu

2016-01-01

Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders. PMID:26839058

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour.

PubMed

Lesch, Klaus-Peter; Araragi, Naozumi; Waider, Jonas; van den Hove, Daniel; Gutknecht, Lise

2012-09-05

Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111-140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581-604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour.

Mobile Phone Application for Supporting Persons with Higher Brain Dysfunctions

NASA Astrophysics Data System (ADS)

Nakayama, Tsuyoshi; Miyaji, Yuka; Kato, Seishi; Sakurada, Nobuhisa; Ueda, Noriyuki; Nomura, Takayuki; Okaya, Kazunori; Uematsu, Hiroshi; Kimura, Eiji

This paper shows a mobile phone application for supporting persons with higher brain dysfunction (HBD) such as a cognitive disorder, a memory disorder, and an attention-deficit disorder. This application serves them as a schedule manager, an alarm and an instructor of work sequences. The development concept of this application is easy handling and simple display, because persons with HBD are easily bewildered by complex procedures in the work. Five persons with HBD participated in the experiments for assessing the application at the vocational training place. The use of the application resulted in the drastic decrease of the number of errors and the increase of the System Usability Score, indicating that the developed application is useful for persons with HBD especially in performing vocational training tasks such as the use of database software on PC.

Cortical excitability and neurology: insights into the pathophysiology

PubMed Central

Badawy, Radwa A.B.; Loetscher, Tobias; Macdonell, Richard A.L.; Brodtmann, Amy

2012-01-01

Summary Transcranial magnetic stimulation (TMS) is a technique developed to non-invasively investigate the integrity of human motor corticospinal tracts. Over the last three decades, the use of stimulation paradigms including single-pulse TMS, paired-pulse TMS, repetitive TMS, and integration with EEG and functional imaging have been developed to facilitate measurement of cortical excitability. Through the use of these protocols, TMS has evolved into an excellent tool for measuring cortical excitability. TMS has high sensitivity in detecting subtle changes in cortical excitability, and therefore it is also a good measure of disturbances associated with brain disorders. In this review, we appraise the current literature on cortical excitability studies using TMS in neurological disorders. We begin with a brief overview of current TMS measures and then show how these have added to our understanding of the underlying mechanisms of brain disorders. PMID:23402674

Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy.

PubMed

Dossat, Amanda M; Sanchez-Gonzalez, Marcos A; Koutnik, Andrew P; Leitner, Stefano; Ruiz, Edda L; Griffin, Brittany; Rosenberg, Jens T; Grant, Samuel C; Fincham, Francis D; Pinto, Jose R; Kabbaj, Mohamed

2017-06-01

Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we used mice bearing a knock-in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3-4 mo) and aged adult (7-8 mo) female mice to examine the effects of HCM on the development of anxiety- and depression-like behaviors. We focused on females because in both humans and rodents, they experience a 2-fold increase in mood disorder prevalence vs. males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety- and depression-like behaviors. Electrocardiographic parameters of sympathetic nervous system activation were increased in aged HCM females vs. controls and correlated with mood disorder-related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood-related brain regions, and reduced hippocampal signaling proteins, such as brain-derived neurotrophic factor and its downstream targets vs. controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus, mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.-Dossat, A. M., Sanchez-Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy. © FASEB.

Altered brain structural networks in attention deficit/hyperactivity disorder children revealed by cortical thickness.

PubMed

Liu, Tian; Chen, Yanni; Li, Chenxi; Li, Youjun; Wang, Jue

2017-07-04

This study investigated the cortical thickness and topological features of human brain anatomical networks related to attention deficit/hyperactivity disorder. Data were collected from 40 attention deficit/hyperactivity disorder children and 40 normal control children. Interregional correlation matrices were established by calculating the correlations of cortical thickness between all pairs of cortical regions (68 regions) of the whole brain. Further thresholds were applied to create binary matrices to construct a series of undirected and unweighted graphs, and global, local, and nodal efficiencies were computed as a function of the network cost. These experimental results revealed abnormal cortical thickness and correlations in attention deficit/hyperactivity disorder, and showed that the brain structural networks of attention deficit/hyperactivity disorder subjects had inefficient small-world topological features. Furthermore, their topological properties were altered abnormally. In particular, decreased global efficiency combined with increased local efficiency in attention deficit/hyperactivity disorder children led to a disorder-related shift of the network topological structure toward regular networks. In addition, nodal efficiency, cortical thickness, and correlation analyses revealed that several brain regions were altered in attention deficit/hyperactivity disorder patients. These findings are in accordance with a hypothesis of dysfunctional integration and segregation of the brain in patients with attention deficit/hyperactivity disorder and provide further evidence of brain dysfunction in attention deficit/hyperactivity disorder patients by observing cortical thickness on magnetic resonance imaging.

Brain temperature and its fundamental properties: a review for clinical neuroscientists

PubMed Central

Wang, Huan; Wang, Bonnie; Normoyle, Kieran P.; Jackson, Kevin; Spitler, Kevin; Sharrock, Matthew F.; Miller, Claire M.; Best, Catherine; Llano, Daniel; Du, Rose

2014-01-01

Brain temperature, as an independent therapeutic target variable, has received increasingly intense clinical attention. To date, brain hypothermia represents the most potent neuroprotectant in laboratory studies. Although the impact of brain temperature is prevalent in a number of common human diseases including: head trauma, stroke, multiple sclerosis, epilepsy, mood disorders, headaches, and neurodegenerative disorders, it is evident and well recognized that the therapeutic application of induced hypothermia is limited to a few highly selected clinical conditions such as cardiac arrest and hypoxic ischemic neonatal encephalopathy. Efforts to understand the fundamental aspects of brain temperature regulation are therefore critical for the development of safe, effective, and pragmatic clinical treatments for patients with brain injuries. Although centrally-mediated mechanisms to maintain a stable body temperature are relatively well established, very little is clinically known about brain temperature's spatial and temporal distribution, its physiological and pathological fluctuations, and the mechanism underlying brain thermal homeostasis. The human brain, a metabolically “expensive” organ with intense heat production, is sensitive to fluctuations in temperature with regards to its functional activity and energy efficiency. In this review, we discuss several critical aspects concerning the fundamental properties of brain temperature from a clinical perspective. PMID:25339859

Abnormal activation of the occipital lobes during emotion picture processing in major depressive disorder patients

PubMed Central

Li, Jianying; Xu, Cheng; Cao, Xiaohua; Gao, Qiang; Wang, Yan; Wang, Yanfang; Peng, Juyi; Zhang, Kerang

2013-01-01

A large number of studies have demonstrated that depression patients have cognitive dysfunction. With recently developed brain functional imaging, studies have focused on changes in brain function to investigate cognitive changes. However, there is still controversy regarding abnormalities in brain functions or correlation between cognitive impairment and brain function changes. Thus, it is important to design an emotion-related task for research into brain function changes. We selected positive, neutral, and negative pictures from the International Affective Picture System. Patients with major depressive disorder were asked to judge emotion pictures. In addition, functional MRI was performed to synchronously record behavior data and imaging data. Results showed that the total correct rate for recognizing pictures was lower in patients compared with normal controls. Moreover, the consistency for recognizing pictures for depressed patients was worse than normal controls, and they frequently recognized positive pictures as negative pictures. The consistency for recognizing pictures was negatively correlated with the Hamilton Depression Rating Scale. Functional MRI suggested that the activation of some areas in the frontal lobe, temporal lobe, parietal lobe, limbic lobe, and cerebellum was enhanced, but that the activation of some areas in the frontal lobe, parietal lobe and occipital lobe was weakened while the patients were watching positive and neutral pictures compared with normal controls. The activation of some areas in the frontal lobe, temporal lobe, parietal lobe, and limbic lobe was enhanced, but the activation of some areas in the occipital lobe were weakened while the patients were watching the negative pictures compared with normal controls. These findings indicate that patients with major depressive disorder have negative cognitive disorder and extensive brain dysfunction. Thus, reduced activation of the occipital lobe may be an initiating factor for cognitive disorder in depressed patients. PMID:25206466

The impact of microbiota on brain and behavior: mechanisms & therapeutic potential.

PubMed

Borre, Yuliya E; Moloney, Rachel D; Clarke, Gerard; Dinan, Timothy G; Cryan, John F

2014-01-01

There is increasing evidence that host-microbe interactions play a key role in maintaining homeostasis. Alterations in gut microbial composition is associated with marked changes in behaviors relevant to mood, pain and cognition, establishing the critical importance of the bi-directional pathway of communication between the microbiota and the brain in health and disease. Dysfunction of the microbiome-brain-gut axis has been implicated in stress-related disorders such as depression, anxiety and irritable bowel syndrome and neurodevelopmental disorders such as autism. Bacterial colonization of the gut is central to postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Moreover, there is now expanding evidence for the view that enteric microbiota plays a role in early programming and later response to acute and chronic stress. This view is supported by studies in germ-free mice and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotics. Although communication between gut microbiota and the CNS are not fully elucidated, neural, hormonal, immune and metabolic pathways have been suggested. Thus, the concept of a microbiome-brain-gut axis is emerging, suggesting microbiota-modulating strategies may be a tractable therapeutic approach for developing novel treatments for CNS disorders.

Excitatory/inhibitory imbalance in autism spectrum disorders: Implications for interventions and therapeutics.

PubMed

Uzunova, Genoveva; Pallanti, Stefano; Hollander, Eric

2016-04-01

Imbalance between excitation and inhibition and increased excitatory-inhibitory (E-I) ratio is a common mechanism in autism spectrum disorders (ASD) that is responsible for the learning and memory, cognitive, sensory, motor deficits, and seizures occurring in these disorders. ASD are very heterogeneous and better understanding of E-I imbalance in brain will lead to better diagnosis and treatments. We perform a critical literature review of the causes and presentations of E-I imbalance in ASD. E-I imbalance in ASD is due primarily to abnormal glutamatergic and GABAergic neurotransmission in key brain regions such as neocortex, hippocampus, amygdala, and cerebellum. Other causes are due to dysfunction of neuropeptides (oxytocin), synaptic proteins (neuroligins), and immune system molecules (cytokines). At the neuropathological level E-I imbalance in ASD is presented as a "minicolumnopathy". E-I imbalance alters the manner by which the brain processes information and regulates behaviour. New developments for investigating E-I imbalance such as optogenetics and transcranial magnetic stimulation (TMS) are presented. Non-invasive brain stimulation methods such as TMS for treatment of the core symptoms of ASD are discussed. Understanding E-I imbalance has important implications for developing better pharmacological and behavioural treatments for ASD, including TMS, new drugs, biomarkers and patient stratification.

Inflammasomes link vascular disease with neuroinflammation and brain disorders

PubMed Central

Lénárt, Nikolett; Brough, David

2016-01-01

The role of inflammation in neurological disorders is increasingly recognised. Inflammatory processes are associated with the aetiology and clinical progression of migraine, psychiatric conditions, epilepsy, cerebrovascular diseases, dementia and neurodegeneration, such as seen in Alzheimer’s or Parkinson’s disease. Both central and systemic inflammatory actions have been linked with the development of brain diseases, suggesting that complex neuro-immune interactions could contribute to pathological changes in the brain across multiple temporal and spatial scales. However, the mechanisms through which inflammation impacts on neurological disease are improperly defined. To develop effective therapeutic approaches, it is imperative to understand how detrimental inflammatory processes could be blocked selectively, or controlled for prolonged periods, without compromising essential immune defence mechanisms. Increasing evidence indicates that common risk factors for brain disorders, such as atherosclerosis, diabetes, hypertension, obesity or infection involve the activation of NLRP3, NLRP1, NLRC4 or AIM2 inflammasomes, which are also associated with various neurological diseases. This review focuses on the mechanisms whereby inflammasomes, which integrate diverse inflammatory signals in response to pathogen-driven stimuli, tissue injury or metabolic alterations in multiple cell types and different organs of the body, could functionally link vascular- and neurological diseases and hence represent a promising therapeutic target. PMID:27486046

Transient Maternal Hypothyroidism Alters Neural Progenitor Cells Resulting in Abnormal Brain Development

EPA Science Inventory

Heterotopias are a birth defect of the brain and have varying etiologies in humans. They are characterized as clusters of mislocalized neurons and are associated with disorders such as autism and epilepsy. We have previously characterized the robust penetrance of a cortical heter...

Primary Cilia as a Possible Link between Left-Right Asymmetry and Neurodevelopmental Diseases.

PubMed

Trulioff, Andrey; Ermakov, Alexander; Malashichev, Yegor

2017-01-25

Cilia have multiple functions in the development of the entire organism, and participate in the development and functioning of the central nervous system. In the last decade, studies have shown that they are implicated in the development of the visceral left-right asymmetry in different vertebrates. At the same time, some neuropsychiatric disorders, such as schizophrenia, autism, bipolar disorder, and dyslexia, are known to be associated with lateralization failure. In this review, we consider possible links in the mechanisms of determination of visceral asymmetry and brain lateralization, through cilia. We review the functions of seven genes associated with both cilia, and with neurodevelopmental diseases, keeping in mind their possible role in the establishment of the left-right brain asymmetry.

Primary Cilia as a Possible Link between Left-Right Asymmetry and Neurodevelopmental Diseases

PubMed Central

Trulioff, Andrey; Ermakov, Alexander; Malashichev, Yegor

2017-01-01

Cilia have multiple functions in the development of the entire organism, and participate in the development and functioning of the central nervous system. In the last decade, studies have shown that they are implicated in the development of the visceral left-right asymmetry in different vertebrates. At the same time, some neuropsychiatric disorders, such as schizophrenia, autism, bipolar disorder, and dyslexia, are known to be associated with lateralization failure. In this review, we consider possible links in the mechanisms of determination of visceral asymmetry and brain lateralization, through cilia. We review the functions of seven genes associated with both cilia, and with neurodevelopmental diseases, keeping in mind their possible role in the establishment of the left-right brain asymmetry. PMID:28125008

Non-invasive brain stimulation in children: applications and future directions

PubMed Central

Rajapakse, Thilinie; Kirton, Adam

2013-01-01

Transcranial magnetic stimulation (TMS) is a neurostimulation and neuromodulation technique that has provided over two decades of data in focal, non-invasive brain stimulation based on the principles of electromagnetic induction. Its minimal risk, excellent tolerability and increasingly sophisticated ability to interrogate neurophysiology and plasticity make it an enviable technology for use in pediatric research with future extension into therapeutic trials. While adult trials show promise in using TMS as a novel, non-invasive, non-pharmacologic diagnostic and therapeutic tool in a variety of nervous system disorders, its use in children is only just emerging. TMS represents an exciting advancement to better understand and improve outcomes from disorders of the developing brain. PMID:24163755

Long-term neural and physiological phenotyping of a single human

PubMed Central

Poldrack, Russell A.; Laumann, Timothy O.; Koyejo, Oluwasanmi; Gregory, Brenda; Hover, Ashleigh; Chen, Mei-Yen; Gorgolewski, Krzysztof J.; Luci, Jeffrey; Joo, Sung Jun; Boyd, Ryan L.; Hunicke-Smith, Scott; Simpson, Zack Booth; Caven, Thomas; Sochat, Vanessa; Shine, James M.; Gordon, Evan; Snyder, Abraham Z.; Adeyemo, Babatunde; Petersen, Steven E.; Glahn, David C.; Reese Mckay, D.; Curran, Joanne E.; Göring, Harald H. H.; Carless, Melanie A.; Blangero, John; Dougherty, Robert; Leemans, Alexander; Handwerker, Daniel A.; Frick, Laurie; Marcotte, Edward M.; Mumford, Jeanette A.

2015-01-01

Psychiatric disorders are characterized by major fluctuations in psychological function over the course of weeks and months, but the dynamic characteristics of brain function over this timescale in healthy individuals are unknown. Here, as a proof of concept to address this question, we present the MyConnectome project. An intensive phenome-wide assessment of a single human was performed over a period of 18 months, including functional and structural brain connectivity using magnetic resonance imaging, psychological function and physical health, gene expression and metabolomics. A reproducible analysis workflow is provided, along with open access to the data and an online browser for results. We demonstrate dynamic changes in brain connectivity over the timescales of days to months, and relations between brain connectivity, gene expression and metabolites. This resource can serve as a testbed to study the joint dynamics of human brain and metabolic function over time, an approach that is critical for the development of precision medicine strategies for brain disorders. PMID:26648521

Brain Lateralization in Mice Is Associated with Zinc Signaling and Altered in Prenatal Zinc Deficient Mice That Display Features of Autism Spectrum Disorder

PubMed Central

Grabrucker, Stefanie; Haderspeck, Jasmin C.; Sauer, Ann Katrin; Kittelberger, Nadine; Asoglu, Harun; Abaei, Alireza; Rasche, Volker; Schön, Michael; Boeckers, Tobias M.; Grabrucker, Andreas M.

2018-01-01

A number of studies have reported changes in the hemispheric dominance in autism spectrum disorder (ASD) patients on functional, biochemical, and morphological level. Since asymmetry of the brain is also found in many vertebrates, we analyzed whether prenatal zinc deficient (PZD) mice, a mouse model with ASD like behavior, show alterations regarding brain lateralization on molecular and behavioral level. Our results show that hemisphere-specific expression of marker genes is abolished in PZD mice on mRNA and protein level. Using magnetic resonance imaging, we found an increased striatal volume in PZD mice with no change in total brain volume. Moreover, behavioral patterns associated with striatal lateralization are altered and the lateralized expression of dopamine receptor 1 (DR1) in the striatum of PZD mice was changed. We conclude that zinc signaling during brain development has a critical role in the establishment of brain lateralization in mice. PMID:29379414

Is Dyslexia a Brain Disorder?

PubMed Central

Parrila, Rauno

2018-01-01

Specific word reading difficulty, commonly termed ‘developmental dyslexia’, refers to the low end of the word reading skill distribution but is frequently considered to be a neurodevelopmental disorder. This term implies that brain development is thought to be disrupted, resulting in an abnormal and dysfunctional brain. We take issue with this view, pointing out that there is no evidence of any obvious neurological abnormality in the vast majority of cases of word reading difficulty cases. The available relevant evidence from neuroimaging studies consists almost entirely of correlational and group-differences studies. However, differences in brains are certain to exist whenever differences in behavior exist, including differences in ability and performance. Therefore, findings of brain differences do not constitute evidence for abnormality; rather, they simply document the neural substrate of the behavioral differences. We suggest that dyslexia is best viewed as one of many expressions of ordinary ubiquitous individual differences in normal developmental outcomes. Thus, terms such as “dysfunctional” or “abnormal” are not justified when referring to the brains of persons with dyslexia. PMID:29621138

Differences in MMPI-2 FBS and RBS scores in brain injury, probable malingering, and conversion disorder groups: a preliminary study.

PubMed

Peck, C P; Schroeder, R W; Heinrichs, R J; Vondran, E J; Brockman, C J; Webster, B K; Baade, L E

2013-01-01

This study examined differences in raw scores on the Symptom Validity Scale and Response Bias Scale (RBS) from the Minnesota Multiphasic Personality Inventory-2 in three criterion groups: (i) valid traumatic brain injured, (ii) invalid traumatic brain injured, and (iii) psychogenic non-epileptic seizure disorders. Results indicate that a >30 raw score cutoff for the Symptom Validity Scale accurately identified 50% of the invalid traumatic brain injured group, while misclassifying none of the valid traumatic brain injured group and 6% of the psychogenic non-epileptic seizure disorder group. Using a >15 RBS raw cutoff score accurately classified 50% of the invalid traumatic brain injured group and misclassified fewer than 10% of the valid traumatic brain injured and psychogenic non-epileptic seizure disorder groups. These cutoff scores used conjunctively did not misclassify any members of the psychogenic non-epileptic seizure disorder or valid traumatic brain injured groups, while accurately classifying 44% of the invalid traumatic brain injured individuals. Findings from this preliminary study suggest that the conjunctive use of the Symptom Validity Scale and the RBS from the Minnesota Multiphasic Personality Inventory-2 may be useful in differentiating probable malingering from individuals with brain injuries and conversion disorders.

Peptide pills for brain diseases? Reality and future perspectives.

PubMed

Serrano Lopez, Dolores Remedios; Lalatsa, Aikaterini

2013-04-01

The peptide therapeutic market is one of the fastest growth areas of the pharmaceutical industry. Although few orally administered peptides are marketed and many are in different phases of clinical development, there is no marketed oral peptide therapeutic used for CNS disorders. The major challenges involved in orally delivering peptides to the brain relate to their enzymatic instability and inability to permeate across physiological barriers. The paucity of therapies for the treatment of brain diseases and the presence of the blood-brain barrier excluding 98% of therapeutic molecules necessitates parenteral administration. Various approaches have been applied to enhance oral peptide bioavailability, but only nanoparticulate strategies were able to deliver orally therapeutic peptides to the brain. Although industry may be reluctant to invest in developing oral peptide nanomedicines, the increasingly unmet clinical need and economic burden associated with brain diseases will fuel the development of the first marketed oral-to-brain peptide therapy.

The role of ionotropic glutamate receptors in childhood neurodevelopmental disorders: autism spectrum disorders and fragile x syndrome.

PubMed

Uzunova, Genoveva; Hollander, Eric; Shepherd, Jason

2014-01-01

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS.

Neurodegenerative disease and iron storage in the brain.

PubMed

Thomas, Madhavi; Jankovic, Joseph

2004-08-01

Iron is very important for normal regulation of various metabolic pathways. Neurons store iron in the form of ferrous ion or neuromelanin. In specific disorders the axonal transport of iron is impaired, leading to iron deposition which in the presence of reactive oxygen species results in neurodegeneration. Recent developments in genetics, including the finding of mutations in the pantothenate kinase gene and ferritin light chain gene, have demonstrated a direct relationship between the presence of a mutation in the iron-regulatory pathways and iron deposition in the brain resulting in neurodegeneration. These two disorders now add to our understanding of the mechanism of disease due to dysfunction of iron-regulatory pathways. In addition to these disorders there may be several other mutations of iron-regulatory genes or related genes that are yet to be found. The animal models of disease have also added value to this area. In this review we provide a summary of recent developments in the field of movement disorders with abnormalities in iron transport, and the current evidence in neurodegenerative disorders such as Parkinson's disease.

Ethical issues when modelling brain disorders innon-human primates.

PubMed

Neuhaus, Carolyn P

2018-05-01

Non-human animal models of human diseases advance our knowledge of the genetic underpinnings of disease and lead to the development of novel therapies for humans. While mice are the most common model organisms, their usefulness is limited. Larger animals may provide more accurate and valuable disease models, but it has, until recently, been challenging to create large animal disease models. Genome editors, such as Clustered Randomised Interspersed Palindromic Repeat (CRISPR), meet some of these challenges and bring routine genome engineering of larger animals and non-human primates (NHPs) well within reach. There is growing interest in creating NHP models of brain disorders such as autism, depression and Alzheimer's, which are very difficult to model or study in other organisms, including humans. New treatments are desperately needed for this set of disorders. This paper is novel in asking: Insofar as NHPs are being considered for use as model organisms for brain disorders, can this be done ethically? The paper concludes that it cannot. Notwithstanding ongoing debate about NHPs' moral status, (1) animal welfare concerns, (2) the availability of alternative methods of studying brain disorders and (3) unmet expectations of benefit justify a stop on the creation of NHP model organisms to study brain disorders. The lure of using new genetic technologies combined with the promise of novel therapeutics presents a formidable challenge to those who call for slow, careful, and only necessary research involving NHPs. But researchers should not create macaques with social deficits or capuchin monkeys with memory deficits just because they can. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

New Treatment Strategies of Depression: Based on Mechanisms Related to Neuroplasticity

PubMed Central

Lane, Hsien-Yuan

2017-01-01

Major depressive disorder is a severe and complex mental disorder. Impaired neurotransmission and disrupted signalling pathways may influence neuroplasticity, which is involved in the brain dysfunction in depression. Traditional neurobiological theories of depression, such as monoamine hypothesis, cannot fully explain the whole picture of depressive disorders. In this review, we discussed new treatment directions of depression, including modulation of glutamatergic system and noninvasive brain stimulation. Dysfunction of glutamatergic neurotransmission plays an important role in the pathophysiology of depression. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has rapid and lasting antidepressive effects in previous studies. In addition to ketamine, other glutamatergic modulators, such as sarcosine, also show potential antidepressant effect in animal models or clinical trials. Noninvasive brain stimulation is another new treatment strategy beyond pharmacotherapy. Growing evidence has demonstrated that superficial brain stimulations, such as transcranial magnetic stimulation, transcranial direct current stimulation, cranial electrotherapy stimulation, and magnetic seizure therapy, can improve depressive symptoms. The antidepressive effect of these brain stimulations may be through modulating neuroplasticity. In conclusion, drugs that modulate neurotransmission via NMDA receptor and noninvasive brain stimulation may provide new directions of treatment for depression. Furthermore, exploring the underlying mechanisms will help in developing novel therapies for depression in the future. PMID:28491480

Association between abnormal brain functional connectivity in children and psychopathology: A study based on graph theory and machine learning.

PubMed

Sato, João Ricardo; Biazoli, Claudinei Eduardo; Salum, Giovanni Abrahão; Gadelha, Ary; Crossley, Nicolas; Vieira, Gilson; Zugman, André; Picon, Felipe Almeida; Pan, Pedro Mario; Hoexter, Marcelo Queiroz; Amaro, Edson; Anés, Mauricio; Moura, Luciana Monteiro; Del'Aquilla, Marco Antonio Gomes; Mcguire, Philip; Rohde, Luis Augusto; Miguel, Euripedes Constantino; Jackowski, Andrea Parolin; Bressan, Rodrigo Affonseca

2018-03-01

One of the major challenges facing psychiatry is how to incorporate biological measures in the classification of mental health disorders. Many of these disorders affect brain development and its connectivity. In this study, we propose a novel method for assessing brain networks based on the combination of a graph theory measure (eigenvector centrality) and a one-class support vector machine (OC-SVM). We applied this approach to resting-state fMRI data from 622 children and adolescents. Eigenvector centrality (EVC) of nodes from positive- and negative-task networks were extracted from each subject and used as input to an OC-SVM to label individual brain networks as typical or atypical. We hypothesised that classification of these subjects regarding the pattern of brain connectivity would predict the level of psychopathology. Subjects with atypical brain network organisation had higher levels of psychopathology (p < 0.001). There was a greater EVC in the typical group at the bilateral posterior cingulate and bilateral posterior temporal cortices; and significant decreases in EVC at left temporal pole. The combination of graph theory methods and an OC-SVM is a promising method to characterise neurodevelopment, and may be useful to understand the deviations leading to mental disorders.

Curcumin boosts DHA in the brain: implications for the prevention of anxiety disorders

PubMed Central

Wu, Aiguo; Noble, Emily E.; Tyagi, Ethika; Ying, Zhe; Zhuang, Yumei; Gomez-Pinilla, Fernando

2015-01-01

Dietary deficiency of docosahexaenoic acid (C22: 6n-3; DHA) is linked to the neuropathology of several cognitive disorders, including anxiety. DHA, which is essential for brain development and protection, is primarily obtained through the diet or synthesized from dietary precursors, however the conversion efficiency is low. Curcumin (diferuloylmethane), which is a principal component of the spice turmeric, complements the action of DHA in the brain, and this study was performed to determine molecular mechanisms involved. We report that curcumin enhances the synthesis of DHA from its precursor, α-linolenic acid (C18: 3n-3; ALA) and elevates levels of enzymes involved in the synthesis of DHA such as FADS2 and elongase 2 in both liver and brain tissue. Furthermore, in vivo treatment with curcumin and ALA reduced anxiety-like behavior in rodents. Taken together, these data suggest that curcumin enhances DHA synthesis, resulting in elevated brain DHA content. These findings have important implications for human health and the prevention of cognitive disease, particularly for populations eating a plant-based diet or who do not consume fish, a primary source of DHA, since DHA is essential for brain function and its deficiency is implicated in many types of neurological disorders. PMID:25550171

Joint Attention and Brain Functional Connectivity in Infants and Toddlers.

PubMed

Eggebrecht, Adam T; Elison, Jed T; Feczko, Eric; Todorov, Alexandre; Wolff, Jason J; Kandala, Sridhar; Adams, Chloe M; Snyder, Abraham Z; Lewis, John D; Estes, Annette M; Zwaigenbaum, Lonnie; Botteron, Kelly N; McKinstry, Robert C; Constantino, John N; Evans, Alan; Hazlett, Heather C; Dager, Stephen; Paterson, Sarah J; Schultz, Robert T; Styner, Martin A; Gerig, Guido; Das, Samir; Kostopoulos, Penelope; Schlaggar, Bradley L; Petersen, Steven E; Piven, Joseph; Pruett, John R

2017-03-01

Initiating joint attention (IJA), the behavioral instigation of coordinated focus of 2 people on an object, emerges over the first 2 years of life and supports social-communicative functioning related to the healthy development of aspects of language, empathy, and theory of mind. Deficits in IJA provide strong early indicators for autism spectrum disorder, and therapies targeting joint attention have shown tremendous promise. However, the brain systems underlying IJA in early childhood are poorly understood, due in part to significant methodological challenges in imaging localized brain function that supports social behaviors during the first 2 years of life. Herein, we show that the functional organization of the brain is intimately related to the emergence of IJA using functional connectivity magnetic resonance imaging and dimensional behavioral assessments in a large semilongitudinal cohort of infants and toddlers. In particular, though functional connections spanning the brain are involved in IJA, the strongest brain-behavior associations cluster within connections between a small subset of functional brain networks; namely between the visual network and dorsal attention network and between the visual network and posterior cingulate aspects of the default mode network. These observations mark the earliest known description of how functional brain systems underlie a burgeoning fundamental social behavior, may help improve the design of targeted therapies for neurodevelopmental disorders, and, more generally, elucidate physiological mechanisms essential to healthy social behavior development. © The Author 2017. Published by Oxford University Press.

[Estrogens and feminine brain maturation during adolescence: emergency contraceptive pill].

PubMed

López Moratalla, Natalia; Errasti Alcalá, Tania; Santiago, Esteban

2011-01-01

In the period between puberty and maturity takes place the process of brain maturation. Hormone levels induce changes in neurons and direct the architecture and structural functionality thus affecting patterns of development of different brain areas. The onset of puberty brings with it the invasion of the female brain by high levels of hormones, cyclic surges of estrogen and progesterone in addition to steroids produced in situ. Control centers of emotions (amygdala), memory and learning (hippocampus) and sexual activity (hypothalamus) are modified according to the cyclical concentrations of both hormones. Sex hormones stimulate multimodal actions, both short and longer terms, because neurons in various brain areas have different types of receptors, membrane, cytoplasmic and nuclear. The composition of emergency contraceptive pill (postcoital pill) with high hormonal content raises the urgency of a thorough knowledge about the possible effect that the lack of control of the menstrual cycle in a time of consolidation of brain maturation, can bring in structuring and development of brain circuitry. Changes in the availability of sex steroids during puberty and adolescence underlie psychiatric disorders whose prevalence is typically feminine, such as depression, anxiety disorders. It is a fundamental ethical duty to present scientific data about the influence of estrogen in young female brain maturation, both for full information to potential users, and also to induce the appropriate public health measures.

Joint Attention and Brain Functional Connectivity in Infants and Toddlers

PubMed Central

Eggebrecht, Adam T.; Elison, Jed T.; Feczko, Eric; Todorov, Alexandre; Wolff, Jason J.; Kandala, Sridhar; Adams, Chloe M.; Snyder, Abraham Z.; Lewis, John D.; Estes, Annette M.; Zwaigenbaum, Lonnie; Botteron, Kelly N.; McKinstry, Robert C.; Constantino, John N.; Evans, Alan; Hazlett, Heather C.; Dager, Stephen; Paterson, Sarah J.; Schultz, Robert T.; Styner, Martin A.; Gerig, Guido; Das, Samir; Kostopoulos, Penelope; Schlaggar, Bradley L.; Petersen, Steven E.; Piven, Joseph; Pruett, John R.

2017-01-01

Abstract Initiating joint attention (IJA), the behavioral instigation of coordinated focus of 2 people on an object, emerges over the first 2 years of life and supports social-communicative functioning related to the healthy development of aspects of language, empathy, and theory of mind. Deficits in IJA provide strong early indicators for autism spectrum disorder, and therapies targeting joint attention have shown tremendous promise. However, the brain systems underlying IJA in early childhood are poorly understood, due in part to significant methodological challenges in imaging localized brain function that supports social behaviors during the first 2 years of life. Herein, we show that the functional organization of the brain is intimately related to the emergence of IJA using functional connectivity magnetic resonance imaging and dimensional behavioral assessments in a large semilongitudinal cohort of infants and toddlers. In particular, though functional connections spanning the brain are involved in IJA, the strongest brain-behavior associations cluster within connections between a small subset of functional brain networks; namely between the visual network and dorsal attention network and between the visual network and posterior cingulate aspects of the default mode network. These observations mark the earliest known description of how functional brain systems underlie a burgeoning fundamental social behavior, may help improve the design of targeted therapies for neurodevelopmental disorders, and, more generally, elucidate physiological mechanisms essential to healthy social behavior development. PMID:28062515

Early brain development in infants at high risk for autism spectrum disorder

PubMed Central

Hazlett, Heather Cody; Gu, Hongbin; Munsell, Brent C.; Kim, Sun Hyung; Styner, Martin; Wolff, Jason J.; Elison, Jed T.; Swanson, Meghan R.; Zhu, Hongtu; Botteron, Kelly N.; Collins, D. Louis; Constantino, John N.; Dager, Stephen R.; Estes, Annette M.; Evans, Alan C.; Fonov, Vladimir S.; Gerig, Guido; Kostopoulos, Penelope; McKinstry, Robert C.; Pandey, Juhi; Paterson, Sarah; Pruett, John R.; Schultz, Robert T.; Shaw, Dennis W.; Zwaigenbaum, Lonnie; Piven, Joseph

2017-01-01

Summary Brain enlargement has been observed in children with Autism Spectrum Disorder (ASD), but the timing of this phenomenon and its relationship to the appearance of behavioral symptoms is unknown. Retrospective head circumference and longitudinal brain volume studies of 2 year olds followed up at age 4 years, have provided evidence that increased brain volume may emerge early in development.1, 2 Studies of infants at high familial risk for autism can provide insight into the early development of autism and have found that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life3,4. These observations suggest that prospective brain imaging studies of infants at high familial risk for ASD might identify early post-natal changes in brain volume occurring before the emergence of an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that cortical surface area hyper-expansion between 6-12 months of age precedes brain volume overgrowth observed between 12-24 months in the 15 high-risk infants diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep learning algorithm primarily using surface area information from brain MRI at 6 and 12 months of age predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81%, sensitivity of 88%). These findings demonstrate that early brain changes unfold during the period in which autistic behaviors are first emerging. PMID:28202961

Early brain development in infants at high risk for autism spectrum disorder.

PubMed

Hazlett, Heather Cody; Gu, Hongbin; Munsell, Brent C; Kim, Sun Hyung; Styner, Martin; Wolff, Jason J; Elison, Jed T; Swanson, Meghan R; Zhu, Hongtu; Botteron, Kelly N; Collins, D Louis; Constantino, John N; Dager, Stephen R; Estes, Annette M; Evans, Alan C; Fonov, Vladimir S; Gerig, Guido; Kostopoulos, Penelope; McKinstry, Robert C; Pandey, Juhi; Paterson, Sarah; Pruett, John R; Schultz, Robert T; Shaw, Dennis W; Zwaigenbaum, Lonnie; Piven, Joseph

2017-02-15

Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development. Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life. These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6-12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging.

Neural markers of social and monetary rewards in children with Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder

PubMed Central

Gonzalez-Gadea, Maria Luz; Sigman, Mariano; Rattazzi, Alexia; Lavin, Claudio; Rivera-Rei, Alvaro; Marino, Julian; Manes, Facundo; Ibanez, Agustin

2016-01-01

Recent theories of decision making propose a shared value-related brain mechanism for encoding monetary and social rewards. We tested this model in children with Attention-Deficit/Hyperactivity Disorder (ADHD), children with Autism Spectrum Disorder (ASD) and control children. We monitored participants’ brain dynamics using high density-electroencephalography while they played a monetary and social reward tasks. Control children exhibited a feedback Error-Related Negativity (fERN) modulation and Anterior Cingulate Cortex (ACC) source activation during both tasks. Remarkably, although cooperation resulted in greater losses for the participants, the betrayal options generated greater fERN responses. ADHD subjects exhibited an absence of fERN modulation and reduced ACC activation during both tasks. ASD subjects exhibited normal fERN modulation during monetary choices and inverted fERN/ACC responses in social options than did controls. These results suggest that in neurotypicals, monetary losses and observed disloyal social decisions induced similar activity in the brain value system. In ADHD children, difficulties in reward processing affected early brain signatures of monetary and social decisions. Conversely, ASD children showed intact neural markers of value-related monetary mechanisms, but no brain modulation by prosociality in the social task. These results offer insight into the typical and atypical developments of neural correlates of monetary and social reward processing. PMID:27464551

Artistic creativity, style and brain disorders.

PubMed

Bogousslavsky, Julien

2005-01-01

The production of novel, motivated or useful material defines creativity, which appears to be one of the higher, specific, human brain functions. While creativity can express itself in virtually any domain, art might particularly well illustrate how creativity may be modulated by the normal or pathological brain. Evidence emphasizes global brain functioning in artistic creativity and output, but critical steps which link perception processing to execution of a work, such as extraction-abstraction, as well as major developments of non-esthetic values attached to art also underline complex activation and inhibition processes mainly localized in the frontal lobe. Neurological diseases in artists provide a unique opportunity to study brain-creativity relationships, in particular through the stylistic changes which may develop after brain lesion. (c) 2005 S. Karger AG, Basel

Developmental psychopathology: a paradigm shift or just a relabeling?

PubMed

Rutter, Michael

2013-11-01

Developmental psychopathology is described as a conceptual approach that involves a set of research methods that capitalize on developmental and psychopathological variations to ask questions about mechanisms and processes. Achievements are described in relation to attachment and attachment disorders, autism, schizophrenia, childhood antecedents of adult psychopathology, testing for environmental mediation of risk effects, gene-environment interplay, intellectual and language functioning, effects of mentally ill parents on the children, stress and vulnerability to depression, ethnicity and schizophrenia, and drug response. Continuities and discontinuities over the course of development are discussed in relation to attention-deficit/hyperactivity disorder, antisocial behavior, eating disorders, substance abuse and dependency, pharmacological and behavioral addictions, and a range of other disorders. Research challenges are considered in relation to spectrum concepts, the adolescent development of a female preponderance for depression, the mechanisms involved in age differences in response to drugs and to lateralized brain injury, the processing of experiences, the biological embedding of experiences, individual differences in response to environmental hazards, nature-nurture integration, and brain plasticity.

Are circadian rhythms new pathways to understand Autism Spectrum Disorder?

PubMed

Geoffray, M-M; Nicolas, A; Speranza, M; Georgieff, N

2016-11-01

Autism Spectrum Disorder (ASD) is a frequent neurodevelopmental disorder. ASD is probably the result of intricate interactions between genes and environment altering progressively the development of brain structures and functions. Circadian rhythms are a complex intrinsic timing system composed of almost as many clocks as there are body cells. They regulate a variety of physiological and behavioral processes such as the sleep-wake rhythm. ASD is often associated with sleep disorders and low levels of melatonin. This first point raises the hypothesis that circadian rhythms could have an implication in ASD etiology. Moreover, circadian rhythms are generated by auto-regulatory genetic feedback loops, driven by transcription factors CLOCK and BMAL1, who drive transcription daily patterns of a wide number of clock-controlled genes (CCGs) in different cellular contexts across tissues. Among these, are some CCGs coding for synapses molecules associated to ASD susceptibility. Furthermore, evidence emerges about circadian rhythms control of time brain development processes. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Protocol for the Administration of Real-Time fMRI Neurofeedback Training

PubMed Central

Sherwood, Matthew S.; Diller, Emily E.; Ey, Elizabeth; Ganapathy, Subhashini; Nelson, Jeremy T.; Parker, Jason G.

2017-01-01

Neurologic disorders are characterized by abnormal cellular-, molecular-, and circuit-level functions in the brain. New methods to induce and control neuroplastic processes and correct abnormal function, or even shift functions from damaged tissue to physiologically healthy brain regions, hold the potential to dramatically improve overall health. Of the current neuroplastic interventions in development, neurofeedback training (NFT) from functional Magnetic Resonance Imaging (fMRI) has the advantages of being completely non-invasive, non-pharmacologic, and spatially localized to target brain regions, as well as having no known side effects. Furthermore, NFT techniques, initially developed using fMRI, can often be translated to exercises that can be performed outside of the scanner without the aid of medical professionals or sophisticated medical equipment. In fMRI NFT, the fMRI signal is measured from specific regions of the brain, processed, and presented to the participant in real-time. Through training, self-directed mental processing techniques, that regulate this signal and its underlying neurophysiologic correlates, are developed. FMRI NFT has been used to train volitional control over a wide range of brain regions with implications for several different cognitive, behavioral, and motor systems. Additionally, fMRI NFT has shown promise in a broad range of applications such as the treatment of neurologic disorders and the augmentation of baseline human performance. In this article, we present an fMRI NFT protocol developed at our institution for modulation of both healthy and abnormal brain function, as well as examples of using the method to target both cognitive and auditory regions of the brain. PMID:28872110

A Protocol for the Administration of Real-Time fMRI Neurofeedback Training.

PubMed

Sherwood, Matthew S; Diller, Emily E; Ey, Elizabeth; Ganapathy, Subhashini; Nelson, Jeremy T; Parker, Jason G

2017-08-24

Neurologic disorders are characterized by abnormal cellular-, molecular-, and circuit-level functions in the brain. New methods to induce and control neuroplastic processes and correct abnormal function, or even shift functions from damaged tissue to physiologically healthy brain regions, hold the potential to dramatically improve overall health. Of the current neuroplastic interventions in development, neurofeedback training (NFT) from functional Magnetic Resonance Imaging (fMRI) has the advantages of being completely non-invasive, non-pharmacologic, and spatially localized to target brain regions, as well as having no known side effects. Furthermore, NFT techniques, initially developed using fMRI, can often be translated to exercises that can be performed outside of the scanner without the aid of medical professionals or sophisticated medical equipment. In fMRI NFT, the fMRI signal is measured from specific regions of the brain, processed, and presented to the participant in real-time. Through training, self-directed mental processing techniques, that regulate this signal and its underlying neurophysiologic correlates, are developed. FMRI NFT has been used to train volitional control over a wide range of brain regions with implications for several different cognitive, behavioral, and motor systems. Additionally, fMRI NFT has shown promise in a broad range of applications such as the treatment of neurologic disorders and the augmentation of baseline human performance. In this article, we present an fMRI NFT protocol developed at our institution for modulation of both healthy and abnormal brain function, as well as examples of using the method to target both cognitive and auditory regions of the brain.

Coping with Brain Disorders using Neurotechnology.

PubMed

Pedro A, Valdes-Sosa

2012-01-01

Brain disorders account for more than 34% of the global burden of disease, crippling nations by decreasing their "mental capital"-with greater effect in developing countries. Early detection is the key to their management, but establishing such programmes seems nearly impossible due to the high prevalence of the dysfunctions as compared with the high cost of neuroimaging devices. Thus, at first sight, the research of the Decade of the Brain and the international Human Brain Mapping Project might seem to be condemned to benefit only a small elite. Cuba has shown that is not so by using neurotechnology for the last 3 decades to implement stratified active screening programmes for brain disorders at the population level. This experience has shown that, by the transformation of health indicators, an appropriate use of technology can be integrated with attention to the population at the primary levels of both health care and education. An essential component of neurotechnology is neuroinformatics, which-like its counterpart bioinformatics-combines databases, analysis tools, and theoretical models to craft tools for early disease diagnosis and management. Much work remains to be done and will depend critically on south-south cooperation to solve problems for countries with similar situations.

Coping with Brain Disorders using Neurotechnology

PubMed Central

Pedro A, Valdes-Sosa

2012-01-01

Brain disorders account for more than 34% of the global burden of disease, crippling nations by decreasing their “mental capital”—with greater effect in developing countries. Early detection is the key to their management, but establishing such programmes seems nearly impossible due to the high prevalence of the dysfunctions as compared with the high cost of neuroimaging devices. Thus, at first sight, the research of the Decade of the Brain and the international Human Brain Mapping Project might seem to be condemned to benefit only a small elite. Cuba has shown that is not so by using neurotechnology for the last 3 decades to implement stratified active screening programmes for brain disorders at the population level. This experience has shown that, by the transformation of health indicators, an appropriate use of technology can be integrated with attention to the population at the primary levels of both health care and education. An essential component of neurotechnology is neuroinformatics, which—like its counterpart bioinformatics—combines databases, analysis tools, and theoretical models to craft tools for early disease diagnosis and management. Much work remains to be done and will depend critically on south—south cooperation to solve problems for countries with similar situations. PMID:22977368

Investigating the Microstructural Correlation of White Matter in Autism Spectrum Disorder.

PubMed

Dean, Douglas C; Travers, Brittany G; Adluru, Nagesh; Tromp, Do P M; Destiche, Daniel J; Samsin, Danica; Prigge, Molly B; Zielinski, Brandon A; Fletcher, P Thomas; Anderson, Jeffrey S; Froehlich, Alyson L; Bigler, Erin D; Lange, Nicholas; Lainhart, Janet E; Alexander, Andrew L

2016-06-01

White matter microstructure forms a complex and dynamical system that is critical for efficient and synchronized brain function. Neuroimaging findings in children with autism spectrum disorder (ASD) suggest this condition is associated with altered white matter microstructure, which may lead to atypical macroscale brain connectivity. In this study, we used diffusion tensor imaging measures to examine the extent that white matter tracts are interrelated within ASD and typical development. We assessed the strength of inter-regional white matter correlations between typically developing and ASD diagnosed individuals. Using hierarchical clustering analysis, clustering patterns of the pairwise white matter correlations were constructed and revealed to be different between the two groups. Additionally, we explored the use of graph theory analysis to examine the characteristics of the patterns formed by inter-regional white matter correlations and compared these properties between ASD and typical development. We demonstrate that the ASD sample has significantly less coherence in white matter microstructure across the brain compared to that in the typical development sample. The ASD group also presented altered topological characteristics, which may implicate less efficient brain networking in ASD. These findings highlight the potential of graph theory based network characteristics to describe the underlying networks as measured by diffusion magnetic resonance imaging and furthermore indicates that ASD may be associated with altered brain network characteristics. Our findings are consistent with those of a growing number of studies and hypotheses that have suggested disrupted brain connectivity in ASD.

Investigating the Microstructural Correlation of White Matter in Autism Spectrum Disorder

PubMed Central

Travers, Brittany G.; Adluru, Nagesh; Tromp, Do P.M.; Destiche, Daniel J.; Samsin, Danica; Prigge, Molly B.; Zielinski, Brandon A.; Fletcher, P. Thomas; Anderson, Jeffrey S.; Froehlich, Alyson L.; Bigler, Erin D.; Lange, Nicholas; Lainhart, Janet E.; Alexander, Andrew L.

2016-01-01

Abstract White matter microstructure forms a complex and dynamical system that is critical for efficient and synchronized brain function. Neuroimaging findings in children with autism spectrum disorder (ASD) suggest this condition is associated with altered white matter microstructure, which may lead to atypical macroscale brain connectivity. In this study, we used diffusion tensor imaging measures to examine the extent that white matter tracts are interrelated within ASD and typical development. We assessed the strength of inter-regional white matter correlations between typically developing and ASD diagnosed individuals. Using hierarchical clustering analysis, clustering patterns of the pairwise white matter correlations were constructed and revealed to be different between the two groups. Additionally, we explored the use of graph theory analysis to examine the characteristics of the patterns formed by inter-regional white matter correlations and compared these properties between ASD and typical development. We demonstrate that the ASD sample has significantly less coherence in white matter microstructure across the brain compared to that in the typical development sample. The ASD group also presented altered topological characteristics, which may implicate less efficient brain networking in ASD. These findings highlight the potential of graph theory based network characteristics to describe the underlying networks as measured by diffusion magnetic resonance imaging and furthermore indicates that ASD may be associated with altered brain network characteristics. Our findings are consistent with those of a growing number of studies and hypotheses that have suggested disrupted brain connectivity in ASD. PMID:27021440

Longitudinal MRI Study of Cortical Development through Early Childhood in Autism

PubMed Central

Schumann, C.M.; Bloss, C.S.; Barnes, C. Carter; Wideman, G.M.; Carper, R.A.; Akshoomoff, N.; Pierce, K.; Hagler, D.; Schork, N.; Lord, C.; Courchesne, E.

2010-01-01

Cross-sectional MRI studies have long hypothesized that the brain in children with autism undergoes an abnormal growth trajectory that includes a period of early overgrowth; however this has never been confirmed by a longitudinal study. We carried out the first longitudinal study of brain growth in toddlers at the time symptoms of autism are becoming clinically apparent utilizing structural MRI scans at multiple time points beginning at 1.5 years up to 5 years of age. We collected 193 scans on 41 toddlers who received a confirmed diagnosis of Autistic Disorder at ~48 months of age and 44 typically developing controls. By 2.5 years of age, both cerebral gray and white matter was significantly enlarged in toddlers with Autistic Disorder, with the most severe enlargement occurring in frontal, temporal and cingulate cortices. In the longitudinal analyses, which we accounted for age and gender effect, we found that all regions (cerebral gray, cerebral white, frontal gray, temporal gray, cingulate gray, and parietal gray) except occipital gray developed at an abnormal growth rate in toddlers with Autistic Disorder that was mainly characterized by a quadratic age effect. Females with Autistic Disorder displayed a more pronounced abnormal growth profile in more brain regions than males with the disorder. Given that overgrowth clearly begins before 2 years of age, future longitudinal studies would benefit from inclusion of even younger populations as well as further characterization of genetic and other biomarkers in order to determine the underlying neuropathological processes causing the onset of autistic symptoms. PMID:20335478

Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain.

PubMed

Patel, Mayur M; Patel, Bhoomika M

2017-02-01

CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood-brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting. Several approaches have been investigated to allow therapeutics to cross the BBB. As the molecular structure of the BBB is better elucidated, several key approaches for brain targeting include physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). The current review discusses the latest advancements in these approaches, with a major focus on articles published in 2015 and 2016. In addition, we also cover the alternative delivery routes, such as intranasal and convection-enhanced diffusion methods, and disruption of the BBB for brain targeting.

75 FR 27351 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-14

... Committee: Biology of Development and Aging Integrated Review Group; Development--2 Study Section. Date...: Center for Scientific Review Special Emphasis Panel; ARRA: Developmental Brain Disorders Competitive...

Prenatal exposure to common environmental factors affects brain lipids and increases risk of developing autism spectrum disorders.

PubMed

Wong, Christine T; Wais, Joshua; Crawford, Dorota A

2015-11-01

The prevalence of autism spectrum disorders (ASDs) has been on the rise over recent years. The presence of diverse subsets of candidate genes in each individual with an ASD and the vast variability of phenotypical differences suggest that the interference of an exogenous environmental component may greatly contribute to the development of ASDs. The lipid mediator prostaglandin E2 (PGE2 ) is released from phospholipids of cell membranes, and is important in brain development and function; PGE2 is involved in differentiation, synaptic plasticity and calcium regulation. The previous review already described extrinsic factors, including deficient dietary supplementation, and exposure to oxidative stress, infections and inflammation that can disrupt signaling of the PGE2 pathway and contribute to ASDs. In this review, the structure and establishment of two key protective barriers for the brain during early development are described: the blood-brain barrier; and the placental barrier. Then, the first comprehensive summary of other environmental factors, such as exposure to chemicals in air pollution, pesticides and consumer products, which can also disturb PGE2 signaling and increase the risk for developing ASDs is provided. Also, how these exogenous agents are capable of crossing the protective barriers of the brain during critical developmental periods when barrier components are still being formed is described. This review underlines the importance of avoiding or limiting exposure to these factors during vulnerable periods in development. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

An informatics approach to integrating genetic and neurological data in speech and language neuroscience.

PubMed

Bohland, Jason W; Myers, Emma M; Kim, Esther

2014-01-01

A number of heritable disorders impair the normal development of speech and language processes and occur in large numbers within the general population. While candidate genes and loci have been identified, the gap between genotype and phenotype is vast, limiting current understanding of the biology of normal and disordered processes. This gap exists not only in our scientific knowledge, but also in our research communities, where genetics researchers and speech, language, and cognitive scientists tend to operate independently. Here we describe a web-based, domain-specific, curated database that represents information about genotype-phenotype relations specific to speech and language disorders, as well as neuroimaging results demonstrating focal brain differences in relevant patients versus controls. Bringing these two distinct data types into a common database ( http://neurospeech.org/sldb ) is a first step toward bringing molecular level information into cognitive and computational theories of speech and language function. One bridge between these data types is provided by densely sampled profiles of gene expression in the brain, such as those provided by the Allen Brain Atlases. Here we present results from exploratory analyses of human brain gene expression profiles for genes implicated in speech and language disorders, which are annotated in our database. We then discuss how such datasets can be useful in the development of computational models that bridge levels of analysis, necessary to provide a mechanistic understanding of heritable language disorders. We further describe our general approach to information integration, discuss important caveats and considerations, and offer a specific but speculative example based on genes implicated in stuttering and basal ganglia function in speech motor control.

Decreased Axon Caliber Underlies Loss of Fiber Tract Integrity, Disproportional Reductions in White Matter Volume, and Microcephaly in Angelman Syndrome Model Mice

PubMed Central

Judson, Matthew C.; Burette, Alain C.; Shen, Mark D.; Rumple, Ashley M.; Del Cid, Wilmer A.; Paniagua, Beatriz

2017-01-01

Angelman syndrome (AS) is a debilitating neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A allele. It is currently unclear how the consequences of this genetic insult unfold to impair neurodevelopment. We reasoned that by elucidating the basis of microcephaly in AS, a highly penetrant syndromic feature with early postnatal onset, we would gain new insights into the mechanisms by which maternal UBE3A loss derails neurotypical brain growth and function. Detailed anatomical analysis of both male and female maternal Ube3a-null mice reveals that microcephaly in the AS mouse model is primarily driven by deficits in the growth of white matter tracts, which by adulthood are characterized by densely packed axons of disproportionately small caliber. Our results implicate impaired axon growth in the pathogenesis of AS and identify noninvasive structural neuroimaging as a potentially valuable tool for gauging therapeutic efficacy in the disorder. SIGNIFICANCE STATEMENT People who maternally inherit a deletion or nonfunctional copy of the UBE3A gene develop Angelman syndrome (AS), a severe neurodevelopmental disorder. To better understand how loss of maternal UBE3A function derails brain development, we analyzed brain structure in a maternal Ube3a knock-out mouse model of AS. We report that the volume of white matter (WM) is disproportionately reduced in AS mice, indicating that deficits in WM development are a major factor underlying impaired brain growth and microcephaly in the disorder. Notably, we find that axons within the WM pathways of AS model mice are abnormally small in caliber. This defect is associated with slowed nerve conduction, which could contribute to behavioral deficits in AS, including motor dysfunction. PMID:28663201

Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor.

PubMed

Esler, Murray; Lambert, Elisabeth; Alvarenga, Marlies; Socratous, Florentia; Richards, Jeff; Barton, David; Pier, Ciaran; Brenchley, Celia; Dawood, Tye; Hastings, Jacqueline; Guo, Ling; Haikerwal, Deepak; Kaye, David; Jennings, Garry; Kalff, Victor; Kelly, Michael; Wiesner, Glen; Lambert, Gavin

2007-08-01

Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.

7,8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders.

PubMed

Du, X; Hill, R A

2015-10-01

Neurodevelopmental disorders are a group of conditions that arises from impairments of the central nervous system during its development. The causes of the various disorders are heterogeneous and the symptoms likewise are multifarious. Most of these disorders currently have very little available treatment that is effective in combating the plethora of serious symptoms. Brain-derived neurotrophic factor (BDNF) is a fundamental neurotrophin with vital functions during brain development. Pre-clinical studies have shown that increasing BDNF signalling may be a potent way to prevent, arrest or even reverse abnormal neurodevelopmental events arising from a variety of genetic or environmental causes. However, many difficulties make BDNF problematic to administer in an efficient manner. The recent discovery of a small BDNF-mimetic, the naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF), may provide an avenue to allow efficient and safe activation of the BDNF pathway in tackling the symptoms of neurodevelopmental disorders. Here, evidence will be provided to support the potential of 7,8-DHF as a novel treatment for several neurodevelopmental disorders where the BDNF signalling pathway is implicated in the pathophysiology and where benefits are therefore most likely to be derived from its implementation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Closed-loop brain-machine-body interfaces for noninvasive rehabilitation of movement disorders.

PubMed

Broccard, Frédéric D; Mullen, Tim; Chi, Yu Mike; Peterson, David; Iversen, John R; Arnold, Mike; Kreutz-Delgado, Kenneth; Jung, Tzyy-Ping; Makeig, Scott; Poizner, Howard; Sejnowski, Terrence; Cauwenberghs, Gert

2014-08-01

Traditional approaches for neurological rehabilitation of patients affected with movement disorders, such as Parkinson's disease (PD), dystonia, and essential tremor (ET) consist mainly of oral medication, physical therapy, and botulinum toxin injections. Recently, the more invasive method of deep brain stimulation (DBS) showed significant improvement of the physical symptoms associated with these disorders. In the past several years, the adoption of feedback control theory helped DBS protocols to take into account the progressive and dynamic nature of these neurological movement disorders that had largely been ignored so far. As a result, a more efficient and effective management of PD cardinal symptoms has emerged. In this paper, we review closed-loop systems for rehabilitation of movement disorders, focusing on PD, for which several invasive and noninvasive methods have been developed during the last decade, reducing the complications and side effects associated with traditional rehabilitation approaches and paving the way for tailored individual therapeutics. We then present a novel, transformative, noninvasive closed-loop framework based on force neurofeedback and discuss several future developments of closed-loop systems that might bring us closer to individualized solutions for neurological rehabilitation of movement disorders.

Closed-loop Brain-Machine-Body Interfaces for Noninvasive Rehabilitation of Movement Disorders

PubMed Central

Broccard, Frédéric D.; Mullen, Tim; Chi, Yu Mike; Peterson, David; Iversen, John R.; Arnold, Mike; Kreutz-Delgado, Kenneth; Jung, Tzyy-Ping; Makeig, Scott; Poizner, Howard; Sejnowski, Terrence; Cauwenberghs, Gert

2014-01-01

Traditional approaches for neurological rehabilitation of patients affected with movement disorders, such as Parkinson's disease (PD), dystonia, and essential tremor (ET) consist mainly of oral medication, physical therapy, and botulinum toxin injections. Recently, the more invasive method of deep brain stimulation (DBS) showed significant improvement of the physical symptoms associated with these disorders. In the past several years, the adoption of feedback control theory helped DBS protocols to take into account the progressive and dynamic nature of these neurological movement disorders that had largely been ignored so far. As a result, a more efficient and effective management of PD cardinal symptoms has emerged. In this paper, we review closed-loop systems for rehabilitation of movement disorders, focusing on PD, for which several invasive and noninvasive methods have been developed during the last decade, reducing the complications and side effects associated with traditional rehabilitation approaches and paving the way for tailored individual therapeutics. We then present a novel, transformative, noninvasive closed-loop framework based on force neurofeedback and discuss several future developments of closed-loop systems that might bring us closer to individualized solutions for neurological rehabilitation of movement disorders. PMID:24833254

Using Ferumoxytol-Enhanced MRI to Measure Inflammation in Patients With Brain Tumors or Other Conditions of the CNS

ClinicalTrials.gov

2017-08-30

Brain Injury; Central Nervous System Degenerative Disorder; Central Nervous System Infectious Disorder; Central Nervous System Vascular Malformation; Hemorrhagic Cerebrovascular Accident; Ischemic Cerebrovascular Accident; Primary Brain Neoplasm; Brain Cancer; Brain Tumors

Modulation of Gut Microbiota-Brain Axis by Probiotics, Prebiotics, and Diet.

PubMed

Liu, Xiaofei; Cao, Shangqing; Zhang, Xuewu

2015-09-16

There exists a bidirectional communication system between the gastrointestinal tract and the brain. Increasing evidence shows that gut microbiota can play a critical role in this communication; thus, the concept of a gut microbiota and brain axis is emerging. Here, we review recent findings in the relationship between intestinal microbes and brain function, such as anxiety, depression, stress, autism, learning, and memory. We highlight the advances in modulating brain development and behavior by probiotics, prebiotics, and diet through the gut microbiota-brain axis. A variety of mechanisms including immune, neural, and metabolic pathways may be involved in modulation of the gut microbiota-brain axis. We also discuss some future challenges. A deeper understanding of the relationship between the gut bacteria and their hosts is implicated in developing microbial-based therapeutic strategies for brain disorders.

A role for neurotransmission and neurodevelopment in attention-deficit/hyperactivity disorder

PubMed Central

2009-01-01

Attention-deficit/hyperactivity disorder (ADHD) has a moderate to high genetic component, probably due to many genes with small effects. Several susceptibility genes have been suggested on the basis of hypotheses that catecholaminergic pathways in the brain are responsible for ADHD. However, many negative association findings have been reported, indicating a limited success for investigations using this approach. The results from genome-wide association studies have suggested that genes related to general brain functions rather than specific aspects of the disorder may contribute to its development. Plausible biological hypotheses linked to neurotransmission and neurodevelopment in general and common to different psychiatric conditions need to be considered when defining candidate genes for ADHD association studies. PMID:19930624

Potential biomarkers in psychiatry: focus on the cholesterol system

PubMed Central

Woods, Alisa G; Sokolowska, Izabela; Taurines, Regina; Gerlach, Manfred; Dudley, Edward; Thome, Johannes; Darie, Costel C

2012-01-01

Abstract Measuring biomarkers to identify and assess illness is a strategy growing in popularity and relevance. Although already in clinical use for treating and predicting cancer, no biological measurement is used clinically for any psychiatric disorder. Biomarkers could predict the course of a medical problem, and aid in determining how and when to treat. Several studies have indicated that of candidate psychiatric biomarkers detected using proteomic techniques, cholesterol and associated proteins, specifically apolipoproteins (Apos), may be of interest. Cholesterol is necessary for brain development and its synthesis continues at a lower rate in the adult brain. Apos are the protein component of lipoproteins responsible for lipid transport. There is extensive evidence that the levels of cholesterol and Apos may be disturbed in psychiatric disorders, including autistic spectrum disorders (ASD). Here, we describe putative serum biomarkers for psychiatric disorders, and the role of cholesterol and Apos in central nervous system (CNS) disorders. PMID:22304330

Schizophrenia: A Systemic Disorder

PubMed Central

Kirkpatrick, Brian; Miller, Brian; García-Rizo, Clemente; Fernandez-Egea, Emilio

2015-01-01

The concept of schizophrenia that is most widely taught is that it is a disorder in which psychotic symptoms are the main problem, and a dysregulation of dopamine signaling is the main feature of pathophysiology. However, this concept limits clinical assessment, the treatments offered to patients, research, and the development of therapeutics. A more appropriate conceptual model is that: 1) schizophrenia is not a psychotic disorder, but a disorder of essentially every brain function in which psychosis is present; 2) it is not a brain disease, but a disorder with impairments throughout the body; 3) for many patients, neuropsychiatric problems other than psychosis contribute more to impairment in function and quality of life than does psychosis; and, 4) some conditions that are considered to be comorbid are integral parts of the illness. In conclusion, students, patients, and family members should be taught this model, along with its implications for assessment, research, and therapeutics. PMID:23518782

Crosstalk between metabolic and neuropsychiatric disorders

PubMed Central

Cha, Danielle S.

2012-01-01

Evidence supporting the concurrence of metabolic disturbances (e.g. insulin resistance, diabetes and obesity) and neuropsychiatric disorders has been demonstrated in both human and animal studies, suggesting the possibility that they have shared pathophysiological mechanisms. During the past decade, our understanding for the role of insulin in both normal and abnormal central nervous system (CNS) processes has become increasingly refined. Evidence indicates that insulin is a pleiotropic peptide, critical to neurotrophism, neuroplasticity, and neuromodulation. Moreover, the role of insulin underscores its importance in the development of several neuropsychiatric disorders, including, but not limited to, mechanisms involved in the pathogenesis and progression towards diabetes, obesity, and neurodegenerative disorders, such as Alzheimer's disease. This review focuses on the insulin-mediated effects on normal and abnormal brain function and discusses why targeting insulin-related pathways in the brain may emerge as a new approach for refining treatment of neurological and psychiatric disorders. PMID:22802875

Crosstalk between metabolic and neuropsychiatric disorders.

PubMed

Kaidanovich-Beilin, Oksana; Cha, Danielle S; McIntyre, Roger S

2012-01-01

Evidence supporting the concurrence of metabolic disturbances (e.g. insulin resistance, diabetes and obesity) and neuropsychiatric disorders has been demonstrated in both human and animal studies, suggesting the possibility that they have shared pathophysiological mechanisms. During the past decade, our understanding for the role of insulin in both normal and abnormal central nervous system (CNS) processes has become increasingly refined. Evidence indicates that insulin is a pleiotropic peptide, critical to neurotrophism, neuroplasticity, and neuromodulation. Moreover, the role of insulin underscores its importance in the development of several neuropsychiatric disorders, including, but not limited to, mechanisms involved in the pathogenesis and progression towards diabetes, obesity, and neurodegenerative disorders, such as Alzheimer's disease. This review focuses on the insulin-mediated effects on normal and abnormal brain function and discusses why targeting insulin-related pathways in the brain may emerge as a new approach for refining treatment of neurological and psychiatric disorders.

Split My Brain: A Case Study of Seizure Disorder and Brain Function

ERIC Educational Resources Information Center

Omarzu, Julia

2004-01-01

This case involves a couple deciding whether or not their son should undergo brain surgery to treat a severe seizure disorder. In examining this dilemma, students apply knowledge of brain anatomy and function. They also learn about brain scanning techniques and discuss the plasticity of the brain.

Project Aims to Bridge Neuroscience and Schools

ERIC Educational Resources Information Center

Samuels, Christina A.

2008-01-01

Using imaging technology that can probe the deepest workings of the brain, researchers have found that children with attention deficit hyperactivity disorder are using less of a certain part of their brains to hold back their itchy trigger fingers, compared with typically developing children performing the same task. This information was shared…

Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery

PubMed Central

2015-01-01

The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery. PMID:26579539

Analysis of shared heritability in common disorders of the brain.

PubMed

Anttila, Verneri; Bulik-Sullivan, Brendan; Finucane, Hilary K; Walters, Raymond K; Bras, Jose; Duncan, Laramie; Escott-Price, Valentina; Falcone, Guido J; Gormley, Padhraig; Malik, Rainer; Patsopoulos, Nikolaos A; Ripke, Stephan; Wei, Zhi; Yu, Dongmei; Lee, Phil H; Turley, Patrick; Grenier-Boley, Benjamin; Chouraki, Vincent; Kamatani, Yoichiro; Berr, Claudine; Letenneur, Luc; Hannequin, Didier; Amouyel, Philippe; Boland, Anne; Deleuze, Jean-François; Duron, Emmanuelle; Vardarajan, Badri N; Reitz, Christiane; Goate, Alison M; Huentelman, Matthew J; Kamboh, M Ilyas; Larson, Eric B; Rogaeva, Ekaterina; St George-Hyslop, Peter; Hakonarson, Hakon; Kukull, Walter A; Farrer, Lindsay A; Barnes, Lisa L; Beach, Thomas G; Demirci, F Yesim; Head, Elizabeth; Hulette, Christine M; Jicha, Gregory A; Kauwe, John S K; Kaye, Jeffrey A; Leverenz, James B; Levey, Allan I; Lieberman, Andrew P; Pankratz, Vernon S; Poon, Wayne W; Quinn, Joseph F; Saykin, Andrew J; Schneider, Lon S; Smith, Amanda G; Sonnen, Joshua A; Stern, Robert A; Van Deerlin, Vivianna M; Van Eldik, Linda J; Harold, Denise; Russo, Giancarlo; Rubinsztein, David C; Bayer, Anthony; Tsolaki, Magda; Proitsi, Petra; Fox, Nick C; Hampel, Harald; Owen, Michael J; Mead, Simon; Passmore, Peter; Morgan, Kevin; Nöthen, Markus M; Rossor, Martin; Lupton, Michelle K; Hoffmann, Per; Kornhuber, Johannes; Lawlor, Brian; McQuillin, Andrew; Al-Chalabi, Ammar; Bis, Joshua C; Ruiz, Agustin; Boada, Mercè; Seshadri, Sudha; Beiser, Alexa; Rice, Kenneth; van der Lee, Sven J; De Jager, Philip L; Geschwind, Daniel H; Riemenschneider, Matthias; Riedel-Heller, Steffi; Rotter, Jerome I; Ransmayr, Gerhard; Hyman, Bradley T; Cruchaga, Carlos; Alegret, Montserrat; Winsvold, Bendik; Palta, Priit; Farh, Kai-How; Cuenca-Leon, Ester; Furlotte, Nicholas; Kurth, Tobias; Ligthart, Lannie; Terwindt, Gisela M; Freilinger, Tobias; Ran, Caroline; Gordon, Scott D; Borck, Guntram; Adams, Hieab H H; Lehtimäki, Terho; Wedenoja, Juho; Buring, Julie E; Schürks, Markus; Hrafnsdottir, Maria; Hottenga, Jouke-Jan; Penninx, Brenda; Artto, Ville; Kaunisto, Mari; Vepsäläinen, Salli; Martin, Nicholas G; Montgomery, Grant W; Kurki, Mitja I; Hämäläinen, Eija; Huang, Hailiang; Huang, Jie; Sandor, Cynthia; Webber, Caleb; Muller-Myhsok, Bertram; Schreiber, Stefan; Salomaa, Veikko; Loehrer, Elizabeth; Göbel, Hartmut; Macaya, Alfons; Pozo-Rosich, Patricia; Hansen, Thomas; Werge, Thomas; Kaprio, Jaakko; Metspalu, Andres; Kubisch, Christian; Ferrari, Michel D; Belin, Andrea C; van den Maagdenberg, Arn M J M; Zwart, John-Anker; Boomsma, Dorret; Eriksson, Nicholas; Olesen, Jes; Chasman, Daniel I; Nyholt, Dale R; Avbersek, Andreja; Baum, Larry; Berkovic, Samuel; Bradfield, Jonathan; Buono, Russell; Catarino, Claudia B; Cossette, Patrick; De Jonghe, Peter; Depondt, Chantal; Dlugos, Dennis; Ferraro, Thomas N; French, Jacqueline; Hjalgrim, Helle; Jamnadas-Khoda, Jennifer; Kälviäinen, Reetta; Kunz, Wolfram S; Lerche, Holger; Leu, Costin; Lindhout, Dick; Lo, Warren; Lowenstein, Daniel; McCormack, Mark; Møller, Rikke S; Molloy, Anne; Ng, Ping-Wing; Oliver, Karen; Privitera, Michael; Radtke, Rodney; Ruppert, Ann-Kathrin; Sander, Thomas; Schachter, Steven; Schankin, Christoph; Scheffer, Ingrid; Schoch, Susanne; Sisodiya, Sanjay M; Smith, Philip; Sperling, Michael; Striano, Pasquale; Surges, Rainer; Thomas, G Neil; Visscher, Frank; Whelan, Christopher D; Zara, Federico; Heinzen, Erin L; Marson, Anthony; Becker, Felicitas; Stroink, Hans; Zimprich, Fritz; Gasser, Thomas; Gibbs, Raphael; Heutink, Peter; Martinez, Maria; Morris, Huw R; Sharma, Manu; Ryten, Mina; Mok, Kin Y; Pulit, Sara; Bevan, Steve; Holliday, Elizabeth; Attia, John; Battey, Thomas; Boncoraglio, Giorgio; Thijs, Vincent; Chen, Wei-Min; Mitchell, Braxton; Rothwell, Peter; Sharma, Pankaj; Sudlow, Cathie; Vicente, Astrid; Markus, Hugh; Kourkoulis, Christina; Pera, Joana; Raffeld, Miriam; Silliman, Scott; Boraska Perica, Vesna; Thornton, Laura M; Huckins, Laura M; William Rayner, N; Lewis, Cathryn M; Gratacos, Monica; Rybakowski, Filip; Keski-Rahkonen, Anna; Raevuori, Anu; Hudson, James I; Reichborn-Kjennerud, Ted; Monteleone, Palmiero; Karwautz, Andreas; Mannik, Katrin; Baker, Jessica H; O'Toole, Julie K; Trace, Sara E; Davis, Oliver S P; Helder, Sietske G; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Danner, Unna N; van Elburg, Annemarie A; Clementi, Maurizio; Forzan, Monica; Docampo, Elisa; Lissowska, Jolanta; Hauser, Joanna; Tortorella, Alfonso; Maj, Mario; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Papezova, Hana; Yilmaz, Zeynep; Wagner, Gudrun; Cohen-Woods, Sarah; Herms, Stefan; Julià, Antonio; Rabionet, Raquel; Dick, Danielle M; Ripatti, Samuli; Andreassen, Ole A; Espeseth, Thomas; Lundervold, Astri J; Steen, Vidar M; Pinto, Dalila; Scherer, Stephen W; Aschauer, Harald; Schosser, Alexandra; Alfredsson, Lars; Padyukov, Leonid; Halmi, Katherine A; Mitchell, James; Strober, Michael; Bergen, Andrew W; Kaye, Walter; Szatkiewicz, Jin Peng; Cormand, Bru; Ramos-Quiroga, Josep Antoni; Sánchez-Mora, Cristina; Ribasés, Marta; Casas, Miguel; Hervas, Amaia; Arranz, Maria Jesús; Haavik, Jan; Zayats, Tetyana; Johansson, Stefan; Williams, Nigel; Dempfle, Astrid; Rothenberger, Aribert; Kuntsi, Jonna; Oades, Robert D; Banaschewski, Tobias; Franke, Barbara; Buitelaar, Jan K; Arias Vasquez, Alejandro; Doyle, Alysa E; Reif, Andreas; Lesch, Klaus-Peter; Freitag, Christine; Rivero, Olga; Palmason, Haukur; Romanos, Marcel; Langley, Kate; Rietschel, Marcella; Witt, Stephanie H; Dalsgaard, Soeren; Børglum, Anders D; Waldman, Irwin; Wilmot, Beth; Molly, Nikolas; Bau, Claiton H D; Crosbie, Jennifer; Schachar, Russell; Loo, Sandra K; McGough, James J; Grevet, Eugenio H; Medland, Sarah E; Robinson, Elise; Weiss, Lauren A; Bacchelli, Elena; Bailey, Anthony; Bal, Vanessa; Battaglia, Agatino; Betancur, Catalina; Bolton, Patrick; Cantor, Rita; Celestino-Soper, Patrícia; Dawson, Geraldine; De Rubeis, Silvia; Duque, Frederico; Green, Andrew; Klauck, Sabine M; Leboyer, Marion; Levitt, Pat; Maestrini, Elena; Mane, Shrikant; De-Luca, Daniel Moreno-; Parr, Jeremy; Regan, Regina; Reichenberg, Abraham; Sandin, Sven; Vorstman, Jacob; Wassink, Thomas; Wijsman, Ellen; Cook, Edwin; Santangelo, Susan; Delorme, Richard; Rogé, Bernadette; Magalhaes, Tiago; Arking, Dan; Schulze, Thomas G; Thompson, Robert C; Strohmaier, Jana; Matthews, Keith; Melle, Ingrid; Morris, Derek; Blackwood, Douglas; McIntosh, Andrew; Bergen, Sarah E; Schalling, Martin; Jamain, Stéphane; Maaser, Anna; Fischer, Sascha B; Reinbold, Céline S; Fullerton, Janice M; Guzman-Parra, José; Mayoral, Fermin; Schofield, Peter R; Cichon, Sven; Mühleisen, Thomas W; Degenhardt, Franziska; Schumacher, Johannes; Bauer, Michael; Mitchell, Philip B; Gershon, Elliot S; Rice, John; Potash, James B; Zandi, Peter P; Craddock, Nick; Ferrier, I Nicol; Alda, Martin; Rouleau, Guy A; Turecki, Gustavo; Ophoff, Roel; Pato, Carlos; Anjorin, Adebayo; Stahl, Eli; Leber, Markus; Czerski, Piotr M; Cruceanu, Cristiana; Jones, Ian R; Posthuma, Danielle; Andlauer, Till F M; Forstner, Andreas J; Streit, Fabian; Baune, Bernhard T; Air, Tracy; Sinnamon, Grant; Wray, Naomi R; MacIntyre, Donald J; Porteous, David; Homuth, Georg; Rivera, Margarita; Grove, Jakob; Middeldorp, Christel M; Hickie, Ian; Pergadia, Michele; Mehta, Divya; Smit, Johannes H; Jansen, Rick; de Geus, Eco; Dunn, Erin; Li, Qingqin S; Nauck, Matthias; Schoevers, Robert A; Beekman, Aartjan Tf; Knowles, James A; Viktorin, Alexander; Arnold, Paul; Barr, Cathy L; Bedoya-Berrio, Gabriel; Bienvenu, O Joseph; Brentani, Helena; Burton, Christie; Camarena, Beatriz; Cappi, Carolina; Cath, Danielle; Cavallini, Maria; Cusi, Daniele; Darrow, Sabrina; Denys, Damiaan; Derks, Eske M; Dietrich, Andrea; Fernandez, Thomas; Figee, Martijn; Freimer, Nelson; Gerber, Gloria; Grados, Marco; Greenberg, Erica; Hanna, Gregory L; Hartmann, Andreas; Hirschtritt, Matthew E; Hoekstra, Pieter J; Huang, Alden; Huyser, Chaim; Illmann, Cornelia; Jenike, Michael; Kuperman, Samuel; Leventhal, Bennett; Lochner, Christine; Lyon, Gholson J; Macciardi, Fabio; Madruga-Garrido, Marcos; Malaty, Irene A; Maras, Athanasios; McGrath, Lauren; Miguel, Eurípedes C; Mir, Pablo; Nestadt, Gerald; Nicolini, Humberto; Okun, Michael S; Pakstis, Andrew; Paschou, Peristera; Piacentini, John; Pittenger, Christopher; Plessen, Kerstin; Ramensky, Vasily; Ramos, Eliana M; Reus, Victor; Richter, Margaret A; Riddle, Mark A; Robertson, Mary M; Roessner, Veit; Rosário, Maria; Samuels, Jack F; Sandor, Paul; Stein, Dan J; Tsetsos, Fotis; Van Nieuwerburgh, Filip; Weatherall, Sarah; Wendland, Jens R; Wolanczyk, Tomasz; Worbe, Yulia; Zai, Gwyneth; Goes, Fernando S; McLaughlin, Nicole; Nestadt, Paul S; Grabe, Hans-Jorgen; Depienne, Christel; Konkashbaev, Anuar; Lanzagorta, Nuria; Valencia-Duarte, Ana; Bramon, Elvira; Buccola, Nancy; Cahn, Wiepke; Cairns, Murray; Chong, Siow A; Cohen, David; Crespo-Facorro, Benedicto; Crowley, James; Davidson, Michael; DeLisi, Lynn; Dinan, Timothy; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Haan, Lieuwe; Hougaard, David; Karachanak-Yankova, Sena; Khrunin, Andrey; Klovins, Janis; Kučinskas, Vaidutis; Lee Chee Keong, Jimmy; Limborska, Svetlana; Loughland, Carmel; Lönnqvist, Jouko; Maher, Brion; Mattheisen, Manuel; McDonald, Colm; Murphy, Kieran C; Nenadic, Igor; van Os, Jim; Pantelis, Christos; Pato, Michele; Petryshen, Tracey; Quested, Digby; Roussos, Panos; Sanders, Alan R; Schall, Ulrich; Schwab, Sibylle G; Sim, Kang; So, Hon-Cheong; Stögmann, Elisabeth; Subramaniam, Mythily; Toncheva, Draga; Waddington, John; Walters, James; Weiser, Mark; Cheng, Wei; Cloninger, Robert; Curtis, David; Gejman, Pablo V; Henskens, Frans; Mattingsdal, Morten; Oh, Sang-Yun; Scott, Rodney; Webb, Bradley; Breen, Gerome; Churchhouse, Claire; Bulik, Cynthia M; Daly, Mark; Dichgans, Martin; Faraone, Stephen V; Guerreiro, Rita; Holmans, Peter; Kendler, Kenneth S; Koeleman, Bobby; Mathews, Carol A; Price, Alkes; Scharf, Jeremiah; Sklar, Pamela; Williams, Julie; Wood, Nicholas W; Cotsapas, Chris; Palotie, Aarno; Smoller, Jordan W; Sullivan, Patrick; Rosand, Jonathan; Corvin, Aiden; Neale, Benjamin M

2018-06-22

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Pathways of Polyunsaturated Fatty Acid Utilization: Implications for Brain Function in Neuropsychiatric Health and Disease

PubMed Central

Liu, Joanne J.; Green, Pnina; Mann, J. John; Rapoport, Stanley I.; Sublette, M. Elizabeth

2014-01-01

Essential polyunsaturated fatty acids (PUFAs) have profound effects on brain development and function. Abnormalities of PUFA status have been implicated in neuropsychiatric diseases such as major depression, bipolar disorder, schizophrenia, Alzheimer’s disease, and attention deficit hyperactivity disorder. Pathophysiologic mechanisms could involve not only suboptimal PUFA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. This article provides an overview of physiologic factors regulating PUFA utilization, highlighting their relevance to neuropsychiatric disease. PMID:25498862

Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders

PubMed Central

Nordahl, Christine Wu; Lange, Nicholas; Li, Deana D.; Barnett, Lou Ann; Lee, Aaron; Buonocore, Michael H.; Simon, Tony J.; Rogers, Sally; Ozonoff, Sally; Amaral, David G.

2011-01-01

Autism is a heterogeneous disorder with multiple behavioral and biological phenotypes. Accelerated brain growth during early childhood is a well-established biological feature of autism. Onset pattern, i.e., early onset or regressive, is an intensely studied behavioral phenotype of autism. There is currently little known, however, about whether, or how, onset status maps onto the abnormal brain growth. We examined the relationship between total brain volume and onset status in a large sample of 2- to 4-y-old boys and girls with autism spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61, regression (REG)] and a comparison group of age-matched typically developing controls (n = 66). We also examined retrospective head circumference measurements from birth through 18 mo of age. We found that abnormal brain enlargement was most commonly found in boys with regressive autism. Brain size in boys without regression did not differ from controls. Retrospective head circumference measurements indicate that head circumference in boys with regressive autism is normal at birth but diverges from the other groups around 4–6 mo of age. There were no differences in brain size in girls with autism (n = 22, ASD; n = 24, controls). These results suggest that there may be distinct neural phenotypes associated with different onsets of autism. For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism. PMID:22123952

ErbB4 in Laminated Brain Structures: A Neurodevelopmental Approach to Schizophrenia

PubMed Central

Perez-Garcia, Carlos G.

2015-01-01

The susceptibility genes for schizophrenia Neuregulin-1 (NRG1) and ErbB4 have critical functions during brain development and in the adult. Alterations in the ErbB4 signaling pathway cause a variety of neurodevelopmental defects including deficiencies in neuronal migration, synaptic plasticity, and myelination. I have used the ErbB4-/- HER4heart KO mice to study the neurodevelopmental insults associated to deficiencies in the NRG1-ErbB4 signaling pathway and their potential implication with brain disorders such as schizophrenia, a chronic psychiatric disease affecting 1% of the population worldwide. ErbB4 deletion results in an array of neurodevelopmental deficits that are consistent with a schizophrenic model. First, similar defects appear in multiple brain structures, from the cortex to the cerebellum. Second, these defects affect multiple aspects of brain development, from deficits in neuronal migration to impairments in excitatory/inhibitory systems, including reductions in brain volume, cortical and cerebellar heterotopias, alterations in number and distribution of specific subpopulations of interneurons, deficiencies in the astrocytic and oligodendrocytic lineages, and additional insults in major brain structures. This suggests that alterations in specific neurodevelopmental genes that play similar functions in multiple neuroanatomical structures might account for some of the symptomatology observed in schizophrenic patients, such as defects in cognition. ErbB4 mutation uncovers flaws in brain development that are compatible with a neurodevelopmental model of schizophrenia, and it establishes a comprehensive model to study the basis of the disorder before symptoms are detected in the adult. PMID:26733804

Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain

PubMed Central

Ratnu, Vikram S.; Emami, Michael R.; Bredy, Timothy W.

2016-01-01

There are inherent biological differences between males and females that contribute to sex differences in brain function and to many sex-specific illnesses and disorders. Traditionally, it has been thought that such differences are largely due to hormonal regulation; however, there are also genetic and epigenetic effects caused by the inheritance and unequal dosage of genes located on the X- and Y-chromosomes. Here we discuss the evidence in favor of a genetic and epigenetic basis for sexually dimorphic behavior, as a consequence of underlying differences in the regulation of genes that drive brain function. A better understanding of sex-specific molecular processes in the brain will provide further insight for the development of novel therapeutic approaches for the treatment of neuropsychiatric disorders characterized by gender/sex differences. PMID:27870402

Research Review: Environmental exposures, neurodevelopment and child mental health – new paradigms for the study of brain and behavioral effects

PubMed Central

Rauh, Virginia A.; Margolis, Amy

2016-01-01

Background Environmental exposures play a critical role in the genesis of some child mental health problems. Methods We open with a discussion of children’s vulnerability to neurotoxic substances, changes in the distribution of toxic exposures, and co-occurrence of social and physical exposures. We address trends in prevalence of mental health disorders, and approaches to the definition of disorders that are sensitive to the subtle effects of toxic exposures. We suggest broadening outcomes to include dimensional measures of autism spectrum disorders, attention deficit hyperactivity disorder, and child learning capacity, as well as direct assessment of brain function. Findings We consider the impact of two important exposures on children’s mental health: lead and pesticides. We argue that longitudinal research designs may capture the cascading effects of exposures across biological systems and the full-range of neuropsychological endpoints. Neuroimaging is a valuable tool for observing brain maturation under varying environmental conditions. A dimensional approach to measurement may be sensitive to subtle sub-clinical toxic effects, permitting the development of exposure-related profiles and testing of complex functional relationships between brain and behavior. Questions about the neurotoxic effects of chemicals become more pressing when viewed through the lens of environmental justice. Conclusions Reduction in the burden of child mental health disorders will require longitudinal study of neurotoxic exposures, incorporating dimensional approaches to outcome assessment and measures of brain function. Research that seeks to identify links between toxic exposures and mental health outcomes has enormous public health and societal value. PMID:26987761

Research Review: Environmental exposures, neurodevelopment, and child mental health - new paradigms for the study of brain and behavioral effects.

PubMed

Rauh, Virginia A; Margolis, Amy E

2016-07-01

Environmental exposures play a critical role in the genesis of some child mental health problems. We open with a discussion of children's vulnerability to neurotoxic substances, changes in the distribution of toxic exposures, and cooccurrence of social and physical exposures. We address trends in prevalence of mental health disorders, and approaches to the definition of disorders that are sensitive to the subtle effects of toxic exposures. We suggest broadening outcomes to include dimensional measures of autism spectrum disorders, attention-deficit hyperactivity disorder, and child learning capacity, as well as direct assessment of brain function. We consider the impact of two important exposures on children's mental health: lead and pesticides. We argue that longitudinal research designs may capture the cascading effects of exposures across biological systems and the full-range of neuropsychological endpoints. Neuroimaging is a valuable tool for observing brain maturation under varying environmental conditions. A dimensional approach to measurement may be sensitive to subtle subclinical toxic effects, permitting the development of exposure-related profiles and testing of complex functional relationships between brain and behavior. Questions about the neurotoxic effects of chemicals become more pressing when viewed through the lens of environmental justice. Reduction in the burden of child mental health disorders will require longitudinal study of neurotoxic exposures, incorporating dimensional approaches to outcome assessment, and measures of brain function. Research that seeks to identify links between toxic exposures and mental health outcomes has enormous public health and societal value. © 2016 Association for Child and Adolescent Mental Health.

Toward a complex system understanding of bipolar disorder: A chaotic model of abnormal circadian activity rhythms in euthymic bipolar disorder.

PubMed

Hadaeghi, Fatemeh; Hashemi Golpayegani, Mohammad Reza; Jafari, Sajad; Murray, Greg

2016-08-01

In the absence of a comprehensive neural model to explain the underlying mechanisms of disturbed circadian function in bipolar disorder, mathematical modeling is a helpful tool. Here, circadian activity as a response to exogenous daily cycles is proposed to be the product of interactions between neuronal networks in cortical (cognitive processing) and subcortical (pacemaker) areas of the brain. To investigate the dynamical aspects of the link between disturbed circadian activity rhythms and abnormalities of neurotransmitter functioning in frontal areas of the brain, we developed a novel mathematical model of a chaotic system which represents fluctuations in circadian activity in bipolar disorder as changes in the model's parameters. A novel map-based chaotic system was developed to capture disturbances in circadian activity across the two extreme mood states of bipolar disorder. The model uses chaos theory to characterize interplay between neurotransmitter functions and rhythm generation; it aims to illuminate key activity phenomenology in bipolar disorder, including prolonged sleep intervals, decreased total activity and attenuated amplitude of the diurnal activity rhythm. To test our new cortical-circadian mathematical model of bipolar disorder, we utilized previously collected locomotor activity data recorded from normal subjects and bipolar patients by wrist-worn actigraphs. All control parameters in the proposed model have an important role in replicating the different aspects of circadian activity rhythm generation in the brain. The model can successfully replicate deviations in sleep/wake time intervals corresponding to manic and depressive episodes of bipolar disorder, in which one of the excitatory or inhibitory pathways is abnormally dominant. Although neuroimaging research has strongly implicated a reciprocal interaction between cortical and subcortical regions as pathogenic in bipolar disorder, this is the first model to mathematically represent this multilevel explanation of the phenomena of bipolar disorder. © The Royal Australian and New Zealand College of Psychiatrists 2016.

Perspectives and new aspects of metalloproteinases' inhibitors in therapy of CNS disorders: from chemistry to medicine.

PubMed

Boguszewska-Czubara, Anna; Budzynska, Barbara; Skalicka-Wozniak, Krystyna; Kurzepa, Jacek

2018-05-13

Matrix metalloproteinases (MMPs) play a key role in remodelling of the extracellular matrix (ECM) and, at the same time, influence cell differentiation, migration, proliferation and survival. Their importance in variety of human diseases including cancer, rheumatoid arthritis, pulmonary emphysema and fibrotic disorders has been known for many years but special attention should be paid on the role of MMPs in the central nervous system (CNS) disorders. Till now, there are not many well documented physiological MMP target proteins in the brain and only some pathological ones. Numerous neurodegenerative diseases is a consequence or result in disturbed remodeling of brain ECM, therefore proper action of MMPs as well as control of their activity may play crucial roles in the development and the progress of these diseases. In present review we discuss the role of metalloproteinase inhibitors, from the well-known natural endogenous tissue inhibitors of metalloproteinases (TIMPs) through exogenous synthetic ones like (4-phenoxyphenylsulfonyl)methylthiirane (SB-3CT), tetracyclines, batimastat (BB-94) and FN-439. As the MMP-TIMP system has been well described in physiological development as well as in pathological conditions mainly in neoplasctic diseases, the knowledge about the enzymatic system in mammalian brain tissue remain still poorly understood in this context. Therefore, we focus on MMPs inhibition in the context of physiological function of adult brain as well as pathological conditions including neurodegenerative diseases, brain injuries and others. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Schizophrenia.

PubMed

Kahn, René S; Sommer, Iris E; Murray, Robin M; Meyer-Lindenberg, Andreas; Weinberger, Daniel R; Cannon, Tyrone D; O'Donovan, Michael; Correll, Christoph U; Kane, John M; van Os, Jim; Insel, Thomas R

2015-11-12

Schizophrenia is a chronic psychiatric disorder with a heterogeneous genetic and neurobiological background that influences early brain development, and is expressed as a combination of psychotic symptoms - such as hallucinations, delusions and disorganization - and motivational and cognitive dysfunctions. The mean lifetime prevalence of the disorder is just below 1%, but large regional differences in prevalence rates are evident owing to disparities in urbanicity and patterns of immigration. Although gross brain pathology is not a characteristic of schizophrenia, the disorder involves subtle pathological changes in specific neural cell populations and in cell-cell communication. Schizophrenia, as a cognitive and behavioural disorder, is ultimately about how the brain processes information. Indeed, neuroimaging studies have shown that information processing is functionally abnormal in patients with first-episode and chronic schizophrenia. Although pharmacological treatments for schizophrenia can relieve psychotic symptoms, such drugs generally do not lead to substantial improvements in social, cognitive and occupational functioning. Psychosocial interventions such as cognitive-behavioural therapy, cognitive remediation and supported education and employment have added treatment value, but are inconsistently applied. Given that schizophrenia starts many years before a diagnosis is typically made, the identification of individuals at risk and those in the early phases of the disorder, and the exploration of preventive approaches are crucial.

Prevalence of cavum vergae in psychosis and mood spectrum disorders.

PubMed

Landin-Romero, Ramón; Sarró, Salvador; Fernández-Corcuera, Paloma; Moro, Noemí; Manuel Goikolea, Jose; Isabel Carrión, María; Pomarol-Clotet, Edith; Amann, Benedikt L; Radua, Joaquim

2015-11-01

Midline brain abnormalities might increase susceptibility to both first-episode and chronic mental disorder. Evidence of cavum vergae (CV) abnormality in mental disorders is scarce. The presence of CV was assessed by a researcher blind to clinical information in a cross-disorder sample of 639 patients with mood and psychotic disorders and in 223 healthy controls. Homogeneous magnetic resonance imaging methods of acquisition and assessment were applied. Seven out of 639 patients with mood or psychotic disorders were detected with CV which corresponds to a prevalence of 1.1%. There were no concurrent cases of CV in the healthy control group. Identified cases which are briefly described were diagnosed from bipolar I disorder (n=2), delusional disorder (n=1), brief psychotic disorder (n=1) and schizoaffective disorder (n=3). Patients with CV had descriptively lower current IQ, executive functioning and memory scores in relation to patients without CV but this was not statistically significant. Effects of medication and lack of statistical power of the CV patient group. Midline brain abnormalities, such as CV, might represent an unspecific risk factor for the development of severe mental disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

An Australian Brain Bank: a critical investment with a high return!

PubMed Central

Garrick, T.; Dedova, I.; Hunt, C.; Miller, R.; Sundqvist, N.; Harper, C.

2012-01-01

Research into neuropsychiatric disorders, including alcohol-related problems, is limited in part by the lack of appropriate animal models. However, the development of new technologies in pathology and molecular biology means that many more questions can be addressed using appropriately stored human brain tissues. The New South Wales Tissue Resource Centre (TRC) in the University of Sydney (Australia) is a human brain bank that can provide tissues to the neuroscience research community studying alcohol-related brain disorders, schizophrenia, depression and bipolar disorders. Carefully standardised operational protocols and integrated information systems means that the TRC can provide high quality, accurately characterised, tissues for research. A recent initiative, the pre-mortem donor program called “Using our Brains”, encourages individuals without neuropsychiatric illness to register as control donors, a critical group for all research. Community support for this program is strong with over 2,000 people registering their interest. Discussed herein are the protocols pertaining to this multifaceted facility and the benefits of investment, both scientific and financial, to neuroscience researchers and the community at large. PMID:18543078

The Development of Psychotic Disorders in Adolescence: A potential role for hormones

PubMed Central

Trotman, Hanan D.; Holtzman, Carrie W.; Ryan, Arthur T.; Shapiro, Daniel I.; MacDonald, Allison N.; Goulding, Sandra M.; Brasfield, Joy L.; Walker, Elaine F.

2013-01-01

The notion that adolescence is characterized by dramatic changes in behavior, and often by emotional upheaval, is widespread and longstanding in popular western culture. In recent decades, this notion has gained increasing support from empirical research showing that the peri- and post-pubertal developmental stages are associated with a significant rise in the rate of psychiatric symptoms and syndromes. As a result, interest in adolescent development has burgeoned among researchers focused on the origins of schizophrenia and other psychotic disorders. Two factors have fueled this trend: 1) increasing evidence from longitudinal research that adolescence is the modal period for the emergence of “prodromal” manifestations, or precursors of psychotic symptoms, and 2) the rapidly accumulating scientific findings on brain structural and functional changes occurring during adolescence and young adulthood. Further, gonadal and adrenal hormones are beginning to play a more prominent role in conceptualizations of adolescent brain development, as well as in the origins of psychiatric symptoms during this period (Walker and Bollini, 2002; Walker et al., 2008). In this paper, we begin by providing an overview of the nature and course of psychotic disorders during adolescence/young adulthood. We then turn to the role of hormones in modulating normal brain development, and the potential role they might play in the abnormal brain changes that characterize youth at clinical high-risk (CHR) for psychosis. The activational and organizational effects of hormones are explored, with a focus on how hormone-induced changes might be linked with neuropathological processes in the emergence of psychosis. PMID:23998682

New frontiers in developmental neuropharmacology: Can long-term therapeutic effects of drugs be optimized through carefully timed early intervention?

PubMed Central

Andersen, Susan L.; Navalta, Carryl P.

2010-01-01

Our aim is to present a working model that may serve as a valuable heuristic to predict enduring effects of drugs when administered during development. Our primary tenet is that a greater understanding of neurodevelopment can lead to improved treatment that intervenes early in the progression of a given disorder and prevents symptoms from manifesting. The immature brain undergoes significant changes during the transitions between childhood, adolescence, and adulthood. Such changes in innervation, neurotransmitter levels, and their respective signaling mechanisms have profound and observable changes on typical behavior, but also increase vulnerability to psychiatric disorders when the maturational process goes awry. Given the remarkable plasticity of the immature brain to adapt to its external milieu, preventive interventions may be possible. We intend for this review to initiate a discussion of how currently used psychotropic agents can influence brain development. Drug exposure during sensitive periods may have beneficial long-term effects, but harmful delayed consequences may be possible as well. Regardless of the outcome, this information needs to be used to improve or develop alternative approaches for the treatment of childhood disorders. With this framework in mind, we present what is known about the effects of stimulants, antidepressants, and antipsychotics on brain maturation (including animal studies that use more clinically-relevant dosing paradigms or relevant animal models). We endeavor to provocatively set the stage for altering treatment approaches for improving mental health in non-adult populations. PMID:21309771

Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions

PubMed Central

Krakowiak, Paula; Walker, Cheryl K.; Tancredi, Daniel; Hertz-Picciotto, Irva; Van de Water, Judy

2016-01-01

Lay Abstract Approximately 23% of mothers of children with autism spectrum disorder (ASD) produce specific patterns of antibodies to fetal brain tissue that have been detected in only 1% of mothers of typically developing children. However, it is unknown what causes these ASD-specific anti-fetal antibodies to be produced. We examined the relationship between ASD-specific anti-fetal antibodies and metabolic conditions during pregnancy in 227 mothers of 2–5 year old children with ASD, enrolled in the CHARGE (Childhood Autism Risk from Genetics and the Environment) Study, and who had blood samples measured for these anti-fetal brain antibodies after study enrollment. Metabolic conditions included diabetes, hypertensive disorders, and prepregnancy obesity or overweight. The presence of ASD-specific anti-fetal brain antibody patterns was more common among mothers diagnosed with diabetes, hypertensive disorders, or overweight during pregnancy compared to healthy mothers, but these differences did not reach statistical significance. In a subset of 145 mothers whose children exhibited severe ASD symptoms, those diagnosed with type 2 or gestational diabetes were nearly 3 times more likely to have ASD-specific anti-fetal antibodies compared to healthy mothers. Further, those diagnosed with gestational diabetes specifically were over 3 times more likely to have these anti-fetal brain antibodies. In this exploratory study, mothers whose children had severe ASD and who were diagnosed with diabetes were more likely to have anti-fetal brain autoantibodies 2–5 years later. Scientific Abstract Approximately 23% of mothers of children with autism spectrum disorder (ASD) produce specific patterns of autoantibodies to fetal brain proteins that have been detected in only 1% of mothers of typically developing children. The biological mechanisms underlying the development of ASD-specific maternal autoantibodies are poorly understood. We sought to determine whether ASD-specific maternal autoantibodies identified postnatally were associated with metabolic conditions (MCs) during gestation. Participants were 227 mothers of 2–5 year old children with confirmed ASD, enrolled in CHARGE (Childhood Autism Risk from Genetics and the Environment) between January 2003 and April 2008, and from whom blood samples were collected and analyzed for anti-fetal brain autoantibodies (Ab+). MCs included diabetes, hypertensive disorders, and prepregnancy obesity or overweight, ascertained from medical records or structured telephone interviews. Log-linear regression models were performed to estimate prevalence ratios (PR) and 95% confidence intervals (CI) based on robust standard errors. Fifty-six (25%) mothers were Ab+. Ab+ prevalence was higher among mothers with diabetes, hypertensive disorders, or overweight compared to healthy mothers, but differences were not statistically significant. In a subset of 145 mothers whose children exhibited severe ASD (31 Ab+), those diagnosed with type 2 or gestational diabetes were 2.7-fold more likely to be Ab+ (95% CI 1.1, 6.6), controlling for delivery payer and smoking. Gestational diabetes specifically was associated with a 3.2-fold increased Ab+ prevalence (95% CI 1.2, 8.6). In this exploratory study, mothers whose children had severe ASD and who experienced diabetes were more likely to have anti-fetal brain autoantibodies 2–5 years later. PMID:27312731

Cross Talk: The Microbiota and Neurodevelopmental Disorders

PubMed Central

Kelly, John R.; Minuto, Chiara; Cryan, John F.; Clarke, Gerard; Dinan, Timothy G.

2017-01-01

Humans evolved within a microbial ecosystem resulting in an interlinked physiology. The gut microbiota can signal to the brain via the immune system, the vagus nerve or other host-microbe interactions facilitated by gut hormones, regulation of tryptophan metabolism and microbial metabolites such as short chain fatty acids (SCFA), to influence brain development, function and behavior. Emerging evidence suggests that the gut microbiota may play a role in shaping cognitive networks encompassing emotional and social domains in neurodevelopmental disorders. Drawing upon pre-clinical and clinical evidence, we review the potential role of the gut microbiota in the origins and development of social and emotional domains related to Autism spectrum disorders (ASD) and schizophrenia. Small preliminary clinical studies have demonstrated gut microbiota alterations in both ASD and schizophrenia compared to healthy controls. However, we await the further development of mechanistic insights, together with large scale longitudinal clinical trials, that encompass a systems level dimensional approach, to investigate whether promising pre-clinical and initial clinical findings lead to clinical relevance. PMID:28966571

GEMC1 is a critical regulator of multiciliated cell differentiation.

PubMed

Terré, Berta; Piergiovanni, Gabriele; Segura-Bayona, Sandra; Gil-Gómez, Gabriel; Youssef, Sameh A; Attolini, Camille Stephan-Otto; Wilsch-Bräuninger, Michaela; Jung, Carole; Rojas, Ana M; Marjanović, Marko; Knobel, Philip A; Palenzuela, Lluís; López-Rovira, Teresa; Forrow, Stephen; Huttner, Wieland B; Valverde, Miguel A; de Bruin, Alain; Costanzo, Vincenzo; Stracker, Travis H

2016-05-02

The generation of multiciliated cells (MCCs) is required for the proper function of many tissues, including the respiratory tract, brain, and germline. Defects in MCC development have been demonstrated to cause a subclass of mucociliary clearance disorders termed reduced generation of multiple motile cilia (RGMC). To date, only two genes, Multicilin (MCIDAS) and cyclin O (CCNO) have been identified in this disorder in humans. Here, we describe mice lacking GEMC1 (GMNC), a protein with a similar domain organization as Multicilin that has been implicated in DNA replication control. We have found that GEMC1-deficient mice are growth impaired, develop hydrocephaly with a high penetrance, and are infertile, due to defects in the formation of MCCs in the brain, respiratory tract, and germline. Our data demonstrate that GEMC1 is a critical regulator of MCC differentiation and a candidate gene for human RGMC or related disorders. © 2016 The Authors.

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.

Disrupted Cerebro-cerebellar Intrinsic Functional Connectivity in Young Adults with High-functioning Autism Spectrum Disorder: A Data-driven, Whole-brain, High Temporal Resolution fMRI Study.

PubMed

Arnold Anteraper, Sheeba; Guell, Xavier; D'Mello, Anila; Joshi, Neha; Whitfield-Gabrieli, Susan; Joshi, Gagan

2018-06-13

To examine the resting-state functional-connectivity (RsFc) in young adults with high-functioning autism spectrum disorder (HF-ASD) using state-of-the-art fMRI data acquisition and analysis techniques. Simultaneous multi-slice, high temporal resolution fMRI acquisition; unbiased whole-brain connectome-wide multivariate pattern analysis (MVPA) techniques for assessing RsFc; and post-hoc whole-brain seed-to-voxel analyses using MVPA results as seeds. MVPA revealed two clusters of abnormal connectivity in the cerebellum. Whole-brain seed-based functional connectivity analyses informed by MVPA-derived clusters showed significant under connectivity between the cerebellum and social, emotional, and language brain regions in the HF-ASD group compared to healthy controls. The results we report are coherent with existing structural, functional, and RsFc literature in autism, extend previous literature reporting cerebellar abnormalities in the neuropathology of autism, and highlight the cerebellum as a potential target for therapeutic, diagnostic, predictive, and prognostic developments in ASD. The description of functional connectivity abnormalities using whole-brain, data-driven analyses as reported in the present study may crucially advance the development of ASD biomarkers, targets for therapeutic interventions, and neural predictors for measuring treatment response.

Neurodegeneration with Brain Iron Accumulation

MedlinePlus

... are here Home » Disorders » All Disorders Neurodegeneration with Brain Iron Accumulation Information Page Neurodegeneration with Brain Iron Accumulation Information Page What research is being ...

Neuropathology and Animal Models of Autism: Genetic and Environmental Factors

PubMed Central

Gadad, Bharathi S.; Young, Keith A.; German, Dwight C.

2013-01-01

Autism is a heterogeneous behaviorally defined neurodevelopmental disorder. It is defined by the presence of marked social deficits, specific language abnormalities, and stereotyped repetitive patterns of behavior. Because of the variability in the behavioral phenotype of the disorder among patients, the term autism spectrum disorder has been established. In the first part of this review, we provide an overview of neuropathological findings from studies of autism postmortem brains and identify the cerebellum as one of the key brain regions that can play a role in the autism phenotype. We review research findings that indicate possible links between the environment and autism including the role of mercury and immune-related factors. Because both genes and environment can alter the structure of the developing brain in different ways, it is not surprising that there is heterogeneity in the behavioral and neuropathological phenotypes of autism spectrum disorders. Finally, we describe animal models of autism that occur following insertion of different autism-related genes and exposure to environmental factors, highlighting those models which exhibit both autism-like behavior and neuropathology. PMID:24151553

Pathological anxiety and function/dysfunction in the brain's fear/defense circuitry.

PubMed

Lang, Peter J; McTeague, Lisa M; Bradley, Margaret M

2014-01-01

Research from the University of Florida Center for the Study of Emotion and Attention aims to develop neurobiological measures that objectively discriminate among symptom patterns in patients with anxiety disorders. From this perspective, anxiety and mood pathologies are considered to be brain disorders, resulting from dysfunction and maladaptive plasticity in the neural circuits that determine fearful/defensive and appetitive/reward behavior (Insel et al., 2010). We review recent studies indicating that an enhanced probe startle reflex during the processing of fear memory cues (mediated by cortico-limbic circuitry and thus indicative of plastic brain changes), varies systematically in strength over a spectrum-wide dimension of anxiety pathology-across and within diagnoses-extending from strong focal fear reactions to a consistently blunted reaction in patients with more generalized anxiety and comorbid mood disorders. Preliminary studies with functional magnetic resonance imaging (fMRI) encourage the hypothesis that fear/defense circuit dysfunction covaries with this same dimension of psychopathology. Plans are described for an extended study of the brain's motivation circuitry in anxiety spectrum patients, with the aim of defining the specifics of circuit dysfunction in severe disorders. A sub-project explores the use of real-time fMRI feedback in circuit analysis and as a modality to up-regulate circuit function in the context of blunted affect.

Maternal high-fat feeding leads to alterations of brain glucose metabolism in the offspring: positron emission tomography study in a porcine model.

PubMed

Sanguinetti, Elena; Liistro, Tiziana; Mainardi, Marco; Pardini, Silvia; Salvadori, Piero A; Vannucci, Alessandro; Burchielli, Silvia; Iozzo, Patricia

2016-04-01

Maternal obesity negatively affects fetal development. Abnormalities in brain glucose metabolism are predictive of metabolic-cognitive disorders. We studied the offspring (aged 0, 1, 6, 12 months) of minipigs fed a normal vs high-fat diet (HFD), by positron emission tomography (PET) to measure brain glucose metabolism, and ex vivo assessments of brain insulin receptors (IRβ) and GLUT4. At birth, brain glucose metabolism and IRβ were twice as high in the offspring of HFD-fed than control mothers. During infancy and youth, brain glucose uptake, GLUT4 and IRβ increased in the offspring of control mothers and decreased in those of HFD-fed mothers, leading to a 40-85% difference (p < 0.05), and severe glycogen depletion, lasting until adulthood. Maternal high-fat feeding leads to brain glucose overexposure during fetal development, followed by long-lasting depression in brain glucose metabolism in minipigs. These features may predispose the offspring to develop metabolic-neurodegenerative diseases.

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.

Searching for the gut microbial contributing factors to social behavior in rodent models of autism spectrum disorder.

PubMed

Needham, Brittany D; Tang, Weiyi; Wu, Wei-Li

2018-05-01

Social impairment is one of the major symptoms in multiple psychiatric disorders, including autism spectrum disorder (ASD). Accumulated studies indicate a crucial role for the gut microbiota in social development, but these mechanisms remain unclear. This review focuses on two strategies adopted to elucidate the complicated relationship between gut bacteria and host social behavior. In a top-down approach, researchers have attempted to correlate behavioral abnormalities with altered gut microbial profiles in rodent models of ASD, including BTBR mice, maternal immune activation (MIA), maternal valproic acid (VPA) and maternal high-fat diet (MHFD) offspring. In a bottom-up approach, researchers use germ-free (GF) animals, antibiotics, probiotics or pathogens to manipulate the intestinal environment and ascertain effects on social behavior. The combination of both approaches will hopefully pinpoint specific bacterial communities that control host social behavior. Further discussion of how brain development and circuitry is impacted by depletion of gut microbiota is also included. The converging evidence strongly suggests that gut microbes affect host social behavior through the alteration of brain neural circuits. Investigation of intestinal microbiota and host social behavior will unveil any bidirectional communication between the gut and brain and provide alternative therapeutic targets for ASD. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 474-499, 2018. © 2018 Wiley Periodicals, Inc.

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.

Nicotinamide Inhibits Ethanol-Induced Caspase-3 and PARP-1 Over-activation and Subsequent Neurodegeneration in the Developing Mouse Cerebellum.

PubMed

Ieraci, Alessandro; Herrera, Daniel G

2018-06-01

Fetal alcohol spectrum disorder (FASD) is the principal preventable cause of mental retardation in the western countries resulting from alcohol exposure during pregnancy. Ethanol-induced massive neuronal cell death occurs mainly in immature neurons during the brain growth spurt period. The cerebellum is one of the brain areas that are most sensitive to ethanol neurotoxicity. Currently, there is no effective treatment that targets the causes of these disorders and efficient treatments to counteract or reverse FASD are desirable. In this study, we investigated the effects of nicotinamide on ethanol-induced neuronal cell death in the developing cerebellum. Subcutaneous administration of ethanol in postnatal 4-day-old mice induced an over-activation of caspase-3 and PARP-1 followed by a massive neurodegeneration in the developing cerebellum. Interestingly, treatment with nicotinamide, immediately or 2 h after ethanol exposure, diminished caspase-3 and PARP-1 over-activation and reduced ethanol-induced neurodegeneration. Conversely, treatment with 3-aminobenzadine, a specific PARP-1 inhibitor, was able to completely block PARP-1 activation, but not caspase-3 activation or ethanol-induced neurodegeneration in the developing cerebellum. Our results showed that nicotinamide reduces ethanol-induced neuronal cell death and inhibits both caspase-3 and PARP-1 alcohol-induced activation in the developing cerebellum, suggesting that nicotinamide might be a promising and safe neuroprotective agent for treating FASD and other neurodegenerative disorders in the developing brain that shares similar cell death pathways.

Rehabilitation of Reading and Visual Exploration in Visual Field Disorders: Transfer or Specificity?

ERIC Educational Resources Information Center

Schuett, Susanne; Heywood, Charles A.; Kentridge, Robert W.; Dauner, Ruth; Zihl, Josef

2012-01-01

Reading and visual exploration impairments in unilateral homonymous visual field disorders are frequent and disabling consequences of acquired brain injury. Compensatory therapies have been developed, which allow patients to regain sufficient reading and visual exploration performance through systematic oculomotor training. However, it is still…

Angubindin-1 opens the blood-brain barrier in vivo for delivery of antisense oligonucleotide to the central nervous system.

PubMed

Zeniya, Satoshi; Kuwahara, Hiroya; Daizo, Kaiichi; Watari, Akihiro; Kondoh, Masuo; Yoshida-Tanaka, Kie; Kaburagi, Hidetoshi; Asada, Ken; Nagata, Tetsuya; Nagahama, Masahiro; Yagi, Kiyohito; Yokota, Takanori

2018-05-17

Within the field of RNA therapeutics, antisense oligonucleotide-based therapeutics are a potentially powerful means of treating intractable diseases. However, if these therapeutics are used for the treatment of neurological disorders, safe yet efficient methods of delivering antisense oligonucleotides across the blood-brain barrier to the central nervous system must be developed. Here, we examined the use of angubindin-1, a binder to the tricellular tight junction, to modulate paracellular transport between brain microvascular endothelial cells in the blood-brain barrier for the delivery of antisense oligonucleotides to the central nervous system. This proof-of-concept study demonstrated that intravenously injected angubindin-1 increased the permeability of the blood-brain barrier and enabled transient delivery of subsequently administered antisense oligonucleotides into the mouse brain and spinal cord, leading to silencing of a target RNA without any overt adverse effects. We also found that two bicellular tight junction modulators did not produce such a silencing effect, suggesting that the tricellular tight junction is likely a better target for the delivery of antisense oligonucleotides than the bicellular tight junction. Our delivery strategy of modulating the tricellular tight junction in the blood-brain barrier via angubindin-1 provides a novel avenue of research for the development of antisense oligonucleotide-based therapeutics for the treatment of neurological disorders. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Is the spatial distribution of brain lesions associated with closed-head injury predictive of subsequent development of attention-deficit/hyperactivity disorder? Analysis with brain-image database

NASA Technical Reports Server (NTRS)

Herskovits, E. H.; Megalooikonomou, V.; Davatzikos, C.; Chen, A.; Bryan, R. N.; Gerring, J. P.

1999-01-01

PURPOSE: To determine whether there is an association between the spatial distribution of lesions detected at magnetic resonance (MR) imaging of the brain in children after closed-head injury and the development of secondary attention-deficit/hyperactivity disorder (ADHD). MATERIALS AND METHODS: Data obtained from 76 children without prior history of ADHD were analyzed. MR images were obtained 3 months after closed-head injury. After manual delineation of lesions, images were registered to the Talairach coordinate system. For each subject, registered images and secondary ADHD status were integrated into a brain-image database, which contains depiction (visualization) and statistical analysis software. Using this database, we assessed visually the spatial distributions of lesions and performed statistical analysis of image and clinical variables. RESULTS: Of the 76 children, 15 developed secondary ADHD. Depiction of the data suggested that children who developed secondary ADHD had more lesions in the right putamen than children who did not develop secondary ADHD; this impression was confirmed statistically. After Bonferroni correction, we could not demonstrate significant differences between secondary ADHD status and lesion burdens for the right caudate nucleus or the right globus pallidus. CONCLUSION: Closed-head injury-induced lesions in the right putamen in children are associated with subsequent development of secondary ADHD. Depiction software is useful in guiding statistical analysis of image data.

A Comparative Review of microRNA Expression Patterns in Autism Spectrum Disorder.

PubMed

Hicks, Steven D; Middleton, Frank A

2016-01-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a wide spectrum of deficits in social interaction, communication, and behavior. There is a significant genetic component to ASD, yet no single gene variant accounts for >1% of incidence. Posttranscriptional mechanisms such as microRNAs (miRNAs) regulate gene expression without altering the genetic code. They are abundant in the developing brain and are dysregulated in children with ASD. Patterns of miRNA expression are altered in the brain, blood, saliva, and olfactory precursor cells of ASD subjects. The ability of miRNAs to regulate broad molecular pathways in response to environmental stimuli makes them an intriguing player in ASD, a disorder characterized by genetic predisposition with ill-defined environmental triggers. In addition, the availability and extracellular stability of miRNAs make them an ideal candidate for biomarker discovery. Here, we discuss 27 miRNAs with overlap across ASD studies, including 3 miRNAs identified in 3 or more studies (miR-23a, miR-146a, and miR-106b). Together, these 27 miRNAs have 1245 high-confidence mRNA targets, a significant number of which are expressed in the brain. Furthermore, these mRNA targets demonstrate over-representation of autism-related genes with enrichment of neurotrophic signaling molecules. Brain-derived neurotrophic factor, a molecule involved in hippocampal neurogenesis and altered in ASD, is targeted by 6 of the 27 miRNAs of interest. This neurotrophic pathway represents one intriguing mechanism by which perturbations in miRNA signaling might influence central nervous system development in children with ASD.

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.

Maternal Brain-Reactive Antibodies and Autism Spectrum Disorder

DTIC Science & Technology

2015-10-01

Autism spectrum disorder (ASD) occurs in 1 in 68 births, preferentially affecting males. It encompasses a group of neurodevelopmental ...AWARD NUMBER: W81XWH-14-1-0369 TITLE: Maternal Brain-Reactive Antibodies and Autism Spectrum Disorder PRINCIPAL INVESTIGATOR: Betty Diamond...Sep 2015 4. TITLE AND SUBTITLE Maternal Brain-Reactive Antibodies and Autism Spectrum 5a. CONTRACT NUMBER Disorder 5b. GRANT NUMBER W81XWH-14-1

Ethanol-BDNF interactions: Still More Questions than Answers

PubMed Central

Davis, Margaret I.

2008-01-01

Brain Derived Neurotrophic Factor (BDNF) has emerged as a regulator of development, plasticity and, recently, addiction. Decreased neurotrophic activity may be involved in ethanol-induced neurodegeneration in the adult brain and in the etiology of alcohol-related neurodevelopmental disorders. This can occur through decreased expression of BDNF or through inability of the receptor to transduce signals in the presence of ethanol. In contrast, recent studies implicate region-specific up-regulation of BDNF and associated signaling pathways in anxiety, addiction and homeostasis after ethanol exposure. Anxiety and depression are precipitating factors for substance abuse and these disorders also involve region-specific changes in BDNF in both pathogenesis and response to pharmacotherapy. Polymorphisms in the genes coding for BDNF and its receptor TrkB are linked to affective, substance abuse and appetitive disorders and therefore may play a role in the development of alcoholism. This review summarizes historical and pre-clinical data on BDNF and TrkB as it relates to ethanol toxicity and addiction. Many unresolved questions about region-specific changes in BDNF expression and the precise role of BDNF in neuropsychiatric disorders and addiction remain to be elucidated. Resolution of these questions will require significant integration of the literature on addiction and comorbid psychiatric disorders that contribute to the development of alcoholism. PMID:18394710

An Evo-Devo Approach to Thyroid Hormones in Cerebral and Cerebellar Cortical Development: Etiological Implications for Autism

PubMed Central

Berbel, Pere; Navarro, Daniela; Román, Gustavo C.

2014-01-01

The morphological alterations of cortical lamination observed in mouse models of developmental hypothyroidism prompted the recognition that these experimental changes resembled the brain lesions of children with autism; this led to recent studies showing that maternal thyroid hormone deficiency increases fourfold the risk of autism spectrum disorders (ASD), offering for the first time the possibility of prevention of some forms of ASD. For ethical reasons, the role of thyroid hormones on brain development is currently studied using animal models, usually mice and rats. Although mammals have in common many basic developmental principles regulating brain development, as well as fundamental basic mechanisms that are controlled by similar metabolic pathway activated genes, there are also important differences. For instance, the rodent cerebral cortex is basically a primary cortex, whereas the primary sensory areas in humans account for a very small surface in the cerebral cortex when compared to the associative and frontal areas that are more extensive. Associative and frontal areas in humans are involved in many neurological disorders, including ASD, attention deficit-hyperactive disorder, and dyslexia, among others. Therefore, an evo-devo approach to neocortical evolution among species is fundamental to understand not only the role of thyroid hormones and environmental thyroid disruptors on evolution, development, and organization of the cerebral cortex in mammals but also their role in neurological diseases associated to thyroid dysfunction. PMID:25250016

BrainAGE score indicates accelerated brain aging in schizophrenia, but not bipolar disorder.

PubMed

Nenadić, Igor; Dietzek, Maren; Langbein, Kerstin; Sauer, Heinrich; Gaser, Christian

2017-08-30

BrainAGE (brain age gap estimation) is a novel morphometric parameter providing a univariate score derived from multivariate voxel-wise analyses. It uses a machine learning approach and can be used to analyse deviation from physiological developmental or aging-related trajectories. Using structural MRI data and BrainAGE quantification of acceleration or deceleration of in individual aging, we analysed data from 45 schizophrenia patients, 22 bipolar I disorder patients (mostly with previous psychotic symptoms / episodes), and 70 healthy controls. We found significantly higher BrainAGE scores in schizophrenia, but not bipolar disorder patients. Our findings indicate significantly accelerated brain structural aging in schizophrenia. This suggests, that despite the conceptualisation of schizophrenia as a neurodevelopmental disorder, there might be an additional progressive pathogenic component. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

A Systematic Review and Meta-analysis of Neuroimaging in Oppositional Defiant Disorder (ODD) and Conduct Disorder (CD) Taking Attention-Deficit Hyperactivity Disorder (ADHD) Into Account.

PubMed

Noordermeer, Siri D S; Luman, Marjolein; Oosterlaan, Jaap

2016-03-01

Oppositional defiant disorder (ODD) and conduct disorder (CD) are common behavioural disorders in childhood and adolescence and are associated with brain abnormalities. This systematic review and meta-analysis investigates structural (sMRI) and functional MRI (fMRI) findings in individuals with ODD/CD with and without attention-deficit hyperactivity disorder (ADHD). Online databases were searched for controlled studies, resulting in 12 sMRI and 17 fMRI studies. In line with current models on ODD/CD, studies were classified in hot and cool executive functioning (EF). Both the meta-analytic and narrative reviews showed evidence of smaller brain structures and lower brain activity in individuals with ODD/CD in mainly hot EF-related areas: bilateral amygdala, bilateral insula, right striatum, left medial/superior frontal gyrus, and left precuneus. Evidence was present in both structural and functional studies, and irrespective of the presence of ADHD comorbidity. There is strong evidence that abnormalities in the amygdala are specific for ODD/CD as compared to ADHD, and correlational studies further support the association between abnormalities in the amygdala and ODD/CD symptoms. Besides the left precuneus, there was no evidence for abnormalities in typical cool EF related structures, such as the cerebellum and dorsolateral prefrontal cortex. Resulting areas are associated with emotion-processing, error-monitoring, problem-solving and self-control; areas associated with neurocognitive and behavioural deficits implicated in ODD/CD. Our findings confirm the involvement of hot, and to a smaller extent cool, EF associated brain areas in ODD/CD, and support an integrated model for ODD/CD (e.g. Blair, Development and Psychopathology, 17(3), 865-891, 2005).

Application and Evaluation of Independent Component Analysis Methods to Generalized Seizure Disorder Activities Exhibited in the Brain.

PubMed

George, S Thomas; Balakrishnan, R; Johnson, J Stanly; Jayakumar, J

2017-07-01

EEG records the spontaneous electrical activity of the brain using multiple electrodes placed on the scalp, and it provides a wealth of information related to the functions of brain. Nevertheless, the signals from the electrodes cannot be directly applied to a diagnostic tool like brain mapping as they undergo a "mixing" process because of the volume conduction effect in the scalp. A pervasive problem in neuroscience is determining which regions of the brain are active, given voltage measurements at the scalp. Because of which, there has been a surge of interest among the biosignal processing community to investigate the process of mixing and unmixing to identify the underlying active sources. According to the assumptions of independent component analysis (ICA) algorithms, the resultant mixture obtained from the scalp can be closely approximated by a linear combination of the "actual" EEG signals emanating from the underlying sources of electrical activity in the brain. As a consequence, using these well-known ICA techniques in preprocessing of the EEG signals prior to clinical applications could result in development of diagnostic tool like quantitative EEG which in turn can assist the neurologists to gain noninvasive access to patient-specific cortical activity, which helps in treating neuropathologies like seizure disorders. The popular and proven ICA schemes mentioned in various literature and applications were selected (which includes Infomax, JADE, and SOBI) and applied on generalized seizure disorder samples using EEGLAB toolbox in MATLAB environment to see their usefulness in source separations; and they were validated by the expert neurologist for clinical relevance in terms of pathologies on brain functionalities. The performance of Infomax method was found to be superior when compared with other ICA schemes applied on EEG and it has been established based on the validations carried by expert neurologist for generalized seizure and its clinical correlation. The results are encouraging for furthering the studies in the direction of developing useful brain mapping tools using ICA methods.

ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice

PubMed Central

Brzozowska, Natalia; Li, Kong M.; Wang, Xiao Suo; Booth, Jessica; Stuart, Jordyn; McGregor, Iain S.

2016-01-01

Cannabidiol (CBD) is currently being investigated as a novel therapeutic for the treatment of CNS disorders like schizophrenia and epilepsy. ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) mediate pharmacoresistance in these disorders. P-gp and Bcrp are expressed at the blood brain barrier (BBB) and reduce the brain uptake of substrate drugs including various antipsychotics and anticonvulsants. It is therefore important to assess whether CBD is prone to treatment resistance mediated by P-gp and Bcrp. Moreover, it has become common practice in the drug development of CNS agents to screen against ABC transporters to help isolate lead compounds with optimal pharmacokinetic properties. The current study aimed to assess whether P-gp and Bcrp impacts the brain transport of CBD by comparing CBD tissue concentrations in wild-type (WT) mice versus mice devoid of ABC transporter genes. P-gp knockout (Abcb1a/b−∕−), Bcrp knockout (Abcg2−∕−), combined P-gp/Bcrp knockout (Abcb1a/b−∕−Abcg2−∕−) and WT mice were injected with CBD, before brain and plasma samples were collected at various time-points. CBD results were compared with the positive control risperidone and 9-hydroxy risperidone, antipsychotic drugs that are established ABC transporter substrates. Brain and plasma concentrations of CBD were not greater in P-gp, Bcrp or P-gp/Bcrp knockout mice than WT mice. In comparison, the brain/plasma concentration ratios of risperidone and 9-hydroxy risperidone were profoundly higher in P-gp knockout mice than WT mice. These results suggest that CBD is not a substrate of P-gp or Bcrp and may be free from the complication of reduced brain uptake by these transporters. Such findings provide favorable evidence for the therapeutic development of CBD in the treatment of various CNS disorders. PMID:27257556

ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice.

PubMed

Brzozowska, Natalia; Li, Kong M; Wang, Xiao Suo; Booth, Jessica; Stuart, Jordyn; McGregor, Iain S; Arnold, Jonathon C

2016-01-01

Cannabidiol (CBD) is currently being investigated as a novel therapeutic for the treatment of CNS disorders like schizophrenia and epilepsy. ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) mediate pharmacoresistance in these disorders. P-gp and Bcrp are expressed at the blood brain barrier (BBB) and reduce the brain uptake of substrate drugs including various antipsychotics and anticonvulsants. It is therefore important to assess whether CBD is prone to treatment resistance mediated by P-gp and Bcrp. Moreover, it has become common practice in the drug development of CNS agents to screen against ABC transporters to help isolate lead compounds with optimal pharmacokinetic properties. The current study aimed to assess whether P-gp and Bcrp impacts the brain transport of CBD by comparing CBD tissue concentrations in wild-type (WT) mice versus mice devoid of ABC transporter genes. P-gp knockout (Abcb1a/b (-∕-)), Bcrp knockout (Abcg2 (-∕-)), combined P-gp/Bcrp knockout (Abcb1a/b (-∕-) Abcg2 (-∕-)) and WT mice were injected with CBD, before brain and plasma samples were collected at various time-points. CBD results were compared with the positive control risperidone and 9-hydroxy risperidone, antipsychotic drugs that are established ABC transporter substrates. Brain and plasma concentrations of CBD were not greater in P-gp, Bcrp or P-gp/Bcrp knockout mice than WT mice. In comparison, the brain/plasma concentration ratios of risperidone and 9-hydroxy risperidone were profoundly higher in P-gp knockout mice than WT mice. These results suggest that CBD is not a substrate of P-gp or Bcrp and may be free from the complication of reduced brain uptake by these transporters. Such findings provide favorable evidence for the therapeutic development of CBD in the treatment of various CNS disorders.

Development of the Aboriginal Communication Assessment After Brain Injury (ACAABI): A screening tool for identifying acquired communication disorders in Aboriginal Australians.

PubMed

Armstrong, Elizabeth M; Ciccone, Natalie; Hersh, Deborah; Katzenellebogen, Judith; Coffin, Juli; Thompson, Sandra; Flicker, Leon; Hayward, Colleen; Woods, Deborah; McAllister, Meaghan

2017-06-01

Acquired communication disorders (ACD), following stroke and traumatic brain injury, may not be correctly identified in Aboriginal Australians due to a lack of linguistically and culturally appropriate assessment tools. Within this paper we explore key issues that were considered in the development of the Aboriginal Communication Assessment After Brain Injury (ACAABI) - a screening tool designed to assess the presence of ACD in Aboriginal populations. A literature review and consultation with key stakeholders were undertaken to explore directions needed to develop a new tool, based on existing tools and recommendations for future developments. The literature searches revealed no existing screening tool for ACD in these populations, but identified tools in the areas of cognition and social-emotional wellbeing. Articles retrieved described details of the content and style of these tools, with recommendations for the development and administration of a new tool. The findings from the interview and focus group views were consistent with the approach recommended in the literature. There is a need for a screening tool for ACD to be developed but any tool must be informed by knowledge of Aboriginal language, culture and community input in order to be acceptable and valid.

Language and reading development in the brain today: neuromarkers and the case for prediction.

PubMed

Buchweitz, Augusto

2016-01-01

The goal of this article is to provide an account of language development in the brain using the new information about brain function gleaned from cognitive neuroscience. This account goes beyond describing the association between language and specific brain areas to advocate the possibility of predicting language outcomes using brain-imaging data. The goal is to address the current evidence about language development in the brain and prediction of language outcomes. Recent studies will be discussed in the light of the evidence generated for predicting language outcomes and using new methods of analysis of brain data. The present account of brain behavior will address: (1) the development of a hardwired brain circuit for spoken language; (2) the neural adaptation that follows reading instruction and fosters the "grafting" of visual processing areas of the brain onto the hardwired circuit of spoken language; and (3) the prediction of language development and the possibility of translational neuroscience. Brain imaging has allowed for the identification of neural indices (neuromarkers) that reflect typical and atypical language development; the possibility of predicting risk for language disorders has emerged. A mandate to develop a bridge between neuroscience and health and cognition-related outcomes may pave the way for translational neuroscience. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

When the Numerator Is Zero: Another Lesson on Risk

ERIC Educational Resources Information Center

Ho, Adrienne K.

2009-01-01

A biology teacher has developed a rare and troubling neurologic disorder. He hears of an experimental treatment that has produced impressive results. The treatment involves surgically ablating selective parts of the brain at close proximity to the brainstem. There is a risk that, during the procedure, vital parts of the brain could be…

Factors Related to Impaired Visual Orienting Behavior in Children with Intellectual Disabilities

ERIC Educational Resources Information Center

Boot, F. H.; Pel, J .J. M.; Evenhuis, H. M.; van der Steen, J.

2012-01-01

It is generally assumed that children with intellectual disabilities (ID) have an increased risk of impaired visual information processing due to brain damage or brain development disorder. So far little evidence has been presented to support this assumption. Abnormal visual orienting behavior is a sensitive tool to evaluate impaired visual…

The role of sex and gender in neuropsychiatric disorders.

PubMed

Thibaut, Florence

2016-12-01

The prevalence, age of onset, and clinical symptoms of many neuropsychiatric diseases substantially differ between males and females. Factors influencing the relationships between brain development and function and sex or gender may help us understand the differences between males and females in terms of risk or resilience factors in brain diseases.

Brain Chemistry and Behaviour: An Update on Neuroscience Research and Its Implications for Understanding Drug Addiction

ERIC Educational Resources Information Center

Robinson, Emma S. J.

2011-01-01

Psychiatric disorders such as drug addiction represent one of the biggest challenges to society. This article reviews clinical and basic science research to illustrate how developments in research methodology have enabled neuroscientists to understand more about the brain mechanisms involved in addiction biology. Treating addiction represents a…

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.

Tics after traumatic brain injury.

PubMed

Ranjan, Nishant; Nair, Krishnan Padmakumari Sivaraman; Romanoski, Charles; Singh, Rajiv; Venketswara, Guruprasad

2011-01-01

Tics are involuntary non-rhythmic, stereotyped muscle contractions which can be suppressed temporarily. Tics usually start during childhood as part of Tourette syndrome. Adult onset tics are infrequent. This study reports on an adult man who developed tics 1 year after severe traumatic brain injury (TBI). Case report and review of literature. A 19-year-old man sustained TBI following a road traffic accident. He did not have tics or features of obsessive compulsive disorder before the brain injury. A year after injury he developed motor and vocal tics. Magnetic resonance image of the brain showed lesions in the basal ganglia. A search of databases Medline, EMBASE and CINHAL found only four publications on tics in adults with TBI. None of these reported cases had lesions in the basal ganglia. Tics are a rare complication of TBI. People with early onset post-traumatic tics may have had a previously unrecognized, mild tic disorder or a genetic predisposition for tics, which was unmasked by the TBI. In contrast, late post-traumatic tics could be due to delayed effects of injury on neural circuits connecting the frontal cortex and basal ganglia.

Reduced Gray Matter Volume in the Social Brain Network in Adults with Autism Spectrum Disorder

PubMed Central

Sato, Wataru; Kochiyama, Takanori; Uono, Shota; Yoshimura, Sayaka; Kubota, Yasutaka; Sawada, Reiko; Sakihama, Morimitsu; Toichi, Motomi

2017-01-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral impairment in social interactions. Although theoretical and empirical evidence suggests that impairment in the social brain network could be the neural underpinnings of ASD, previous structural magnetic resonance imaging (MRI) studies in adults with ASD have not provided clear support for this, possibly due to confounding factors, such as language impairments. To further explore this issue, we acquired structural MRI data and analyzed gray matter volume in adults with ASD (n = 36) who had no language impairments (diagnosed with Asperger’s disorder or pervasive developmental disorder not otherwise specified, with symptoms milder than those of Asperger’s disorder), had no comorbidity, and were not taking medications, and in age- and sex-matched typically developing (TD) controls (n = 36). Univariate voxel-based morphometry analyses revealed that regional gray matter volume was lower in the ASD than in the control group in several brain regions, including the right inferior occipital gyrus, left fusiform gyrus, right middle temporal gyrus, bilateral amygdala, right inferior frontal gyrus, right orbitofrontal cortex, and left dorsomedial prefrontal cortex. A multivariate approach using a partial least squares (PLS) method showed that these regions constituted a network that could be used to discriminate between the ASD and TD groups. A PLS discriminant analysis using information from these regions showed high accuracy, sensitivity, specificity, and precision (>80%) in discriminating between the groups. These results suggest that reduced gray matter volume in the social brain network represents the neural underpinnings of behavioral social malfunctioning in adults with ASD. PMID:28824399

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.

Default mode network, motor network, dorsal and ventral basal ganglia networks in the rat brain: comparison to human networks using resting state-fMRI.

PubMed

Sierakowiak, Adam; Monnot, Cyril; Aski, Sahar Nikkhou; Uppman, Martin; Li, Tie-Qiang; Damberg, Peter; Brené, Stefan

2015-01-01

Rodent models are developed to enhance understanding of the underlying biology of different brain disorders. However, before interpreting findings from animal models in a translational aspect to understand human disease, a fundamental step is to first have knowledge of similarities and differences of the biological systems studied. In this study, we analyzed and verified four known networks termed: default mode network, motor network, dorsal basal ganglia network, and ventral basal ganglia network using resting state functional MRI (rsfMRI) in humans and rats. Our work supports the notion that humans and rats have common robust resting state brain networks and that rsfMRI can be used as a translational tool when validating animal models of brain disorders. In the future, rsfMRI may be used, in addition to short-term interventions, to characterize longitudinal effects on functional brain networks after long-term intervention in humans and rats.

Default Mode Network, Motor Network, Dorsal and Ventral Basal Ganglia Networks in the Rat Brain: Comparison to Human Networks Using Resting State-fMRI

PubMed Central

Sierakowiak, Adam; Monnot, Cyril; Aski, Sahar Nikkhou; Uppman, Martin; Li, Tie-Qiang; Damberg, Peter; Brené, Stefan

2015-01-01

Rodent models are developed to enhance understanding of the underlying biology of different brain disorders. However, before interpreting findings from animal models in a translational aspect to understand human disease, a fundamental step is to first have knowledge of similarities and differences of the biological systems studied. In this study, we analyzed and verified four known networks termed: default mode network, motor network, dorsal basal ganglia network, and ventral basal ganglia network using resting state functional MRI (rsfMRI) in humans and rats. Our work supports the notion that humans and rats have common robust resting state brain networks and that rsfMRI can be used as a translational tool when validating animal models of brain disorders. In the future, rsfMRI may be used, in addition to short-term interventions, to characterize longitudinal effects on functional brain networks after long-term intervention in humans and rats. PMID:25789862

Biomarkers for Success: Using Neuroimaging to Predict Relapse and Develop Brain Stimulation Treatments for Cocaine-Dependent Individuals.

PubMed

Hanlon, C A; Dowdle, L T; Jones, J L

2016-01-01

Cocaine dependence is one of the most difficult substance use disorders to treat. While the powerful effects of cocaine use on behavior were documented in the 19th century, it was not until the late 20th century that we realized cocaine use was affecting brain tissue and function. Following a brief introduction (Section 1), this chapter will summarize our current knowledge regarding alterations in neural circuit function typically observed in chronic cocaine users (Section 2) and highlight an emerging body of literature which suggests that pretreatment limbic circuit activity may be a reliable predictor of clinical outcomes among individuals seeking treatment for cocaine (Section 3). Finally, as the field of addiction research strives to translate this neuroimaging data into something clinically meaningful, we will highlight several new brain stimulation approaches which utilize functional brain imaging data to design noninvasive brain stimulation interventions for individuals seeking treatment for substance dependence disorders (Section 4). © 2016 Elsevier Inc. All rights reserved.

Closed loop deep brain stimulation: an evolving technology.

PubMed

Hosain, Md Kamal; Kouzani, Abbas; Tye, Susannah

2014-12-01

Deep brain stimulation is an effective and safe medical treatment for a variety of neurological and psychiatric disorders including Parkinson's disease, essential tremor, dystonia, and treatment resistant obsessive compulsive disorder. A closed loop deep brain stimulation (CLDBS) system automatically adjusts stimulation parameters by the brain response in real time. The CLDBS continues to evolve due to the advancement in the brain stimulation technologies. This paper provides a study on the existing systems developed for CLDBS. It highlights the issues associated with CLDBS systems including feedback signal recording and processing, stimulation parameters setting, control algorithm, wireless telemetry, size, and power consumption. The benefits and limitations of the existing CLDBS systems are also presented. Whilst robust clinical proof of the benefits of the technology remains to be achieved, it has the potential to offer several advantages over open loop DBS. The CLDBS can improve efficiency and efficacy of therapy, eliminate lengthy start-up period for programming and adjustment, provide a personalized treatment, and make parameters setting automatic and adaptive.

New developments in brain research of internet and gaming disorder.

PubMed

Weinstein, Aviv; Livny, Abigail; Weizman, Abraham

2017-04-01

There is evidence that the neural mechanisms underlying Internet Gaming Disorder (IGD) resemble those of drug addiction. Functional Magnetic Resonance Imaging (fMRI) studies of the resting state and measures of gray matter volume have shown that Internet game playing was associated with changes to brain regions responsible for attention and control, impulse control, motor function, emotional regulation, sensory-motor coordination. Furthermore, Internet game playing was associated with lower white matter density in brain regions that are involved in decision-making, behavioral inhibition and emotional regulation. Videogame playing involved changes in reward inhibitory mechanisms and loss of control. Structural brain imaging studies showed alterations in the volume of the ventral striatum that is an important part of the brain's reward mechanisms. Finally, videogame playing was associated with dopamine release similar in magnitude to those of drugs of abuse and lower dopamine transporter and dopamine receptor D 2 occupancy indicating sub-sensitivity of dopamine reward mechanisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Envisioning the future of polymer therapeutics for brain disorders.

PubMed

Rodriguez-Otormin, Fernanda; Duro-Castano, Aroa; Conejos-Sánchez, Inmaculada; Vicent, María J

2018-06-14

The growing incidence of brain-related pathologies and the problems that undermine the development of efficient and effective treatments have prompted both researchers and the pharmaceutical industry to search for novel therapeutic alternatives. Polymer therapeutics (PT) display properties well suited to the treatment of neuro-related disorders, which help to overcome the many hidden obstacles on the journey to the central nervous system (CNS). The inherent features of PT, derived from drug(s) conjugation, in parallel with the progress in synthesis and analytical methods, the increasing knowledge in molecular basis of diseases, and collected clinical data through the last four decades, have driven the translation from "bench to bedside" for various biomedical applications. However, since the approval of Gliadel® wafers, little progress has been made in the CNS field, even though brain targeting represents an ever-growing challenge. A thorough assessment of the steps required for successful brain delivery via different administration routes and the consideration of the disease-specific hallmarks are essential to progress in the field. Within this review, we hope to summarize the latest developments, successes, and failures and discuss considerations on designs and strategies for PT in the treatment of CNS disorders. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease. © 2018 Wiley Periodicals, Inc.

Devastating metabolic brain disorders of newborns and young infants.

PubMed

Yoon, Hyun Jung; Kim, Ji Hye; Jeon, Tae Yeon; Yoo, So-Young; Eo, Hong

2014-01-01

Metabolic disorders of the brain that manifest in the neonatal or early infantile period are usually associated with acute and severe illness and are thus referred to as devastating metabolic disorders. Most of these disorders may be classified as organic acid disorders, amino acid metabolism disorders, primary lactic acidosis, or fatty acid oxidation disorders. Each disorder has distinctive clinical, biochemical, and radiologic features. Early diagnosis is important both for prompt treatment to prevent death or serious sequelae and for genetic counseling. However, diagnosis is often challenging because many findings overlap and may mimic those of more common neonatal conditions, such as hypoxic-ischemic encephalopathy and infection. Ultrasonography (US) may be an initial screening method for the neonatal brain, and magnetic resonance (MR) imaging is the modality of choice for evaluating metabolic brain disorders. Although nonspecific imaging findings are common in early-onset metabolic disorders, characteristic patterns of brain involvement have been described for several disorders. In addition, diffusion-weighted images may be used to characterize edema during an acute episode of encephalopathy, and MR spectroscopy depicts changes in metabolites that may help diagnose metabolic disorders and assess response to treatment. Imaging findings, including those of advanced MR imaging techniques, must be closely reviewed. If one of these rare disorders is suspected, the appropriate biochemical test or analysis of the specific gene should be performed to confirm the diagnosis. ©RSNA, 2014.

Delayed-onset progressive movement disorders after static brain lesions.

PubMed

Scott, B L; Jankovic, J

1996-01-01

We studied 53 patients (64% females) with static brain lesions who developed progressive movement disorders. Of these, 50 (94%) had dystonia, 17 (32%) tremor, eight (15%) parkinsonism, seven (13%) myoclonus, and three (6%) chorea. The precipitating insults included perinatal hypoxia/ischemia in 22 (42%), stroke in 12 (23%), head injury in eight (15%), encephalitis in eight (15%), and carbon monoxide poisoning, kernicterus, and radiation necrosis in one patient (2%) each. Among the 30 patients with initial insult occurring at age 2 years or younger (Infant group), distribution of dystonia at follow-up was focal in three (10%), segmental in eight (27%), unilateral in 10 (33%), and generalized in nine (30%). The mean latency between the original injury and onset of movement disorder was 25.5 +/- 16.7 years. Among the nine patients who developed dystonia after an insult occurring between ages 6 and 17 (Childhood group), the distribution of dystonia at follow-up was segmental in two (33%) and unilateral in seven (78%); the mean latency of dystonia onset was 4.9 +/- 7.8 years. Of the 14 patients in the Adult group (injury at age 25 or older), 11 developed dystonia, two developed parkinsonism, and one had carbon monoxide encephalopathy and parkinsonism. The distribution of dystonia in the 11 patients at follow-up was segmental in three (27%) and unilateral in eight (73%). The mean latency of movement disorder onset in the 14 patients of the Adult group was 2.5 +/- 4.9 years. No individuals in the Childhood or Adult groups became left-hand dominant; by comparison, nine of the 30 individuals in the Infant group became left-handed. In conclusion, brain injury at a young age is associated with a longer latency to onset of subsequent movement disorder, a greater tendency to development of generalized dystonia, and a greater probability of altered handedness. These tendencies may result from differences in age-related neuroplasticity.

Sex dependence of brain size and shape in bipolar disorder: an exploratory study.

PubMed

Mackay, Clare E; Roddick, Elina; Barrick, Thomas R; Lloyd, Adrian J; Roberts, Neil; Crow, Tim J; Young, Allan H; Ferrier, I Nicol

2010-05-01

Anomalies of asymmetry and sex differences in brain structure have frequently been described in schizophrenic illnesses but have seldom been explored in bipolar disorder. We measured volumes of the left and right frontal, temporal, parietal, and occipital lobes and computed the magnitude of brain torque (i.e., rightward frontal and leftward occipital asymmetry) for 49 patients with bipolar disorder and 47 healthy controls and performed an exploratory analysis of sex differences in patients and controls. Patients had significantly greater cerebrospinal fluid volume than controls, but no difference in total brain volume. There were no main effects of diagnosis in gray matter lobe volume or brain torque, but when analyses were performed separately for male and female subjects, significant sex-by-diagnosis interactions were found in the volume of the left frontal, left temporal, right parietal, and right occipital lobes, such that male patients with bipolar disorder tend toward larger, more symmetric brains than male controls, whereas female patients tend toward smaller, more asymmetric brains than female controls. The lateralised nature of these interactions was such that the normal sex difference in volume was significantly accentuated, whilst the normal sex difference in asymmetry tended to be diminished in patients with bipolar disorder. We conclude that bipolar disorder in part reflects an interaction between brain growth and sex along the anterior-posterior axis of the human brain.

The Gut Microbiota and Autism Spectrum Disorders

PubMed Central

Li, Qinrui; Han, Ying; Dy, Angel Belle C.; Hagerman, Randi J.

2017-01-01

Gastrointestinal (GI) symptoms are a common comorbidity in patients with autism spectrum disorder (ASD), but the underlying mechanisms are unknown. Many studies have shown alterations in the composition of the fecal flora and metabolic products of the gut microbiome in patients with ASD. The gut microbiota influences brain development and behaviors through the neuroendocrine, neuroimmune and autonomic nervous systems. In addition, an abnormal gut microbiota is associated with several diseases, such as inflammatory bowel disease (IBD), ASD and mood disorders. Here, we review the bidirectional interactions between the central nervous system and the gastrointestinal tract (brain-gut axis) and the role of the gut microbiota in the central nervous system (CNS) and ASD. Microbiome-mediated therapies might be a safe and effective treatment for ASD. PMID:28503135

Photobiomodulation of the brain: a new paradigm (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hamblin, Michael R.

2017-02-01

Photobiomodulation (PBM) describes the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. One of the organ systems of the human body that is most necessary to life, and whose optimum functioning is most worried about by humankind in general, is the brain. The brain suffers from many different disorders that can be classified into three broad groupings: traumatic events (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric disorders (depression, anxiety, post traumatic stress disorder). There is some evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head. There is even the possibility that PBM could be used for cognitive enhancement in normal healthy people. In this transcranial PBM (tPBM) application, near-infrared (NIR) light is often applied to the forehead because of the better penetration (no hair, longer wavelength). Some workers have used lasers, but recently the introduction of inexpensive light emitting diode (LED) arrays has allowed the development of light emitting helmets or "brain caps". This presentation will cover the mechanisms of action of photobiomodulation to the brain, and summarize some of the key pre-clinical studies and clinical trials that have been undertaken in this area.

Sleep in adolescence: physiology, cognition and mental health

PubMed Central

Tarokh, Leila; Saletin, Jared M.; Carskadon, Mary A.

2016-01-01

Sleep is a core behavior of adolescents, consuming up to a third or more of each day. As part of this special issue on the adolescent brain, we review changes to sleep behaviors and sleep physiology during adolescence with a particular focus on the sleeping brain. We posit that brain activity during sleep may provide a unique window onto adolescent cortical maturation and compliment waking measures. In addition, we review how sleep actively supports waking cognitive functioning in adolescence. Though this review is focused on sleep in healthy adolescents, the striking comorbidity of sleep disruption with nearly all psychiatric and developmental disorders (for reviews see 1,2) further highlights the importance of understanding the determinants and consequences of adolescent sleep for the developing brain. Figure 1 illustrates the overarching themes of our review, linking brain development, sleep development, and behavioral outcomes. PMID:27531236

Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy

PubMed Central

Dossat, Amanda M.; Sanchez-Gonzalez, Marcos A.; Koutnik, Andrew P.; Leitner, Stefano; Ruiz, Edda L.; Griffin, Brittany; Rosenberg, Jens T.; Grant, Samuel C.; Fincham, Francis D.; Pinto, Jose R.; Kabbaj, Mohamed

2017-01-01

Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we used mice bearing a knock-in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3–4 mo) and aged adult (7–8 mo) female mice to examine the effects of HCM on the development of anxiety- and depression-like behaviors. We focused on females because in both humans and rodents, they experience a 2-fold increase in mood disorder prevalence vs. males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety- and depression-like behaviors. Electrocardiographic parameters of sympathetic nervous system activation were increased in aged HCM females vs. controls and correlated with mood disorder–related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood-related brain regions, and reduced hippocampal signaling proteins, such as brain-derived neurotrophic factor and its downstream targets vs. controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus, mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.—Dossat, A. M., Sanchez-Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy. PMID:28235781

Large-Scale Brain Simulation and Disorders of Consciousness. Mapping Technical and Conceptual Issues.

PubMed

Farisco, Michele; Kotaleski, Jeanette H; Evers, Kathinka

2018-01-01

Modeling and simulations have gained a leading position in contemporary attempts to describe, explain, and quantitatively predict the human brain's operations. Computer models are highly sophisticated tools developed to achieve an integrated knowledge of the brain with the aim of overcoming the actual fragmentation resulting from different neuroscientific approaches. In this paper we investigate the plausibility of simulation technologies for emulation of consciousness and the potential clinical impact of large-scale brain simulation on the assessment and care of disorders of consciousness (DOCs), e.g., Coma, Vegetative State/Unresponsive Wakefulness Syndrome, Minimally Conscious State. Notwithstanding their technical limitations, we suggest that simulation technologies may offer new solutions to old practical problems, particularly in clinical contexts. We take DOCs as an illustrative case, arguing that the simulation of neural correlates of consciousness is potentially useful for improving treatments of patients with DOCs.

Brain delivery research in public-private partnerships: The IMI-JU COMPACT consortium as an example.

PubMed

Meyer, Axel H; Untucht, Christopher; Terstappen, Georg C

2017-07-01

The Blood-Brain Barrier (BBB) represents a major hurdle in the development of treatments for CNS disorders due to the fact that it very effectively keeps drugs, especially biological macromolecules, out of the brain. Concomitantly with the increasing importance of biologics research on the BBB and, more specifically, on brain delivery technologies has intensified in recent years. Public-Private Partnerships (PPPs) represent an innovative opportunity to address such complex challenges as they bring together the best expertise from both industry and academia. Here we present the IMI-JU COMPACT (Collaboration on the Optimisation of Macromolecular Pharmaceutical Access to Cellular Targets) consortium working on nanocarriers for targeted delivery of macromolecules as an example. The scope of the consortium, its goals and the expertise within the consortium are outlined. This article is part of the Special Issue entitled "Beyond small molecules for neurological disorders". Copyright © 2016 Elsevier Ltd. All rights reserved.

Previous Exposure to Anesthesia and Autism Spectrum Disorder (ASD): A Puerto Rican Population-Based Sibling Cohort Study.

PubMed

Creagh, O; Torres, H; Rivera, K; Morales-Franqui, M; Altieri-Acevedo, G; Warner, D

2015-01-01

Autism Spectrum Disorder (ASD) is characterized by impaired social interaction and communication, and by restricted and repetitive behavior, that begins usually before a child is three years old.1 Researchers have shown that prevalence rates in the U.S. may be as high as 1 in 68.52 A number of studies have examined the effects of early exposure to anesthesia on brain development and subsequent impairment in neurocognitive function; yet, little is known about the possible effects of anesthetic agents on social-behavioral functioning. The association between exposure to anesthesia either in uterus, during the first years of life, or later and development of Autistic Spectrum Disorder (ASD) or its severity was determined in a retrospective population based cohort study. Identify if children who had previous exposure to anesthesia either in uterus, first years of life during their developing brain years, or later, are at risk of developing ASD and its severe form of the disease. Data was obtained from structured interviews administered to a sample of 515 parents/guardians distributed in two groups: ASD = 262 children diagnosed with this condition and Non-ASD: 253 children (siblings of ASD group) without diagnosis (p = 0.8069) when comparing exposure to anesthesia in uterus to subsequent severe form of ASD. Of the 262 ASD patients, 99 had exposure to anesthetics before their diagnosis, while in Non-ASD population, 110 had exposure to anesthesia, demonstrating no statistically significant association between both groups (p = 0.2091). Out of 99 ASD patients exposed to anesthesia prior to their diagnosis, 72 were exposed before age 2. When compared to the 110 Non-ASD patients exposed to anesthesia, 86 had exposure during this developing brain period, which indicates no statistically significant association (p = 0.4207). In addition, most of the ASD children exposed to anesthesia during developing brain were diagnosed with mild degree of the disorder when compared to ASD children without any previous exposure to anesthesia (p = 0.9700) during the same period. When the exposure occurred after age 2, ASD children developed mild form of the disorder as compared with ASD children without any previous exposure to anesthesia (p = 0.1699) in that period. Children under early exposure to anesthesia in uterus, first 2 years of life, or later are not more likely to develop neither ASD nor severe form of the disorder. INDEX WORDS: Anesthesia, Autism Spectrum Disorder, Puerto Rico. (95% confidence interval) that freely decided to participate and agreed to a consent form. Variables studied, include: demographics, diagnosis and severity of ASD, exposure to anesthesia, method of childbirth, and age of exposure. Children less than 2 years of age were considered into have developing brain period. Data was analyzed using Chi-square or Fisher exact test. In contrast to non-ASD group, most of the children within ASD group were male, 76% (p = 0.0001). With regards to methods of childbirth, 64% of the ASD population were vaginal delivery (VD; Non-anesthesia exposure group) and 36% cesarean delivery (CD) compared to non-autistic population with 71% VD and 29% CD, which demonstrates no statistical difference between both groups (p = 0.1113). Out of the 36% of ASD population that underwent CD, 7% were performed using general anesthesia and 93% regional anesthesia, while the 29% of the CD of non-ASD, 5% were performed using general anesthesia and 95% regional anesthesia. This reveals no statistical significance (p = 0.7569) with the development of ASD and the type of anesthesia used when comparing ASD with non-ASD patients. In view of severity of autism, in VD, 56% of ASD population had mild form of the disorder, 34% moderate, and 10% severe; while CD had a 54% mild form of the disorder, 33% moderate, and 13% severe. This shows no statistical association.

A psychology of the human brain-gut-microbiome axis.

PubMed

Allen, Andrew P; Dinan, Timothy G; Clarke, Gerard; Cryan, John F

2017-04-01

In recent years, we have seen increasing research within neuroscience and biopsychology on the interactions between the brain, the gastrointestinal tract, the bacteria within the gastrointestinal tract, and the bidirectional relationship between these systems: the brain-gut-microbiome axis. Although research has demonstrated that the gut microbiota can impact upon cognition and a variety of stress-related behaviours, including those relevant to anxiety and depression, we still do not know how this occurs. A deeper understanding of how psychological development as well as social and cultural factors impact upon the brain-gut-microbiome axis will contextualise the role of the axis in humans and inform psychological interventions that improve health within the brain-gut-microbiome axis. Interventions ostensibly aimed at ameliorating disorders in one part of the brain-gut-microbiome axis (e.g., psychotherapy for depression) may nonetheless impact upon other parts of the axis (e.g., microbiome composition and function), and functional gastrointestinal disorders such as irritable bowel syndrome represent a disorder of the axis, rather than an isolated problem either of psychology or of gastrointestinal function. The discipline of psychology needs to be cognisant of these interactions and can help to inform the future research agenda in this emerging field of research. In this review, we outline the role psychology has to play in understanding the brain-gut-microbiome axis, with a focus on human psychology and the use of research in laboratory animals to model human psychology.

Speech impairment (adult)

MedlinePlus

... sound different from the way it normally sounds. Causes Some of these disorders develop gradually, but anyone can develop a speech and language impairment suddenly, usually in a trauma. APHASIA Alzheimer disease Brain tumor (more common in aphasia than ...

The role of maternal obesity in the risk of neuropsychiatric disorders

PubMed Central

Rivera, Heidi M.; Christiansen, Kelly J.; Sullivan, Elinor L.

2015-01-01

Recent evidence indicates that perinatal exposure to maternal obesity, metabolic disease, including diabetes and hypertension, and unhealthy maternal diet has a long-term impact on offspring behavior and physiology. During the past three decades, the prevalence of both obesity and neuropsychiatric disorders has rapidly increased. Epidemiologic studies provide evidence that maternal obesity and metabolic complications increase the risk of attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, anxiety, depression, schizophrenia, eating disorders (food addiction, anorexia nervosa, and bulimia nervosa), and impairments in cognition in offspring. Animal models of maternal high-fat diet (HFD) induced obesity also document persistent changes in offspring behavior and impairments in critical neural circuitry. Animals exposed to maternal obesity and HFD consumption display hyperactivity, impairments in social behavior, increased anxiety-like and depressive-like behaviors, substance addiction, food addiction, and diminished cognition. During development, these offspring are exposed to elevated levels of nutrients (fatty acids, glucose), hormones (leptin, insulin), and inflammatory factors (C-reactive protein, interleukin, and tumor necrosis factor). Such factors appear to permanently change neuroendocrine regulation and brain development in offspring. In addition, inflammation of the offspring brain during gestation impairs the development of neural pathways critical in the regulation of behavior, such as serotoninergic, dopaminergic, and melanocortinergic systems. Dysregulation of these circuits increases the risk of mental health disorders. Given the high rates of obesity in most developed nations, it is critical that the mechanisms by which maternal obesity programs offspring behavior are thoroughly characterized. Such knowledge will be critical in the development of preventative strategies and therapeutic interventions. PMID:26150767

Sialic Acids in the Brain: Gangliosides and Polysialic Acid in Nervous System Development, Stability, Disease, and Regeneration

PubMed Central

Gerardy-Schahn, Rita; Hildebrandt, Herbert

2014-01-01

Every cell in nature carries a rich surface coat of glycans, its glycocalyx, which constitutes the cell's interface with its environment. In eukaryotes, the glycocalyx is composed of glycolipids, glycoproteins, and proteoglycans, the compositions of which vary among different tissues and cell types. Many of the linear and branched glycans on cell surface glycoproteins and glycolipids of vertebrates are terminated with sialic acids, nine-carbon sugars with a carboxylic acid, a glycerol side-chain, and an N-acyl group that, along with their display at the outmost end of cell surface glycans, provide for varied molecular interactions. Among their functions, sialic acids regulate cell-cell interactions, modulate the activities of their glycoprotein and glycolipid scaffolds as well as other cell surface molecules, and are receptors for pathogens and toxins. In the brain, two families of sialoglycans are of particular interest: gangliosides and polysialic acid. Gangliosides, sialylated glycosphingolipids, are the most abundant sialoglycans of nerve cells. Mouse genetic studies and human disorders of ganglioside metabolism implicate gangliosides in axon-myelin interactions, axon stability, axon regeneration, and the modulation of nerve cell excitability. Polysialic acid is a unique homopolymer that reaches >90 sialic acid residues attached to select glycoproteins, especially the neural cell adhesion molecule in the brain. Molecular, cellular, and genetic studies implicate polysialic acid in the control of cell-cell and cell-matrix interactions, intermolecular interactions at cell surfaces, and interactions with other molecules in the cellular environment. Polysialic acid is essential for appropriate brain development, and polymorphisms in the human genes responsible for polysialic acid biosynthesis are associated with psychiatric disorders including schizophrenia, autism, and bipolar disorder. Polysialic acid also appears to play a role in adult brain plasticity, including regeneration. Together, vertebrate brain sialoglycans are key regulatory components that contribute to proper development, maintenance, and health of the nervous system. PMID:24692354

Brain Mechanisms of Affective Language Comprehension in Autism Spectrum Disorders

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-14-1-0457 TITLE: Brain Mechanisms of Affective Language Comprehension in Autism Spectrum Disorders PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE Brain Mechanisms of Affective Language Comprehension in Autism Spectrum Disorders 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Profound deficits in the domain of social communication are a hallmark of autism spectrum disorders (ASD

Association Between Traumatic Brain Injury and Risk of Posttraumatic Stress Disorder in Active-Duty Marines

DTIC Science & Technology

2013-01-01

traumatic brain injury (TBI) is a risk factor for posttraumatic stress disorder ( PTSD ) has been difficult to determine because of the prevalence of...Qualification Test; CAPS, Clinician-Administered PTSD Scale; PTSD , posttraumatic stress disorder ; TBI, traumatic brain injury. a For the zeromodel, base...New onset and persistent symptoms of post - traumatic stress disorder self reported after deployment and combat exposures. BMJ.

Mental disorders are not brain disorders.

PubMed

Banner, Natalie F

2013-06-01

As advances in neuroscience and genetics reveal complex associations between brain structures, functions and symptoms of mental disorders, there have been calls for psychiatric classifications to be reconfigured, to conceptualize mental disorders as disorders of the brain. In this paper, I argue that this view is mistaken, and that the level at which we identify mental disorders is, and should be, the person, not the brain. This is not to deny physicalism or argue that the mental realm is somehow distinct from the physical, but rather to suggest the things that are going 'wrong' in mental disorder are picked out at the person-level: they are characterized by breaches in epistemic, rational, evaluative, emotional, social and moral norms. However, as our scientific understanding of the brain becomes advanced, what makes an identified neurobiological difference in brain structure or functioning indicative of pathology is its association with these behaviours at the person-level. Instead of collapsing psychiatry into biomedicine, biomedicine may benefit from drawing closer to the expertise of psychiatry, as it is able to accommodate social, psychological and biological explanations while focusing on the person, within their environment. © 2013 John Wiley & Sons Ltd.

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders

PubMed Central

Hagihara, Hideo; Catts, Vibeke S; Katayama, Yuta; Shoji, Hirotaka; Takagi, Tsuyoshi; Huang, Freesia L; Nakao, Akito; Mori, Yasuo; Huang, Kuo-Ping; Ishii, Shunsuke; Graef, Isabella A; Nakayama, Keiichi I; Shannon Weickert, Cynthia; Miyakawa, Tsuyoshi

2018-01-01

Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder. PMID:28776581

77 FR 297 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-04

... of Committee: Brain Disorders and Clinical Neuroscience Integrated Review Group, Developmental Brain...- 9866, [email protected] . Name of Committee: Brain Disorders and Clinical Neuroscience Integrated...

Age-associated changes in rich-club organisation in autistic and neurotypical human brains

PubMed Central

Watanabe, Takamitsu; Rees, Geraint

2015-01-01

Macroscopic structural networks in the human brain have a rich-club architecture comprising both highly inter-connected central regions and sparsely connected peripheral regions. Recent studies show that disruption of this functionally efficient organisation is associated with several psychiatric disorders. However, despite increasing attention to this network property, whether age-associated changes in rich-club organisation occur during human adolescence remains unclear. Here, analysing a publicly shared diffusion tensor imaging dataset, we found that, during adolescence, brains of typically developing (TD) individuals showed increases in rich-club organisation and inferred network functionality, whereas individuals with autism spectrum disorders (ASD) did not. These differences between TD and ASD groups were statistically significant for both structural and functional properties. Moreover, this typical age-related changes in rich-club organisation were characterised by progressive involvement of the right anterior insula. In contrast, in ASD individuals, did not show typical increases in grey matter volume, and this relative anatomical immaturity was correlated with the severity of ASD social symptoms. These results provide evidence that rich-club architecture is one of the bases of functionally efficient brain networks underpinning complex cognitive functions in adult human brains. Furthermore, our findings suggest that immature rich-club organisation might be associated with some neurodevelopmental disorders. PMID:26537477

Chapter 36: history of aphasia: from brain to language.

PubMed

Eling, Paul; Whitaker, Harry

2010-01-01

An historical overview is presented that focuses on the changes both in approach and topics with respect to language disturbances due to brain lesions. Early cases of language disorders were described without any theorizing about language or its relation to the brain. Also, three forms of speech disorder were distinguished: traulotes, psellotes and ischophonia, which are only marginally related to aphasia. In the 18th century some authors, in particular Gesner and Crichton, attempted to explain language disorders in terms of mental processes. The great debate on both the anatomical (Broca, Wernicke) and functional (Wernicke, Lichtheim) aspects of aphasia dominated late 19th century discussion of localization of function, leading to the development of what we now call the cognitive neurosciences. In this period, language processing was described in terms of a simple functional model of word recognition and production; linguistic principles played no role. At the beginning of the 20th century the discussion on language disorders waned due to a decrease of interest in the issue of localization; aphasia became primarily a clinical issue of how best to classify patients. In the second half of the 20th century, the field of aphasia developed rapidly due to studies performed at the Boston Aphasia Unit and, more importantly, to a change of orientation to linguistic notions of language structure, as introduced by Chomsky.

Learning problems, delayed development, and puberty

PubMed Central

Wright, Beverly A.; Zecker, Steven G.

2004-01-01

Language-based learning disorders such as dyslexia affect millions of people, but there is little agreement as to their cause. New evidence from behavioral measures of the ability to hear tones in the presence of background noise indicates that the brains of affected individuals develop more slowly than those of their unaffected counterparts. In addition, it seems that brain changes occurring at ≈10 years of age, presumably associated with puberty, may prematurely halt this slower-than-normal development when improvements would normally continue into adolescence. The combination of these ideas can account for a wide range of previous results, suggesting that delayed brain development, and its interaction with puberty, may be key factors contributing to learning problems. PMID:15210987

Prediction of brain maturity based on cortical thickness at different spatial resolutions.

PubMed

Khundrakpam, Budhachandra S; Tohka, Jussi; Evans, Alan C

2015-05-01

Several studies using magnetic resonance imaging (MRI) scans have shown developmental trajectories of cortical thickness. Cognitive milestones happen concurrently with these structural changes, and a delay in such changes has been implicated in developmental disorders such as attention-deficit/hyperactivity disorder (ADHD). Accurate estimation of individuals' brain maturity, therefore, is critical in establishing a baseline for normal brain development against which neurodevelopmental disorders can be assessed. In this study, cortical thickness derived from structural magnetic resonance imaging (MRI) scans of a large longitudinal dataset of normally growing children and adolescents (n=308), were used to build a highly accurate predictive model for estimating chronological age (cross-validated correlation up to R=0.84). Unlike previous studies which used kernelized approach in building prediction models, we used an elastic net penalized linear regression model capable of producing a spatially sparse, yet accurate predictive model of chronological age. Upon investigating different scales of cortical parcellation from 78 to 10,240 brain parcels, we observed that the accuracy in estimated age improved with increased spatial scale of brain parcellation, with the best estimations obtained for spatial resolutions consisting of 2560 and 10,240 brain parcels. The top predictors of brain maturity were found in highly localized sensorimotor and association areas. The results of our study demonstrate that cortical thickness can be used to estimate individuals' brain maturity with high accuracy, and the estimated ages relate to functional and behavioural measures, underscoring the relevance and scope of the study in the understanding of biological maturity. Copyright © 2015 Elsevier Inc. All rights reserved.

Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

PubMed Central

SAAVEDRA, Juan M.

2012-01-01

The effects of brain AngII (angiotensin II) depend on AT1 receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT1 receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood–brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT1 receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT1 receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer’s disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer’s disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic brain injury. PMID:22827472

Neurofeedback: One of today's techniques in psychiatry?

PubMed

Arns, M; Batail, J-M; Bioulac, S; Congedo, M; Daudet, C; Drapier, D; Fovet, T; Jardri, R; Le-Van-Quyen, M; Lotte, F; Mehler, D; Micoulaud-Franchi, J-A; Purper-Ouakil, D; Vialatte, F

2017-04-01

Neurofeedback is a technique that aims to teach a subject to regulate a brain parameter measured by a technical interface to modulate his/her related brain and cognitive activities. However, the use of neurofeedback as a therapeutic tool for psychiatric disorders remains controversial. The aim of this review is to summarize and to comment the level of evidence of electroencephalogram (EEG) neurofeedback and real-time functional magnetic resonance imaging (fMRI) neurofeedback for therapeutic application in psychiatry. Literature on neurofeedback and mental disorders but also on brain computer interfaces (BCI) used in the field of neurocognitive science has been considered by the group of expert of the Neurofeedback evaluation & training (NExT) section of the French Association of biological psychiatry and neuropsychopharmacology (AFPBN). Results show a potential efficacy of EEG-neurofeedback in the treatment of attentional-deficit/hyperactivity disorder (ADHD) in children, even if this is still debated. For other mental disorders, there is too limited research to warrant the use of EEG-neurofeedback in clinical practice. Regarding fMRI neurofeedback, the level of evidence remains too weak, for now, to justify clinical use. The literature review highlights various unclear points, such as indications (psychiatric disorders, pathophysiologic rationale), protocols (brain signals targeted, learning characteristics) and techniques (EEG, fMRI, signal processing). The field of neurofeedback involves psychiatrists, neurophysiologists and researchers in the field of brain computer interfaces. Future studies should determine the criteria for optimizing neurofeedback sessions. A better understanding of the learning processes underpinning neurofeedback could be a key element to develop the use of this technique in clinical practice. Copyright © 2016 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

The neurobiology of retinoic acid in affective disorders.

PubMed

Bremner, J Douglas; McCaffery, Peter

2008-02-15

Current models of affective disorders implicate alterations in norepinephrine, serotonin, dopamine, and CRF/cortisol; however treatments targeted at these neurotransmitters or hormones have led to imperfect resolution of symptoms, suggesting that the neurobiology of affective disorders is incompletely understood. Until now retinoids have not been considered as possible contributors to affective disorders. Retinoids represent a family of compounds derived from vitamin A that perform a large number of functions, many via the vitamin A product, retinoic acid. This signaling molecule binds to specific retinoic acid receptors in the brain which, like the glucocorticoid and thyroid hormone receptors, are part of the nuclear receptor superfamily and regulate gene transcription. Research in the field of retinoic acid in the CNS has focused on the developing brain, in part stimulated by the observation that isotretinoin (13-cis retinoic acid), an isomer of retinoic acid used in the treatment of acne, is highly teratogenic for the CNS. More recent work has suggested that retinoic acid may influence the adult brain; animal studies indicated that the administration of isotretinoin is associated with alterations in behavior as well as inhibition of neurogenesis in the hippocampus. Clinical evidence for an association between retinoids and depression includes case reports in the literature, studies of health care databases, and other sources. A preliminary PET study in human subjects showed that isotretinoin was associated with a decrease in orbitofrontal metabolism. Several studies have shown that the molecular components required for retinoic acid signaling are expressed in the adult brain; the overlap of brain areas implicated in retinoic acid function and stress and depression suggest that retinoids could play a role in affective disorders. This report reviews the evidence in this area and describes several systems that may be targets of retinoic acid and which contribute to the pathophysiology of depression.

The Neurobiology of Retinoic Acid in Affective Disorders

PubMed Central

Bremner, J Douglas; McCaffery, Peter

2009-01-01

Current models of affective disorders implicate alterations in norepinephrine, serotonin, dopamine, and CRF/cortisol; however treatments targeted at these neurotransmitters or hormones have led to imperfect resolution of symptoms, suggesting that the neurobiology of affective disorders is incompletely understood. Until now retinoids have not been considered as possible contributors to affective disorders. Retinoids represent a family of compounds derived from Vitamin A that perform a large number of functions, many via the vitamin A product, retinoic acid. This signaling molecule binds to specific retinoic acid receptors in the brain which, like the glucocorticoid and thyroid hormone receptors, are part of the nuclear receptor superfamily and regulate gene transcription. Research in the field of retinoic acid in the CNS has focused on the developing brain, in part stimulated by the observation that isotretinoin (13-cis retinoic acid), an isomer of retinoic acid used in the treatment of acne, is highly teratogenic for the CNS. More recent work has suggested that retinoic acid may influence the adult brain; animal studies indicated that the administration of isotretinoin is associated with alterations in behavior as well as inhibition of neurogenesis in the hippocampus. Clinical evidence for an association between retinoids and depression includes case reports in the literature, studies of health care databases, and other sources. A preliminary PET study in human subjects showed that isotretinoin was associated with a decrease in orbitofrontal metabolism. Several studies have shown that the molecular components required for retinoic acid signaling are expressed in the adult brain ; the overlap of brain areas implicated in retinoic acid function and stress and depression suggest that retinoids could play a role in affective disorders. This report reviews the evidence in this area and describes several systems that may be targets of retinoic acid and which contribute to the pathophysiology of depression. PMID:17707566

An Update Overview on Brain Imaging Studies of Internet Gaming Disorder

PubMed Central

Weinstein, Aviv M.

2017-01-01

There are a growing number of studies on structural and functional brain mechanisms underlying Internet gaming disorder (IGD). Recent functional magnetic resonance imaging studies showed that IGD adolescents and adults had reduced gray matter volume in regions associated with attention motor coordination executive function and perception. Adolescents with IGD showed lower white matter (WM) integrity measures in several brain regions that are involved in decision-making, behavioral inhibition, and emotional regulation. IGD adolescents had also disruption in the functional connectivity in areas responsible for learning memory and executive function, processing of auditory, visual, and somatosensory stimuli and relay of sensory and motor signals. IGD adolescents also had decreased functional connectivity of PFC-striatal circuits, increased risk-taking choices, and impaired ability to control their impulses similar to other impulse control disorders. Recent studies indicated that altered executive control mechanisms in attention deficit hyperactivity disorder (ADHD) would be a predisposition for developing IGD. Finally, patients with IGD have also shown an increased functional connectivity of several executive control brain regions that may related to comorbidity with ADHD and depression. The behavioral addiction model argues that IGD shows the features of excessive use despite adverse consequences, withdrawal phenomena, and tolerance that characterize substance use disorders. The evidence supports the behavioral addiction model of IGD by showing structural and functional changes in the mechanisms of reward and craving (but not withdrawal) in IGD. Future studies need to investigate WM density and functional connectivity in IGD in order to validate these findings. Furthermore, more research is required about the similarity in neurochemical and neurocognitive brain circuits in IGD and comorbid conditions such as ADHD and depression. PMID:29033857

Neuromodulation and neurofeedback treatments in eating disorders and obesity.

PubMed

Dalton, Bethan; Campbell, Iain C; Schmidt, Ulrike

2017-11-01

Psychological interventions are the treatment of choice for most eating disorders; however, significant proportions of patients do not recover with these. Advances in understanding of the neurobiology of eating disorders have led to the development of targeted treatments, such as deep brain stimulation (DBS), noninvasive brain stimulation (NIBS), and neurofeedback. We review the emerging clinical evidence for the use of these interventions in eating disorders and obesity, together with their theoretical rationale. Finally, we reflect on future developments. During the last 20 months, seven case studies/series and seven randomized controlled trials (RCTs) of NIBS or neurofeedback in different eating disorders, obesity, or food craving have appeared. These have largely had promising results. One NIBS trial, using a multisession protocol, was negative. A case series of subcallosal DBS in anorexia nervosa has also shown promise. A search of trial registries identified a further 21 neuromodulation/feedback studies in progress, indicating that neuromodulation/feedback is an area of growing interest. At present, neuromodulation and neurofeedback are largely experimental interventions; however, growing understanding of the mechanisms involved, together with the rising number of studies in this area, means that the clinical utility of these interventions is likely to become clearer soon.

The Role of Ionotropic Glutamate Receptors in Childhood Neurodevelopmental Disorders: Autism Spectrum Disorders and Fragile X Syndrome

PubMed Central

Uzunova, Genoveva; Hollander, Eric; Shepherd, Jason

2014-01-01

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS. PMID:24533017

High-resolution temporal and regional mapping of MAPT expression and splicing in human brain development.

PubMed

Hefti, Marco M; Farrell, Kurt; Kim, SoongHo; Bowles, Kathryn R; Fowkes, Mary E; Raj, Towfique; Crary, John F

2018-01-01

The microtubule associated protein tau plays a critical role in the pathogenesis of neurodegenerative disease. Recent studies suggest that tau also plays a role in disorders of neuronal connectivity, including epilepsy and post-traumatic stress disorder. Animal studies have shown that the MAPT gene, which codes for the tau protein, undergoes complex pre-mRNA alternative splicing to produce multiple isoforms during brain development. Human data, particularly on temporal and regional variation in tau splicing during development are however lacking. In this study, we present the first detailed examination of the temporal and regional sequence of MAPT alternative splicing in the developing human brain. We used a novel computational analysis of large transcriptomic datasets (total n = 502 patients), quantitative polymerase chain reaction (qPCR) and western blotting to examine tau expression and splicing in post-mortem human fetal, pediatric and adult brains. We found that MAPT exons 2 and 10 undergo abrupt shifts in expression during the perinatal period that are unique in the canonical human microtubule-associated protein family, while exon 3 showed small but significant temporal variation. Tau isoform expression may be a marker of neuronal maturation, temporally correlated with the onset of axonal growth. Immature brain regions such as the ganglionic eminence and rhombic lip had very low tau expression, but within more mature regions, there was little variation in tau expression or splicing. We thus demonstrate an abrupt, evolutionarily conserved shift in tau isoform expression during the human perinatal period that may be due to tau expression in maturing neurons. Alternative splicing of the MAPT pre-mRNA may play a vital role in normal brain development across multiple species and provides a basis for future investigations into the developmental and pathological functions of the tau protein.

[Neuroanatomical, genetic and neurochemical aspects of infantile autism].

PubMed

Gerhant, Aneta; Olajossy, Marcin; Olajossy-Hilkesberger, Luiza

2013-01-01

Infantile autism is a neurodevelopmental disorder characterized by impairments in communication, reciprocal social interaction and restricted repetitive behaviors or interests. Although the cause of these disorders is not yet known, studies strongly suggest a genetic basis with a complex mode of inheritance. The etiopathogenetic processes of autism are extremely complex, which is reflected in the varying course and its symptomatology. Trajectories of brain development and volumes of its structures are aberrant in autistic patients. It is suggested that disturbances in sertotoninergic, gabaergic, glutaminergic, cholinergic and dopaminergic neurotransmission can be responsible for symptoms of autism as well as can disturb the development of the young brain. The objective of this article is to present the results of reasearch on neuroanatomical, neurochemical and genetic aspects of autism.

[Eating disorders].

PubMed

Miyake, Yoshie; Okamoto, Yuri; Jinnin, Ran; Shishida, Kazuhiro; Okamoto, Yasumasa

2015-02-01

Eating disorders are characterized by aberrant patterns of eating behavior, including such symptoms as extreme restriction of food intake or binge eating, and severe disturbances in the perception of body shape and weight, as well as a drive for thinness and obsessive fears of becoming fat. Eating disorder is an important cause for physical and psychosocial morbidity in young women. Patients with eating disorders have a deficit in the cognitive process and functional abnormalities in the brain system. Recently, brain-imaging techniques have been used to identify specific brain areas that function abnormally in patients with eating disorders. We have discussed the clinical and cognitive aspects of eating disorders and summarized neuroimaging studies of eating disorders.

The development, past achievements, and future directions of brain PET

PubMed Central

Jones, Terry; Rabiner, Eugenii A

2012-01-01

The early developments of brain positron emission tomography (PET), including the methodological advances that have driven progress, are outlined. The considerable past achievements of brain PET have been summarized in collaboration with contributing experts in specific clinical applications including cerebrovascular disease, movement disorders, dementia, epilepsy, schizophrenia, addiction, depression and anxiety, brain tumors, drug development, and the normal healthy brain. Despite a history of improving methodology and considerable achievements, brain PET research activity is not growing and appears to have diminished. Assessments of the reasons for decline are presented and strategies proposed for reinvigorating brain PET research. Central to this is widening the access to advanced PET procedures through the introduction of lower cost cyclotron and radiochemistry technologies. The support and expertize of the existing major PET centers, and the recruitment of new biologists, bio-mathematicians and chemists to the field would be important for such a revival. New future applications need to be identified, the scope of targets imaged broadened, and the developed expertize exploited in other areas of medical research. Such reinvigoration of the field would enable PET to continue making significant contributions to advance the understanding of the normal and diseased brain and support the development of advanced treatments. PMID:22434067

Recommendations for Development of New Standardized Forms of Cocoa Breeds and Cocoa Extract Processing for the Prevention of Alzheimer's Disease: Role of Cocoa in Promotion of Cognitive Resilience and Healthy Brain Aging.

PubMed

Dubner, Lauren; Wang, Jun; Ho, Lap; Ward, Libby; Pasinetti, Giulio M

2015-01-01

It is currently thought that the lackluster performance of translational paradigms in the prevention of age-related cognitive deteriorative disorders, such as Alzheimer's disease (AD), may be due to the inadequacy of the prevailing approach of targeting only a single mechanism. Age-related cognitive deterioration and certain neurodegenerative disorders, including AD, are characterized by complex relationships between interrelated biological phenotypes. Thus, alternative strategies that simultaneously target multiple underlying mechanisms may represent a more effective approach to prevention, which is a strategic priority of the National Alzheimer's Project Act and the National Institute on Aging. In this review article, we discuss recent strategies designed to clarify the mechanisms by which certain brain-bioavailable, bioactive polyphenols, in particular, flavan-3-ols also known as flavanols, which are highly represented in cocoa extracts, may beneficially influence cognitive deterioration, such as in AD, while promoting healthy brain aging. However, we note that key issues to improve consistency and reproducibility in the development of cocoa extracts as a potential future therapeutic agent requires a better understanding of the cocoa extract sources, their processing, and more standardized testing including brain bioavailability of bioactive metabolites and brain target engagement studies. The ultimate goal of this review is to provide recommendations for future developments of cocoa extracts as a therapeutic agent in AD.

Altered Brain Network Segregation in Fragile X Syndrome Revealed by Structural Connectomics.

PubMed

Bruno, Jennifer Lynn; Hosseini, S M Hadi; Saggar, Manish; Quintin, Eve-Marie; Raman, Mira Michelle; Reiss, Allan L

2017-03-01

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder, is associated with significant behavioral, social, and neurocognitive deficits. Understanding structural brain network topology in FXS provides an important link between neurobiological and behavioral/cognitive symptoms of this disorder. We investigated the connectome via whole-brain structural networks created from group-level morphological correlations. Participants included 100 individuals: 50 with FXS and 50 with typical development, age 11-23 years. Results indicated alterations in topological properties of structural brain networks in individuals with FXS. Significantly reduced small-world index indicates a shift in the balance between network segregation and integration and significantly reduced clustering coefficient suggests that reduced local segregation shifted this balance. Caudate and amygdala were less interactive in the FXS network further highlighting the importance of subcortical region alterations in the neurobiological signature of FXS. Modularity analysis indicates that FXS and typically developing groups' networks decompose into different sets of interconnected sub networks, potentially indicative of aberrant local interconnectivity in individuals with FXS. These findings advance our understanding of the effects of fragile X mental retardation protein on large-scale brain networks and could be used to develop a connectome-level biological signature for FXS. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion.

PubMed

Lin, Mingyan; Pedrosa, Erika; Hrabovsky, Anastasia; Chen, Jian; Puliafito, Benjamin R; Gilbert, Stephanie R; Zheng, Deyou; Lachman, Herbert M

2016-11-15

Individuals with 22q11.2 Deletion Syndrome (22q11.2 DS) are a specific high-risk group for developing schizophrenia (SZ), schizoaffective disorder (SAD) and autism spectrum disorders (ASD). Several genes in the deleted region have been implicated in the development of SZ, e.g., PRODH and DGCR8. However, the mechanistic connection between these genes and the neuropsychiatric phenotype remains unclear. To elucidate the molecular consequences of 22q11.2 deletion in early neural development, we carried out RNA-seq analysis to investigate gene expression in early differentiating human neurons derived from induced pluripotent stem cells (iPSCs) of 22q11.2 DS SZ and SAD patients. Eight cases (ten iPSC-neuron samples in total including duplicate clones) and seven controls (nine in total including duplicate clones) were subjected to RNA sequencing. Using a systems level analysis, differentially expressed genes/gene-modules and pathway of interests were identified. Lastly, we related our findings from in vitro neuronal cultures to brain development by mapping differentially expressed genes to BrainSpan transcriptomes. We observed ~2-fold reduction in expression of almost all genes in the 22q11.2 region in SZ (37 genes reached p-value < 0.05, 36 of which reached a false discovery rate < 0.05). Outside of the deleted region, 745 genes showed significant differences in expression between SZ and control neurons (p < 0.05). Function enrichment and network analysis of the differentially expressed genes uncovered converging evidence on abnormal expression in key functional pathways, such as apoptosis, cell cycle and survival, and MAPK signaling in the SZ and SAD samples. By leveraging transcriptome profiles of normal human brain tissues across human development into adulthood, we showed that the differentially expressed genes converge on a sub-network mediated by CDC45 and the cell cycle, which would be disrupted by the 22q11.2 deletion during embryonic brain development, and another sub-network modulated by PRODH, which could contribute to disruption of brain function during adolescence. This study has provided evidence for disruption of potential molecular events in SZ patient with 22q11.2 deletion and related our findings from in vitro neuronal cultures to functional perturbations that can occur during brain development in SZ.

Role of neurotrophic factors in attention deficit hyperactivity disorder.

PubMed

Tsai, Shih-Jen

2017-04-01

Neurotrophins (NTs), a family of proteins including nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4, are essential for neural growth, survival, and differentiation, and are therefore crucial for brain development. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by problems of inattention and/or hyperactivity-impulsivity. ADHD is one of the most common childhood onset psychiatric disorders. Studies have suggested that both genetic and environmental factors influence the development of the disorder, although the precise causes of ADHD have not yet been identified. In this review, we assess the role of NTs in the pathophysiology of ADHD. Preclinical evidence indicates that BDNF knockout mice are hyperactive, and an ADHD rodent model exhibited decreased cerebral BDNF levels. Several lines of evidence from clinical studies, including blood level and genetic studies, have suggested that NTs are involved in the pathogenesis of ADHD and in the mechanism of biological treatments for ADHD. Future directions for research are proposed, such as using blood NTs as ADHD biomarkers, optimizing NT genetic studies in ADHD, considering NTs as a link between ADHD and other comorbid mental disorders, and investigating methods for optimally modulating NT signaling to discover novel therapeutics for treating ADHD. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Systems Neuroscience Approach to the Pathophysiology of Pediatric Mood and Anxiety Disorders

PubMed Central

Leibenluft, Ellen; Brotman, Melissa A.

2015-01-01

Emotional dysregulation is a core feature of pediatric mood and anxiety disorders. Emerging evidence suggests that these disorders are mediated by abnormalities in the functions and structures of the developing brain. This chapter reviews recent behavioral and functional magnetic resonance imaging (fMRI) research on pediatric mood and anxiety disorders, focusing on the neural mechanisms underlying these disorders. Throughout the chapter, we highlight the relationship between neural and behavioral findings, and potential novel treatments. The chapter concludes with directions for future research. PMID:24281907

Introduction to the special issue from the 2014 meeting of the International Behavioral Neuroscience Society.

PubMed

Young, Jared W; Hall, F Scott; Pletnikov, Mikhail; Kent, Stephen

2015-11-01

In 2013, President Obama launched what has been optimistically described as the "decade of the brain". The launch of this effort comes on the back of widespread acknowledgement that more is required to aid those suffering from mental health disorders. Specifically, a greater understanding of the neural circuitry related to behaviors specific to mental health disorders is needed. The field of research that relates the circuitry of the brain to specific aspects of behavior is referred to as behavioral neuroscience. The International Behavioral Neuroscience Society (IBNS) was founded in 1992 specifically to meet on an annual basis and present the latest research findings in this field, and to gather together the international research community to discuss issues important for the development and progress of this scientific discipline. This special issue includes reviews of topics of emerging interest and advancing knowledge in behavioral neuroscience, based on symposia presented at the 2014 IBNS meeting. Topics discussed at the annual IBNS meeting ranged from investigations of the neural mechanisms underlying bipolar disorder, schizophrenia, depression, traumatic brain injury, and risk-taking behavior, to behavioral consequences of obesity and immune dysfunction. Novel treatment areas are covered such as the use of deep brain stimulation, as well as investigation of the behavioral impacts of nicotine withdrawal and how this research will influence the development of nicotine cessation treatments. Hence, this special issue covers a wide-range of topics in behavioral neuroscience offering an insight into the challenges faced by researchers in this decade of the brain. Copyright © 2015 Elsevier Ltd. All rights reserved.

The microbiota-gut-brain axis as a key regulator of neural function and the stress response: Implications for human and animal health.

PubMed

Wiley, N C; Dinan, T G; Ross, R P; Stanton, C; Clarke, G; Cryan, J F

2017-07-01

The brain-gut-microbiota axis comprises an extensive communication network between the brain, the gut, and the microbiota residing there. Development of a diverse gut microbiota is vital for multiple features of behavior and physiology, as well as many fundamental aspects of brain structure and function. Appropriate early-life assembly of the gut microbiota is also believed to play a role in subsequent emotional and cognitive development. If the composition, diversity, or assembly of the gut microbiota is impaired, this impairment can have a negative impact on host health and lead to disorders such as obesity, diabetes, inflammatory diseases, and even potentially neuropsychiatric illnesses, including anxiety and depression. Therefore, much research effort in recent years has focused on understanding the potential of targeting the intestinal microbiota to prevent and treat such disorders. This review aims to explore the influence of the gut microbiota on host neural function and behavior, particularly those of relevance to stress-related disorders. The involvement of microbiota in diverse neural functions such as myelination, microglia function, neuronal morphology, and blood-brain barrier integrity across the life span, from early life to adolescence to old age, will also be discussed. Nurturing an optimal gut microbiome may also prove beneficial in animal science as a means to manage stressful situations and to increase productivity of farm animals. The implications of these observations are manifold, and researchers are hopeful that this promising body of preclinical work can be successfully translated to the clinic and beyond.

Helping Children with Sensory Processing Disorders: The Role of Occupational Therapy

ERIC Educational Resources Information Center

Sweet, Margarita

2010-01-01

Normally functioning sensory systems develop through sensory experiences. Children are stimulated through their senses in many different ways. Even though a person's sensory system is intact, he or she may have a sensory processing disorder (SPD), also known as sensory integration dysfunction. This means the person's brain does not correctly…

A Neurophysiological Marker of Impaired Preparation in an 11-Year Follow-Up Study of Attention-Deficit/Hyperactivity Disorder (ADHD)

ERIC Educational Resources Information Center

Doehnert, Mirko; Brandeis, Daniel; Schneider, Gudrun; Drechsler, Renate; Steinhausen, Hans-Christoph

2013-01-01

Background: This longitudinal electrophysiological study investigated the course of multiple impaired cognitive brain functions in attention-deficit/hyperactivity disorder (ADHD) from childhood to adulthood by comparing developmental trajectories of individuals with ADHD and typically developing controls. Methods: Subjects with ADHD ("N"…

Emerging therapeutics in sleep.

PubMed

Saper, Clifford B; Scammell, Thomas E

2013-09-01

The development of new therapeutics for sleep disorders is increasingly dependent upon understanding the basic brain circuitry that underlies sleep-wake regulation, and how it may be pharmacologically manipulated. In this review, we consider the pathophysiological basis of major sleep disorders that often are seen by neurologists, including excessive daytime sleepiness, insomnia, narcolepsy, rapid eye movement sleep behavior disorder, and restless legs syndrome, as well as circadian disorders, and we review the current and potential future therapeutic approaches. Copyright © 2013 American Neurological Association.

Early alterations of social brain networks in young children with autism

PubMed Central

Kojovic, Nada; Rihs, Tonia Anahi; Jan, Reem Kais; Franchini, Martina; Plomp, Gijs; Vulliemoz, Serge; Eliez, Stephan; Michel, Christoph Martin; Schaer, Marie

2018-01-01

Social impairments are a hallmark of Autism Spectrum Disorders (ASD), but empirical evidence for early brain network alterations in response to social stimuli is scant in ASD. We recorded the gaze patterns and brain activity of toddlers with ASD and their typically developing peers while they explored dynamic social scenes. Directed functional connectivity analyses based on electrical source imaging revealed frequency specific network atypicalities in the theta and alpha frequency bands, manifesting as alterations in both the driving and the connections from key nodes of the social brain associated with autism. Analyses of brain-behavioural relationships within the ASD group suggested that compensatory mechanisms from dorsomedial frontal, inferior temporal and insular cortical regions were associated with less atypical gaze patterns and lower clinical impairment. Our results provide strong evidence that directed functional connectivity alterations of social brain networks is a core component of atypical brain development at early stages of ASD. PMID:29482718

Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?

PubMed

Washington, Patricia M; Villapol, Sonia; Burns, Mark P

2016-01-01

Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer's disease (AD), while repeat mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position-examining epidemiological and case control human studies, neuropathological evidence, and preclinical data. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson's disease. Further, human post-mortem studies on both single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a 'polypathology'. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI is viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI. Copyright © 2015 Elsevier Inc. All rights reserved.

The development of psychotic disorders in adolescence: a potential role for hormones.

PubMed

Trotman, Hanan D; Holtzman, Carrie W; Ryan, Arthur T; Shapiro, Daniel I; MacDonald, Allison N; Goulding, Sandra M; Brasfield, Joy L; Walker, Elaine F

2013-07-01

This article is part of a Special Issue "Puberty and Adolescence". The notion that adolescence is characterized by dramatic changes in behavior, and often by emotional upheaval, is widespread and longstanding in popular western culture. In recent decades, this notion has gained increasing support from empirical research showing that the peri- and post-pubertal developmental stages are associated with a significant rise in the rate of psychiatric symptoms and syndromes. As a result, interest in adolescent development has burgeoned among researchers focused on the origins of schizophrenia and other psychotic disorders. Two factors have fueled this trend: 1) increasing evidence from longitudinal research that adolescence is the modal period for the emergence of "prodromal" manifestations, or precursors of psychotic symptoms, and 2) the rapidly accumulating scientific findings on brain structural and functional changes occurring during adolescence and young adulthood. Further, gonadal and adrenal hormones are beginning to play a more prominent role in conceptualizations of adolescent brain development, as well as in the origins of psychiatric symptoms during this period (Walker and Bollini, 2002; Walker et al., 2008). In this paper, we begin by providing an overview of the nature and course of psychotic disorders during adolescence/young adulthood. We then turn to the role of hormones in modulating normal brain development, and the potential role they might play in the abnormal brain changes that characterize youth at clinical high-risk (CHR) for psychosis. The activational and organizational effects of hormones are explored, with a focus on how hormone-induced changes might be linked with neuropathological processes in the emergence of psychosis. Copyright © 2013 Elsevier Inc. All rights reserved.

Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should it be classified together as traumatic encephalopathy?

PubMed Central

Washington, Patricia M.; Villapol, Sonia; Burns, Mark P.

2015-01-01

Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer’s disease (AD), while mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position—examining epidemiological and case-control human studies, neuropathological evidence, and preclinical studies. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson’s disease. Further, human post-mortem studies on either single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a ‘polypathology’. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI are viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI. PMID:26091850

[Voxel-Based Morphometry in Autism Spectrum Disorder].

PubMed

Yamasue, Hidenori

2017-05-01

Autism spectrum disorder shows deficits in social communication and interaction including nonverbal communicative behaviors (e.g., eye contact, gestures, voice prosody, and facial expressions) and restricted and repetitive behaviors as its core symptoms. These core symptoms are emerged as an atypical behavioral development in toddlers with the disorder. Atypical neural development is considered to be a neural underpinning of such behaviorally atypical development. A number of studies using voxel-based morphometry have already been conducted to compare regional brain volumes between individuals with autism spectrum disorder and those with typical development. Furthermore, more than ten papers employing meta-analyses of the comparisons using voxel based morphometry between individuals with autism spectrum disorder and those with typical development have already been published. The current review paper adds some brief discussions about potential factors contributing to the inconsistency observed in the previous findings such as difficulty in controlling the confounding effects of different developmental phases among study participants.

Rett syndrome and MeCP2.

PubMed

Liyanage, Vichithra R B; Rastegar, Mojgan

2014-06-01

Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.

Delayed Maturation in Brain Electrical Activity Partially Explains the Association Between Early Environmental Deprivation and Symptoms of Attention-Deficit/Hyperactivity Disorder

PubMed Central

McLaughlin, Katie A.; Fox, Nathan A.; Zeanah, Charles H.; Sheridan, Margaret A.; Marshall, Peter; Nelson, Charles A.

2010-01-01

Background Children raised in institutional settings are exposed to social and environmental circumstances that may deprive them of expected environmental inputs during sensitive periods of brain development that are necessary to foster healthy development. This deprivation is thought to underlie the abnormalities in neurodevelopment that have been found in previously institutionalized children. It is unknown whether deviations in neurodevelopment explain the high rates of developmental problems evident in previously institutionalized children, including psychiatric disorders. Methods We present data from a sample of children raised in institutions in Bucharest, Romania (n = 117) and an age- and sex-matched sample of community control subjects (n = 49). Electroencephalogram data were acquired following entry into the study at age 6 to 30 months, and a structured diagnostic interview of psychiatric disorders was completed at age 54 months. Results Children reared in institutions evidenced greater symptoms of attention-deficit/hyperactivity disorder, anxiety, depression, and disruptive behavior disorders than community controls. Electroencephalogram revealed significant reductions in alpha relative power and increases in theta relative power among children reared in institutions in frontal, temporal, and occipital regions, suggesting a delay in cortical maturation. This pattern of brain activity predicted symptoms of hyperactivity and impulsivity at age 54 months, and significantly mediated the association between institutionalization and attention-deficit/hyperactivity disorder symptoms. Electroencephalogram power was unrelated to depression, anxiety, or disruptive behaviors. Conclusions These findings document a potential neurodevelopmental mechanism underlying the association between institutionalization and psychiatric morbidity. Deprivation in social and environmental conditions may perturb early patterns of neurodevelopment and manifest as psychiatric problems later in life. PMID:20497899

Neuroimaging the neural correlates of increased risk for substance use disorders in attention-deficit/hyperactivity disorder-A systematic review.

PubMed

Adisetiyo, Vitria; Gray, Kevin M

2017-03-01

Children with attention-deficit/hyperactivity disorder (ADHD) are nearly three times more likely to develop substance use disorders (SUD) than their typically developing peers. Our objective was to review the existing neuroimaging research on high-risk ADHD (ie, ADHD with disruptive behavior disorders, familial SUD and/or early substance use), focusing on impulsivity as one possible mechanism underlying SUD risk. A PubMed literature search was conducted using combinations of the keywords "ADHD," "substance use," "substance use disorder," "SUD," "addiction," "dependence," "abuse," "risk," "brain" "MRI," "imaging" and "neuroimaging." Studies had to include cohorts that met diagnostic criteria for ADHD; studies of individuals with ADHD who all met criteria for SUD were excluded. Eight studies met the search criteria. Individuals with high-risk ADHD have hyperactivation in the motivation-reward processing brain network during tasks of impulsive choice, emotion processing, and risky decision-making. During response inhibition tasks, they have hypoactivation in the inhibitory control brain network. However, studies focusing on this latter circuit found hypoactivation during inhibitory control tasks, decreased white matter microstructure coherence and reduced cortical thickness in ADHD independent of substance use history. An exaggerated imbalance between the inhibitory control network and the motivation-reward processing network is theorized to distinguish individuals with high-risk ADHD. Preliminary findings suggest that an exaggerated aberrant reward processing network may be the driving neural correlate of increased SUD risk in ADHD. Neural biomarkers of increased SUD risk in ADHD could help clinicians identify which patients may benefit most from SUD prevention. Thus, more neuroimaging research on this vulnerable population is needed. (Am J Addict 2017;26:99-111). © 2017 American Academy of Addiction Psychiatry.

fMRI brain activation in patients with insomnia disorder during a working memory task.

PubMed

Son, Young-Don; Kang, Jae Myeong; Cho, Seong-Jin; Lee, Jung-Sun; Hwang, Hee Young; Kang, Seung-Gul

2018-05-01

This study used functional magnetic resonance imaging (fMRI) to investigate differences in the functional brain activation of patients with insomnia disorder (n = 21, mean age = 36.6) and of good sleepers (n = 26, mean age = 33.2) without other comorbidities or structural brain abnormalities during a working memory task. All participants completed a clinical questionnaire, were subjected to portable polysomnography (PSG), and performed the working memory task during an fMRI scan. The subjects who were suspected of major sleep disorder and comorbid psychiatric disorders except insomnia disorder were excluded. To compare the brain activation on working memory from the insomnia group with those from the good-sleeper group, a two-sample t test was performed. Statistical significance was determined using 3DClustSim with the updated algorithm to obtain a reasonable cluster size and p value for each analysis. We observed higher levels of brain activation in the right lateral inferior frontal cortex and the right superior temporal pole in the insomnia group compared to good sleepers (cluster-based multiple comparison correction, p < 0.001, k = 34 @ α = 0.01). Thus, patients with insomnia disorder showed increased brain activation during working memory relative to good sleepers, and this may be indicative of compensatory brain activation to maintain cognitive performance in patients with insomnia disorder without other comorbidities.

Role of ghrelin in the pathophysiology of eating disorders: implications for pharmacotherapy.

PubMed

Cardona Cano, Sebastian; Merkestein, Myrte; Skibicka, Karolina P; Dickson, Suzanne L; Adan, Roger A H

2012-04-01

Ghrelin is the only known circulating orexigenic hormone. It increases food intake by interacting with hypothalamic and brainstem circuits involved in energy balance, as well as reward-related brain areas. A heightened gut-brain ghrelin axis is an emerging feature of certain eating disorders such as anorexia nervosa and Prader-Willi syndrome. In common obesity, ghrelin levels are lowered, whereas post-meal ghrelin levels remain higher than in lean individuals. Agents that interfere with ghrelin signalling have therapeutic potential for eating disorders, including obesity. However, most of these drugs are only in the preclinical phase of development. Data obtained so far suggest that ghrelin agonists may have potential in the treatment of anorexia nervosa, while ghrelin antagonists seem promising for other eating disorders such as obesity and Prader-Willi syndrome. However, large clinical trials are needed to evaluate the efficacy and safety of these drugs.

Individual differences in the neuropsychopathology of addiction

PubMed Central

George, Olivier; Koob, George F.

2017-01-01

Drug addiction or substance-use disorder is a chronically relapsing disorder that progresses through binge/intoxication, withdrawal/negative affect and preoccupation/anticipation stages. These stages represent diverse neurobiological mechanisms that are differentially involved in the transition from recreational to compulsive drug use and from positive to negative reinforcement. The progression from recreational to compulsive substance use is associated with downregulation of the brain reward systems and upregulation of the brain stress systems. Individual differences in the neurobiological systems that underlie the processing of reward, incentive salience, habits, stress, pain, and executive function may explain (i) the vulnerability to substance-use disorder; (ii) the diversity of emotional, motivational, and cognitive profiles of individuals with substance-use disorders; and (iii) heterogeneous responses to cognitive and pharmacological treatments. Characterization of the neuropsychological mechanisms that underlie individual differences in addiction-like behaviors is the key to understanding the mechanisms of addiction and development of personalized pharmacotherapy. PMID:29302219

Offspring neuroimmune consequences of maternal malnutrition: Potential mechanism for behavioral impairments that underlie metabolic and neurodevelopmental disorders.

PubMed

Smith, B L; Reyes, T M

2017-10-01

Maternal malnutrition significantly increases offspring risk for both metabolic and neurodevelopmental disorders. Animal models of maternal malnutrition have identified behavioral changes in the adult offspring related to executive function and reward processing. Together, these changes in executive and reward-based behaviors likely contribute to the etiology of both metabolic and neurodevelopmental disorders associated with maternal malnutrition. Concomitant with the behavioral effects, maternal malnutrition alters offspring expression of reward-related molecules and inflammatory signals in brain pathways that control executive function and reward. Neuroimmune pathways and microglial interactions in these specific brain circuits, either in early development or later in adulthood, could directly contribute to the maternal malnutrition-induced behavioral phenotypes. Understanding these mechanisms will help advance treatment strategies for metabolic and neurodevelopmental disorders, especially noninvasive dietary supplementation interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of Ethanol on Brain Extracellular Matrix: Implications for Alcohol Use Disorder

PubMed Central

Lasek, Amy W.

2016-01-01

The brain extracellular matrix (ECM) occupies the space between cells and is involved in cell-matrix and cell-cell adhesion. However, in addition to providing structural support to brain tissue, the ECM activates cell signaling and controls synaptic transmission. The expression and activity of brain ECM components are regulated by alcohol exposure. This review will discuss what is currently known about the effects of alcohol on the activity and expression of brain ECM components. An interpretation of how these changes might promote alcohol use disorder (AUD) will be also provided. Ethanol exposure decreases levels of structural proteins involved in the interstitial matrix and basement membrane, with a concomitant increase in proteolytic enzymes that degrade these components. In contrast, ethanol exposure generally increases perineuronal net (PN) components. Because the ECM has been shown to regulate both synaptic plasticity and behavioral responses to drugs of abuse, regulation of the brain ECM by alcohol may be relevant to the development of alcoholism. Although investigation of the function of brain ECM in alcohol abuse is still in early stages, a greater understanding of the interplay between ECM and alcohol might lead to novel therapeutic strategies for treating AUD. PMID:27581478

Increased gray-matter volume in medication-naive high-functioning children with autism spectrum disorder.

PubMed

Palmen, Saskia J M C; Hulshoff Pol, Hilleke E; Kemner, Chantal; Schnack, Hugo G; Durston, Sarah; Lahuis, Bertine E; Kahn, René S; Van Engeland, Herman

2005-04-01

To establish whether high-functioning children with autism spectrum disorder (ASD) have enlarged brains in later childhood, and if so, whether this enlargement is confined to the gray and/or to the white matter and whether it is global or more prominent in specific brain regions. Brain MRI scans were acquired from 21 medication-naive, high-functioning children with ASD between 7 and 15 years of age and 21 comparison subjects matched for gender, age, IQ, height, weight, handedness, and parental education, but not pubertal status. Patients showed a significant increase of 6% in intracranium, total brain, cerebral gray matter, cerebellum, and of more than 40% in lateral and third ventricles compared to controls. The cortical gray-matter volume was evenly affected in all lobes. After correction for brain volume, ventricular volumes remained significantly larger in patients. High-functioning children with ASD showed a global increase in gray-matter, but not white-matter and cerebellar volume, proportional to the increase in brain volume, and a disproportional increase in ventricular volumes, still present after correction for brain volume. Advanced pubertal development in the patients compared to the age-matched controls may have contributed to the findings reported in the present study.

Neuroinflammation in Autism: Plausible Role of Maternal Inflammation, Dietary Omega 3, and Microbiota

PubMed Central

Madore, Charlotte; Leyrolle, Quentin; Lacabanne, Chloé; Benmamar-Badel, Anouk; Joffre, Corinne; Nadjar, Agnes

2016-01-01

Several genetic causes of autism spectrum disorder (ASD) have been identified. However, more recent work has highlighted that certain environmental exposures early in life may also account for some cases of autism. Environmental insults during pregnancy, such as infection or malnutrition, seem to dramatically impact brain development. Maternal viral or bacterial infections have been characterized as disruptors of brain shaping, even if their underlying mechanisms are not yet fully understood. Poor nutritional diversity, as well as nutrient deficiency, is strongly associated with neurodevelopmental disorders in children. For instance, imbalanced levels of essential fatty acids, and especially polyunsaturated fatty acids (PUFAs), are observed in patients with ASD and other neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder (ADHD) and schizophrenia). Interestingly, PUFAs, and specifically n-3 PUFAs, are powerful immunomodulators that exert anti-inflammatory properties. These prenatal dietary and immunologic factors not only impact the fetal brain, but also affect the microbiota. Recent work suggests that the microbiota could be the missing link between environmental insults in prenatal life and future neurodevelopmental disorders. As both nutrition and inflammation can massively affect the microbiota, we discuss here how understanding the crosstalk between these three actors could provide a promising framework to better elucidate ASD etiology. PMID:27840741

Stress and the Microbiota-Gut-Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome.

PubMed

Moloney, Rachel D; Johnson, Anthony C; O'Mahony, Siobhain M; Dinan, Timothy G; Greenwood-Van Meerveld, Beverley; Cryan, John F

2016-02-01

Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut-brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gut-brain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain. © 2015 John Wiley & Sons Ltd.

Gamma knife radiosurgery in movement disorders: Indications and limitations.

PubMed

Higuchi, Yoshinori; Matsuda, Shinji; Serizawa, Toru

2017-01-01

Functional radiosurgery has advanced steadily during the past half century since the development of the gamma knife technique for treating intractable cancer pain. Applications of radiosurgery for intracranial diseases have increased with a focus on understanding radiobiology. Currently, the use of gamma knife radiosurgery to ablate deep brain structures is not widespread because visualization of the functional targets remains difficult despite the increased availability of advanced neuroimaging technology. Moreover, most existing reports have a small sample size or are retrospective. However, increased experience with intraoperative neurophysiological evaluations in radiofrequency thalamotomy and deep brain stimulation supports anatomical and neurophysiological approaches to the ventralis intermedius nucleus. Two recent prospective studies have promoted the clinical application of functional radiosurgery for movement disorders. For example, unilateral gamma knife thalamotomy is a potential alternative to radiofrequency thalamotomy and deep brain stimulation techniques for intractable tremor patients with contraindications for surgery. Despite the promising efficacy of gamma knife thalamotomy, however, these studies did not include sufficient follow-up to confirm long-term effects. Herein, we review the radiobiology literature, various techniques, and the treatment efficacy of gamma knife radiosurgery for patients with movement disorders. Future research should focus on randomized controlled studies and long-term effects. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms

PubMed Central

Levi, Sonia; Finazzi, Dario

2014-01-01

Perturbation of iron distribution is observed in many neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease, but the comprehension of the metal role in the development and progression of such disorders is still very limited. The combination of more powerful brain imaging techniques and faster genomic DNA sequencing procedures has allowed the description of a set of genetic disorders characterized by a constant and often early accumulation of iron in specific brain regions and the identification of the associated genes; these disorders are now collectively included in the category of neurodegeneration with brain iron accumulation (NBIA). So far 10 different genetic forms have been described but this number is likely to increase in short time. Two forms are linked to mutations in genes directly involved in iron metabolism: neuroferritinopathy, associated to mutations in the FTL gene and aceruloplasminemia, where the ceruloplasmin gene product is defective. In the other forms the connection with iron metabolism is not evident at all and the genetic data let infer the involvement of other pathways: Pank2, Pla2G6, C19orf12, COASY, and FA2H genes seem to be related to lipid metabolism and to mitochondria functioning, WDR45 and ATP13A2 genes are implicated in lysosomal and autophagosome activity, while the C2orf37 gene encodes a nucleolar protein of unknown function. There is much hope in the scientific community that the study of the NBIA forms may provide important insight as to the link between brain iron metabolism and neurodegenerative mechanisms and eventually pave the way for new therapeutic avenues also for the more common neurodegenerative disorders. In this work, we will review the most recent findings in the molecular mechanisms underlining the most common forms of NBIA and analyze their possible link with brain iron metabolism. PMID:24847269

The Geriatric Population and Psychiatric Medication

PubMed Central

Varma, Sannidhya; Sareen, Himanshu; Trivedi, J.K.

2010-01-01

With improvement in medical services in the last few years, there has been a constant rise in the geriatric population throughout the world, more so in the developing countries. The elderly are highly prone to develop psychiatric disorders, probably because of age related changes in the brain, concomitant physical disorders, as well as increased stress in later life. Psychiatric disorders in this population may have a different presentation than in other groups and some of psychopathologies might be mistaken for normal age related changes by an unwary clinician. Therefore the need of the day is to train psychiatrists and physicians to better recognize and manage mental disorders in this age group. PMID:21327169

Neuroimaging Endophenotypes in Autism Spectrum Disorder

PubMed Central

Mahajan, Rajneesh; Mostofsky, Stewart H.

2015-01-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has a strong genetic basis, and is heterogeneous in its etiopathogenesis and clinical presentation. Neuroimaging studies, in concert with neuropathological and clinical research, have been instrumental in delineating trajectories of development in children with ASD. Structural neuroimaging has revealed ASD to be a disorder with general and regional brain enlargement, especially in the frontotemporal cortices, while functional neuroimaging studies have highlighted diminished connectivity, especially between frontal-posterior regions. The diverse and specific neuroimaging findings may represent potential neuroendophenotypes, and may offer opportunities to further understand the etiopathogenesis of ASD, predict treatment response and lead to the development of new therapies. PMID:26234701

Neurobiology of dynamic psychotherapy: an integration possible?

PubMed

Mundo, Emanuela

2006-01-01

In the last decades, Kandel's innovative experiments have demonstrated that brain structures and synaptic connections are dynamic. Synapses can be modified by a wide variety of environmental factors, including learning and memory processes. The hypothesis that dynamic psychotherapy process involves memory and learning processes has opened the possibility of a dialogue between neuroscience and psychoanalysis and related psychotherapy techniques. The primary aim of the present article is to critically review the more recent data on neurobiological effects of dynamic psychotherapy in psychiatric disorders. Relevant literature has been selected using the databases currently available online (i.e., PubMed). The literature search has been limited to the past 10 years and to genetic, molecular biology, and neuroimaging studies that have addressed the issue of changes induced by psychotherapy. Most of the genetic studies on mental disorders have demonstrated that psychiatric conditions result from a complex interaction of genetic susceptibility and environmental effects. For none of the many psychiatric conditions investigated has a purely genetic background been found. Molecular biology studies have indicated that gene expression is influenced by several environmental factors, including early experiences, traumas, learning, and memory processes. Neuroimaging studies (using fMRI and PET) have found that not only cognitive but also dynamic psychotherapy has measurable effects on the brain. In addition, psychotherapy may modify brain function and metabolism in specific brain areas. Most of these studies have considered patients with major depressive disorders and compared the effects of psychotherapy with the effect of standard pharmacotherapy. In conclusion, recent results from neuroscience studies have suggested that dynamic psychotherapy has a significant impact on brain function and metabolism in specific brain areas. The possible applications and developments of this new area of research toward the conceptualization of an integrative approach to treatment of psychiatric disorders are discussed.

Swallowing Disorders

MedlinePlus

... most common cause of dysphagia); traumatic brain injury; cerebral palsy; Parkinson disease and other degenerative neurological disorders such ... most common cause of dysphagia); traumatic brain injury; cerebral palsy; Parkinson disease and other degenerative neurological disorders such ...

Large-Scale Brain Systems in ADHD: Beyond the Prefrontal-Striatal Model

PubMed Central

Castellanos, F. Xavier; Proal, Erika

2012-01-01

Attention-deficit/hyperactivity disorder (ADHD) has long been thought to reflect dysfunction of prefrontal-striatal circuitry, with involvement of other circuits largely ignored. Recent advances in systems neuroscience-based approaches to brain dysfunction enable the development of models of ADHD pathophysiology that encompass a number of different large-scale “resting state” networks. Here we review progress in delineating large-scale neural systems and illustrate their relevance to ADHD. We relate frontoparietal, dorsal attentional, motor, visual, and default networks to the ADHD functional and structural literature. Insights emerging from mapping intrinsic brain connectivity networks provide a potentially mechanistic framework for understanding aspects of ADHD, such as neuropsychological and behavioral inconsistency, and the possible role of primary visual cortex in attentional dysfunction in the disorder. PMID:22169776

Progress in mind: focus on alcohol use disorders, an elsevier resource centre.

PubMed

Nutt, D J; Rehm, J; van den Brink, W; Gorwood, P; Buchsbaum, M S

2015-04-30

Harmful use of alcohol is one of the top five risks for burden of disease globally and in Europe; in 2012, 3.3 million net deaths (approximately 6% of all global deaths) were attributable to this risk factor. It is also linked to the development of a wide spectrum of alcohol use disorders, ranging from mild manifestations to a severe disease known as alcohol dependence. Alcohol dependence is a progressive, chronic, and relapsing brain disease resulting from the prolonged effects of alcohol on the brain. Alcohol dependence imposes a significant societal burden, with indirect societal costs reaching up to 0.64% of European countries׳ annual gross domestic product. With these facts in mind, it is important to recognize and manage alcohol dependence. Although the biological mechanisms behind the development of alcohol dependence are not fully known, factors that have been shown to influence its development include genetic predisposition, psychological problems, and social interactions. Alcohol use has also been linked to the development of hypertension, liver cirrhosis, chronic pancreatitis, multiple types of cancer, and psychiatric comorbidities such as depression and anxiety disorders. With such severe effects on both individuals and society, it is important to recognize the characteristic signs and symptoms of alcohol dependence and explore new ways to better manage patients with this brain disease. Effective treatment approaches for alcohol dependence include biological, behavioral, and social components addressing the multiple aspects of this disease. Comprehensive, educational platforms in which to explore the many facets of this disease such as the Progress in Mind: Focus on Alcohol Use Disorders Resource Centre, will provide clinicians with the tools necessary for recognizing patients with alcohol dependence and managing their disease along with related comorbidities. Online Access: http://progressinmind.elsevierresource.com. Copyright © 2015. Published by Elsevier Ireland Ltd.

Developmental dyscalculia.

PubMed

Kucian, Karin; von Aster, Michael

2015-01-01

Numerical skills are essential in our everyday life, and impairments in the development of number processing and calculation have a negative impact on schooling and professional careers. Approximately 3 to 6 % of children are affected from specific disorders of numerical understanding (developmental dyscalculia (DD)). Impaired development of number processing skills in these children is characterized by problems in various aspects of numeracy as well as alterations of brain activation and brain structure. Moreover, DD is assumed to be a very heterogeneous disorder putting special challenges to define homogeneous diagnostic criteria. Finally, interdisciplinary perspectives from psychology, neuroscience and education can contribute to the design for interventions, and although results are still sparse, they are promising and have shown positive effects on behaviour as well as brain function. In the current review, we are going to give an overview about typical and atypical development of numerical abilities at the behavioural and neuronal level. Furthermore, current status and obstacles in the definition and diagnostics of DD are discussed, and finally, relevant points that should be considered to make an intervention as successful as possible are summarized.

Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity.

PubMed

Witteveen, Josefine S; Willemsen, Marjolein H; Dombroski, Thaís C D; van Bakel, Nick H M; Nillesen, Willy M; van Hulten, Josephus A; Jansen, Eric J R; Verkaik, Dave; Veenstra-Knol, Hermine E; van Ravenswaaij-Arts, Conny M A; Wassink-Ruiter, Jolien S Klein; Vincent, Marie; David, Albert; Le Caignec, Cedric; Schieving, Jolanda; Gilissen, Christian; Foulds, Nicola; Rump, Patrick; Strom, Tim; Cremer, Kirsten; Zink, Alexander M; Engels, Hartmut; de Munnik, Sonja A; Visser, Jasper E; Brunner, Han G; Martens, Gerard J M; Pfundt, Rolph; Kleefstra, Tjitske; Kolk, Sharon M

2016-08-01

Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.

Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease.

PubMed

Ashbrook, David G; Williams, Robert W; Lu, Lu; Stein, Jason L; Hibar, Derrek P; Nichols, Thomas E; Medland, Sarah E; Thompson, Paul M; Hager, Reinmar

2014-10-03

Variation in hippocampal volume has been linked to significant differences in memory, behavior, and cognition among individuals. To identify genetic variants underlying such differences and associated disease phenotypes, multinational consortia such as ENIGMA have used large magnetic resonance imaging (MRI) data sets in human GWAS studies. In addition, mapping studies in mouse model systems have identified genetic variants for brain structure variation with great power. A key challenge is to understand how genetically based differences in brain structure lead to the propensity to develop specific neurological disorders. We combine the largest human GWAS of brain structure with the largest mammalian model system, the BXD recombinant inbred mouse population, to identify novel genetic targets influencing brain structure variation that are linked to increased risk for neurological disorders. We first use a novel cross-species, comparative analysis using mouse and human genetic data to identify a candidate gene, MGST3, associated with adult hippocampus size in both systems. We then establish the coregulation and function of this gene in a comprehensive systems-analysis. We find that MGST3 is associated with hippocampus size and is linked to a group of neurodegenerative disorders, such as Alzheimer's.

Alterations in Sociability and Functional Brain Connectivity Caused by Early-Life Seizures is Reversed by Bumetanide

PubMed Central

Holmes, Gregory L.; Tian, Chengju; Hernan, Amanda E.; Flynn, Sean; Camp, Devon; Barry, Jeremy

2015-01-01

There is a well-described association between infantile epilepsy and pervasive cognitive and behavioral deficits, including a high incidence of autism spectrum disorders. Despite the robustness of the relationship between early-life seizures and the development of autism, the pathophysiological mechanism by which this occurs has not been explored. As a result of increasing evidence that autism is a disorder of brain connectivity we hypothesized that early-life seizures would interrupt normal brain connectivity during brain maturation and result in an autistic phenotype. Normal rat pups underwent recurrent flurothyl-induced seizures from postnatal (P) day 5-14 and then tested, along with controls, for developmental alterations of development brain oscillatory activity from P18-25. Specifically we wished to understand how normal changes in rhythmicity in and between brain regions change as a function of age and if this rhythmicity is altered or interrupted by early life seizures. In rat pups with early-life seizures, field recordings from dorsal and ventral hippocampus and prefrontal cortex demonstrated marked increase in coherence as well as a decrease in voltage correlation at all bandwidths compared to controls while there were minimal differences in total power and relative power spectral densities. Rats with early-life seizures had resulting impairment in the sociability and social novelty tests but demonstrated no evidence of increased activity or generalized anxiety as measured in the open field. In addition, rats with early-life seizures had lower seizure thresholds than controls, indicating long-standing alterations in the excitatory/inhibition balance. Bumetanide, a pharmacological agent that blocks the activity of NKCC1 and induces a significant shift of ECl toward more hyperpolarized values, administration at the time of the seizures precluded the subsequent abnormalities in coherence and voltage correlation and resulted in normal sociability and seizure threshold. Taken together these findings indicate that early-life seizures alter the development of oscillations and result in autistic-like behaviors. The altered communication between these brain regions could reflect the physiological underpinnings underlying social cognitive deficits seen in autism spectrum disorders. PMID:25766676

Childhood adversity is linked to differential brain volumes in adolescents with alcohol use disorder: a voxel-based morphometry study.

PubMed

Brooks, Samantha J; Dalvie, Shareefa; Cuzen, Natalie L; Cardenas, Valerie; Fein, George; Stein, Dan J

2014-06-01

Previous neuroimaging studies link both alcohol use disorder (AUD) and early adversity to neurobiological differences in the adult brain. However, the association between AUD and childhood adversity and effects on the developing adolescent brain are less clear, due in part to the confound of psychiatric comorbidity. Here we examine early life adversity and its association with brain volume in a unique sample of 116 South African adolescents (aged 12-16) with AUD but without psychiatric comorbidity. Participants were 58 adolescents with DSM-IV alcohol dependence and with no other psychiatric comorbidities, and 58 age-, gender- and protocol-matched light/non-drinking controls (HC). Assessments included the Childhood Trauma Questionnaire (CTQ). MR images were acquired on a 3T Siemens Magnetom Allegra scanner. Volumes of global and regional structures were estimated using SPM8 Voxel Based Morphometry (VBM), with analysis of covariance (ANCOVA) and regression analyses. In whole brain ANCOVA analyses, a main effect of group when examining the AUD effect after covarying out CTQ was observed on brain volume in bilateral superior temporal gyrus. Subsequent regression analyses to examine how childhood trauma scores are linked to brain volumes in the total cohort revealed a negative correlation in the left hippocampus and right precentral gyrus. Furthermore, bilateral (but most significantly left) hippocampal volume was negatively associated with sub-scores on the CTQ in the total cohort. These findings support our view that some alterations found in brain volumes in studies of adolescent AUD may reflect the impact of confounding factors such as psychiatric comorbidity rather than the effects of alcohol per se. In particular, early life adversity may influence the developing adolescent brain in specific brain regions, such as the hippocampus.

Microtubule-Actin Crosslinking Factor 1 Is Required for Dendritic Arborization and Axon Outgrowth in the Developing Brain.

PubMed

Ka, Minhan; Kim, Woo-Yang

2016-11-01

Dendritic arborization and axon outgrowth are critical steps in the establishment of neural connectivity in the developing brain. Changes in the connectivity underlie cognitive dysfunction in neurodevelopmental disorders. However, molecules and associated mechanisms that play important roles in dendritic and axon outgrowth in the brain are only partially understood. Here, we show that microtubule-actin crosslinking factor 1 (MACF1) regulates dendritic arborization and axon outgrowth of developing pyramidal neurons by arranging cytoskeleton components and mediating GSK-3 signaling. MACF1 deletion using conditional mutant mice and in utero gene transfer in the developing brain markedly decreased dendritic branching of cortical and hippocampal pyramidal neurons. MACF1-deficient neurons showed reduced density and aberrant morphology of dendritic spines. Also, loss of MACF1 impaired the elongation of callosal axons in the brain. Actin and microtubule arrangement appeared abnormal in MACF1-deficient neurites. Finally, we found that GSK-3 is associated with MACF1-controlled dendritic differentiation. Our findings demonstrate a novel role for MACF1 in neurite differentiation that is critical to the creation of neuronal connectivity in the developing brain.

Brain connectivity and psychiatric comorbidity in adolescents with Internet gaming disorder.

PubMed

Han, Doug Hyun; Kim, Sun Mi; Bae, Sujin; Renshaw, Perry F; Anderson, Jeffrey S

2017-05-01

Prolonged Internet video game play may have multiple and complex effects on human cognition and brain development in both negative and positive ways. There is not currently a consensus on the principle effects of video game play neither on brain development nor on the relationship to psychiatric comorbidity. In this study, 78 adolescents with Internet gaming disorder (IGD) and 73 comparison subjects without IGD, including subgroups with no other psychiatric comorbid disease, with major depressive disorder and with attention deficit hyperactivity disorder (ADHD), were included in a 3 T resting state functional magnetic resonance imaging analysis. The severity of Internet gaming disorder, depression, anxiety and ADHD symptoms were assessed with the Young Internet Addiction Scale, the Beck Depression Inventory, the Beck Anxiety Inventory and the Korean ADHD rating scales, respectively. Patients with IGD showed an increased functional correlation between seven pairs of regions, all satisfying q < 0.05 False discovery rates in light of multiple statistical tests: left frontal eye field to dorsal anterior cingulate, left frontal eye field to right anterior insula, left dorsolateral prefrontal cortex (DLPFC) to left temporoparietal junction (TPJ), right DLPFC to right TPJ, right auditory cortex to right motor cortex, right auditory cortex to supplementary motor area and right auditory cortex to dorsal anterior cingulate. These findings may represent a training effect of extended game play and suggest a risk or predisposition in game players for over-connectivity of the default mode and executive control networks that may relate to psychiatric comorbidity. © 2015 Society for the Study of Addiction.

Developing a clinical translational neuroscience taxonomy for anxiety and mood disorder: protocol for the baseline-follow up Research domain criteria Anxiety and Depression ("RAD") project.

PubMed

Williams, Leanne M; Goldstein-Piekarski, Andrea N; Chowdhry, Nowreen; Grisanzio, Katherine A; Haug, Nancy A; Samara, Zoe; Etkin, Amit; O'Hara, Ruth; Schatzberg, Alan F; Suppes, Trisha; Yesavage, Jerome

2016-03-15

Understanding how brain circuit dysfunctions relate to specific symptoms offers promise for developing a brain-based taxonomy for classifying psychopathology, identifying targets for mechanistic studies and ultimately for guiding treatment choice. The goal of the Research Domain Criteria (RDoC) initiative of the National Institute of Mental Health is to accelerate the development of such neurobiological models of mental disorder independent of traditional diagnostic criteria. In our RDoC Anxiety and Depression ("RAD") project we focus trans-diagnostically on the spectrum of depression and anxiety psychopathology. Our aims are a) to use brain imaging to define cohesive dimensions defined by dysfunction of circuits involved in reactivity to and regulation of negatively valenced emotional stimulation and in cognitive control, b) to assess the relationships between these dimension and specific symptoms, behavioral performance and the real world capacity to function socially and at work and c) to assess the stability of brain-symptom-behavior-function relationships over time. Here we present the protocol for the "RAD" project, one of the first RDoC studies to use brain circuit functioning to define new dimensions of psychopathology. The RAD project follows baseline-follow up design. In line with RDoC principles we use a strategy for recruiting all clients who "walk through the door" of a large community mental health clinic as well as the surrounding community. The clinic attends to a broad spectrum of anxiety and mood-related symptoms. Participants are unmedicated and studied at baseline using a standardized battery of functional brain imaging, structural brain imaging and behavioral probes that assay constructs of threat reactivity, threat regulation and cognitive control. The battery also includes self-report measures of anxiety and mood symptoms, and social and occupational functioning. After baseline assessments, therapists in the clinic apply treatment planning as usual. Follow-up assessments are undertaken at 3 months, to establish the reliability of brain-based subgroups over time and to assess whether these subgroups predict real-world functional capacity over time. First enrollment was August 2013, and is ongoing. This project is designed to advance knowledge toward a neural circuit taxonomy for mental disorder. Data will be shared via the RDoC database for dissemination to the scientific community. The clinical translational neuroscience goals of the project are to develop brain-behavior profile reports for each individual participant and to refine these reports with therapist feedback. Reporting of results is expected from December 2016 onward. ClinicalTrials.gov Identifier: NCT02220309 . Registered: August 13, 2014.

Salience network-based classification and prediction of symptom severity in children with autism.

PubMed

Uddin, Lucina Q; Supekar, Kaustubh; Lynch, Charles J; Khouzam, Amirah; Phillips, Jennifer; Feinstein, Carl; Ryali, Srikanth; Menon, Vinod

2013-08-01

Autism spectrum disorder (ASD) affects 1 in 88 children and is characterized by a complex phenotype, including social, communicative, and sensorimotor deficits. Autism spectrum disorder has been linked with atypical connectivity across multiple brain systems, yet the nature of these differences in young children with the disorder is not well understood. To examine connectivity of large-scale brain networks and determine whether specific networks can distinguish children with ASD from typically developing (TD) children and predict symptom severity in children with ASD. Case-control study performed at Stanford University School of Medicine of 20 children 7 to 12 years old with ASD and 20 age-, sex-, and IQ-matched TD children. Between-group differences in intrinsic functional connectivity of large-scale brain networks, performance of a classifier built to discriminate children with ASD from TD children based on specific brain networks, and correlations between brain networks and core symptoms of ASD. We observed stronger functional connectivity within several large-scale brain networks in children with ASD compared with TD children. This hyperconnectivity in ASD encompassed salience, default mode, frontotemporal, motor, and visual networks. This hyperconnectivity result was replicated in an independent cohort obtained from publicly available databases. Using maps of each individual's salience network, children with ASD could be discriminated from TD children with a classification accuracy of 78%, with 75% sensitivity and 80% specificity. The salience network showed the highest classification accuracy among all networks examined, and the blood oxygen-level dependent signal in this network predicted restricted and repetitive behavior scores. The classifier discriminated ASD from TD in the independent sample with 83% accuracy, 67% sensitivity, and 100% specificity. Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD.

Salience Network–Based Classification and Prediction of Symptom Severity in Children With Autism

PubMed Central

Uddin, Lucina Q.; Supekar, Kaustubh; Lynch, Charles J.; Khouzam, Amirah; Phillips, Jennifer; Feinstein, Carl; Ryali, Srikanth; Menon, Vinod

2014-01-01

IMPORTANCE Autism spectrum disorder (ASD) affects 1 in 88 children and is characterized by a complex phenotype, including social, communicative, and sensorimotor deficits. Autism spectrum disorder has been linked with atypical connectivity across multiple brain systems, yet the nature of these differences in young children with the disorder is not well understood. OBJECTIVES To examine connectivity of large-scale brain networks and determine whether specific networks can distinguish children with ASD from typically developing (TD) children and predict symptom severity in children with ASD. DESIGN, SETTING, AND PARTICIPANTS Case-control study performed at Stanford University School of Medicine of 20 children 7 to 12 years old with ASD and 20 age-, sex-, and IQ-matched TD children. MAIN OUTCOMES AND MEASURES Between-group differences in intrinsic functional connectivity of large-scale brain networks, performance of a classifier built to discriminate children with ASD from TD children based on specific brain networks, and correlations between brain networks and core symptoms of ASD. RESULTS We observed stronger functional connectivity within several large-scale brain networks in children with ASD compared with TD children. This hyperconnectivity in ASD encompassed salience, default mode, frontotemporal, motor, and visual networks. This hyperconnectivity result was replicated in an independent cohort obtained from publicly available databases. Using maps of each individual’s salience network, children with ASD could be discriminated from TD children with a classification accuracy of 78%, with 75% sensitivity and 80% specificity. The salience network showed the highest classification accuracy among all networks examined, and the blood oxygen–level dependent signal in this network predicted restricted and repetitive behavior scores. The classifier discriminated ASD from TD in the independent sample with 83% accuracy, 67% sensitivity, and 100% specificity. CONCLUSIONS AND RELEVANCE Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD. PMID:23803651

Modulatory Effects of Dietary Amino Acids on Neurodegenerative Diseases.

PubMed

Rajagopal, Senthilkumar; Sangam, Supraj Raja; Singh, Shubham; Joginapally, Venkateswara Rao

2016-01-01

Proteins are playing a vital role in maintaining the cellular integrity and function, as well as for brain cells. Protein intake and supplementation of individual amino acids can affect the brain functioning and mental health, and many of the neurotransmitters in the brain are made from amino acids. The amino acid supplementation has been found to reduce symptoms, as they are converted into neurotransmitters which in turn extenuate the mental disorders. The biosynthesis of amino acids in the brain is regulated by the concentration of amino acids in plasma. The brain diseases such as depression, bipolar disorder, schizophrenia, obsessive-compulsive disorder (OCD), and Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD) are the most common mental disorders that are currently widespread in numerous countries. The intricate biochemical and molecular machinery contributing to the neurological disorders is still unknown, and in this chapter, we revealed the involvement of dietary amino acids on neurological diseases.

Regional infant brain development: an MRI-based morphometric analysis in 3 to 13 month olds.

PubMed

Choe, Myong-Sun; Ortiz-Mantilla, Silvia; Makris, Nikos; Gregas, Matt; Bacic, Janine; Haehn, Daniel; Kennedy, David; Pienaar, Rudolph; Caviness, Verne S; Benasich, April A; Grant, P Ellen

2013-09-01

Elucidation of infant brain development is a critically important goal given the enduring impact of these early processes on various domains including later cognition and language. Although infants' whole-brain growth rates have long been available, regional growth rates have not been reported systematically. Accordingly, relatively less is known about the dynamics and organization of typically developing infant brains. Here we report global and regional volumetric growth of cerebrum, cerebellum, and brainstem with gender dimorphism, in 33 cross-sectional scans, over 3 to 13 months, using T1-weighted 3-dimensional spoiled gradient echo images and detailed semi-automated brain segmentation. Except for the midbrain and lateral ventricles, all absolute volumes of brain regions showed significant growth, with 6 different patterns of volumetric change. When normalized to the whole brain, the regional increase was characterized by 5 differential patterns. The putamen, cerebellar hemispheres, and total cerebellum were the only regions that showed positive growth in the normalized brain. Our results show region-specific patterns of volumetric change and contribute to the systematic understanding of infant brain development. This study greatly expands our knowledge of normal development and in future may provide a basis for identifying early deviation above and beyond normative variation that might signal higher risk for neurological disorders.

Regional Infant Brain Development: An MRI-Based Morphometric Analysis in 3 to 13 Month Olds

PubMed Central

Choe, Myong-sun; Ortiz-Mantilla, Silvia; Makris, Nikos; Gregas, Matt; Bacic, Janine; Haehn, Daniel; Kennedy, David; Pienaar, Rudolph; Caviness, Verne S.; Benasich, April A.; Grant, P. Ellen

2013-01-01

Elucidation of infant brain development is a critically important goal given the enduring impact of these early processes on various domains including later cognition and language. Although infants’ whole-brain growth rates have long been available, regional growth rates have not been reported systematically. Accordingly, relatively less is known about the dynamics and organization of typically developing infant brains. Here we report global and regional volumetric growth of cerebrum, cerebellum, and brainstem with gender dimorphism, in 33 cross-sectional scans, over 3 to 13 months, using T1-weighted 3-dimensional spoiled gradient echo images and detailed semi-automated brain segmentation. Except for the midbrain and lateral ventricles, all absolute volumes of brain regions showed significant growth, with 6 different patterns of volumetric change. When normalized to the whole brain, the regional increase was characterized by 5 differential patterns. The putamen, cerebellar hemispheres, and total cerebellum were the only regions that showed positive growth in the normalized brain. Our results show region-specific patterns of volumetric change and contribute to the systematic understanding of infant brain development. This study greatly expands our knowledge of normal development and in future may provide a basis for identifying early deviation above and beyond normative variation that might signal higher risk for neurological disorders. PMID:22772652

PARADISE 24: A Measure to Assess the Impact of Brain Disorders on People’s Lives

PubMed Central

Cieza, Alarcos; Sabariego, Carla; Anczewska, Marta; Ballert, Carolina; Bickenbach, Jerome; Cabello, Maria; Giovannetti, Ambra; Kaskela, Teemu; Mellor, Blanca; Pitkänen, Tuuli; Quintas, Rui; Raggi, Alberto; Świtaj, Piotr; Chatterji, Somnath

2015-01-01

Objective To construct a metric of the impact of brain disorders on people’s lives, based on the psychosocial difficulties (PSDs) that are experienced in common across brain disorders. Study Design Psychometric study using data from a cross-sectional study with a convenience sample of 722 persons with 9 different brain disorders interviewed in four European countries: Italy, Poland, Spain and Finland. Questions addressing 64 PSDs were first reduced based on statistical considerations, patient’s perspective and clinical expertise. Rasch analyses for polytomous data were also applied. Setting In and outpatient settings. Results A valid and reliable metric with 24 items was created. The infit of all questions ranged between 0.7 and 1.3. There were no disordered thresholds. The targeting between item thresholds and persons’ abilities was good and the person-separation index was 0.92. Persons’ abilities were linearly transformed into a more intuitive scale ranging from zero (no PSDs) to 100 (extreme PSDs). Conclusion The metric, called PARADISE 24, is based on the hypothesis of horizontal epidemiology, which affirms that people with brain disorders commonly experience PSDs. This metric is a useful tool to carry out cardinal comparisons over time of the magnitude of the psychosocial impact of brain disorders and between persons and groups in clinical practice and research. PMID:26147343

Psychoradiology: The Frontier of Neuroimaging in Psychiatry

PubMed Central

Lui, Su; Zhou, Xiaohong Joe; Sweeney, John A.

2016-01-01

Unlike neurologic conditions, such as brain tumors, dementia, and stroke, the neural mechanisms for all psychiatric disorders remain unclear. A large body of research obtained with structural and functional magnetic resonance imaging, positron emission tomography/single photon emission computed tomography, and optical imaging has demonstrated regional and illness-specific brain changes at the onset of psychiatric disorders and in individuals at risk for such disorders. Many studies have shown that psychiatric medications induce specific measurable changes in brain anatomy and function that are related to clinical outcomes. As a result, a new field of radiology, termed psychoradiology, seems primed to play a major clinical role in guiding diagnostic and treatment planning decisions in patients with psychiatric disorders. This article will present the state of the art in this area, as well as perspectives regarding preparations in the field of radiology for its evolution. Furthermore, this article will (a) give an overview of the imaging and analysis methods for psychoradiology; (b) review the most robust and important radiologic findings and their potential clinical value from studies of major psychiatric disorders, such as depression and schizophrenia; and (c) describe the main challenges and future directions in this field. An ongoing and iterative process of developing biologically based nomenclatures with which to delineate psychiatric disorders and translational research to predict and track response to different therapeutic drugs is laying the foundation for a shift in diagnostic practice in psychiatry from a psychologic symptom–based approach to an imaging-based approach over the next generation. This shift will require considerable innovations for the acquisition, analysis, and interpretation of brain images, all of which will undoubtedly require the active involvement of radiologists. © RSNA, 2016 Online supplemental material is available for this article. PMID:27755933

The hubs of the human connectome are generally implicated in the anatomy of brain disorders.

PubMed

Crossley, Nicolas A; Mechelli, Andrea; Scott, Jessica; Carletti, Francesco; Fox, Peter T; McGuire, Philip; Bullmore, Edward T

2014-08-01

Brain networks or 'connectomes' include a minority of highly connected hub nodes that are functionally valuable, because their topological centrality supports integrative processing and adaptive behaviours. Recent studies also suggest that hubs have higher metabolic demands and longer-distance connections than other brain regions, and therefore could be considered biologically costly. Assuming that hubs thus normally combine both high topological value and high biological cost, we predicted that pathological brain lesions would be concentrated in hub regions. To test this general hypothesis, we first identified the hubs of brain anatomical networks estimated from diffusion tensor imaging data on healthy volunteers (n = 56), and showed that computational attacks targeted on hubs disproportionally degraded the efficiency of brain networks compared to random attacks. We then prepared grey matter lesion maps, based on meta-analyses of published magnetic resonance imaging data on more than 20 000 subjects and 26 different brain disorders. Magnetic resonance imaging lesions that were common across all brain disorders were more likely to be located in hubs of the normal brain connectome (P < 10(-4), permutation test). Specifically, nine brain disorders had lesions that were significantly more likely to be located in hubs (P < 0.05, permutation test), including schizophrenia and Alzheimer's disease. Both these disorders had significantly hub-concentrated lesion distributions, although (almost completely) distinct subsets of cortical hubs were lesioned in each disorder: temporal lobe hubs specifically were associated with higher lesion probability in Alzheimer's disease, whereas in schizophrenia lesions were concentrated in both frontal and temporal cortical hubs. These results linking pathological lesions to the topological centrality of nodes in the normal diffusion tensor imaging connectome were generally replicated when hubs were defined instead by the meta-analysis of more than 1500 task-related functional neuroimaging studies of healthy volunteers to create a normative functional co-activation network. We conclude that the high cost/high value hubs of human brain networks are more likely to be anatomically abnormal than non-hubs in many (if not all) brain disorders. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

The role of polyhalogenated aromatic hydrocarbons on thyroid hormone disruption and cognitive function: a review.

PubMed

Builee, T L; Hatherill, J R

2004-11-01

Thyroid hormones (TH) are essential to normal brain development, influencing behavior and cognitive function in both adult and children. It is suggested that conditions found in TH abnormalities such as hypothyroidism, hyperthyroidism and generalized resistance to thyroid hormone (GRTH) share symptomatic behavioral impulses found in cases of attention deficit hyperactivity disorder (ADHD) and other cognitive disorders. Disrupters of TH are various and prevalent in the environment. This paper reviews the mechanisms of TH disruption caused by the general class of polyhalogenated aromatic hydrocarbons (PHAH)'s acting as thyroid disrupters (TD). PHAHs influence the hypothalamus-pituitary-thyroid (HPT) axis, as mimicry agents affecting synthesis and secretion of TH. Exposure to PHAH induces liver microsomal enzymes UDP-glucuronosyltransferase (UGT) resulting in accelerated clearance of TH. PHAHs can compromise function of transport and receptor binding proteins such as transthyretin and aryl hydrocarbon receptors (Ahr). Glucose metabolism and catecholamine synthesis are disrupted in the brain by the presence of PHAH. Further, PHAH can alter brain growth and development by perturbing cytoskeletal formation, thereby affecting neuronal migration, elongation and branching. The complex relationships between PHAH and cognitive function are examined in regard to the disruption of T4 regulation in the hypothalamus-pituitary-thyroid axis, blood, brain, neurons, liver and pre and postnatal development.

Characterisation of Cdkl5 transcript isoforms in rat.

PubMed

Hector, Ralph D; Dando, Owen; Ritakari, Tuula E; Kind, Peter C; Bailey, Mark E S; Cobb, Stuart R

2017-03-01

CDKL5 deficiency is a severe neurological disorder caused by mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5). The predominant human CDKL5 brain isoform is a 9.7kb transcript comprised of 18 exons with a large 6.6kb 3'-untranslated region (UTR). Mammalian models of CDKL5 disorder are currently limited to mouse, and little is known about Cdkl5 in other organisms used to model neurodevelopmental disorders, such as rat. In this study we characterise, both bioinformatically and experimentally, the rat Cdkl5 gene structure and its associated transcript isoforms. New exonic regions, splice sites and UTRs are described, confirming the presence of four distinct transcript isoforms. The predominant isoform in the brain, which we name rCdkl5_1, is orthologous to the human hCDKL5_1 and mouse mCdkl5_1 isoforms and is the most highly expressed isoform across all brain regions tested. This updated gene model of Cdkl5 in rat provides a framework for studies into its protein products and provides a reference for the development of molecular therapies for testing in rat models of CDKL5 disorder. Copyright © 2016 Elsevier B.V. All rights reserved.

Low doses of methylmercury intoxication solely or associated to ethanol binge drinking induce psychiatric-like disorders in adolescent female rats.

PubMed

Belém-Filho, Ivaldo Jesus Almeida; Ribera, Paula Cardoso; Nascimento, Aline Lima; Gomes, Antônio Rafael Quadros; Lima, Rafael Rodrigues; Crespo-Lopez, Maria Elena; Monteiro, Marta Chagas; Fontes-Júnior, Enéas Andrade; Lima, Marcelo Oliveira; Maia, Cristiane Socorro Ferraz

2018-04-30

Methylmercury (MeHg) is an environmental contaminant that provokes damage to developing brain. Simultaneously, the consumption of ethanol among adolescents has increased. Evidence concerning the effects of MeHg low doses per se or associated with ethanol during adolescence are scarce. Thus, we investigate behavioral disorders resulted from exposure to MeHg low doses and co-intoxicated with ethanol in adolescent rats. Wistar rats received chronic exposure to low doses of MeHg (40 μg/kg/day for 5 weeks) and/or ethanol binge drinking (3 g/kg/day at 3 days per week for 5 weeks). Animals were submitted to behavioral assays to assess emotionality and cognitive function. Total mercury content was evaluated in the brain and hair. Oxidative parameters were analyzed in blood samples. MeHg at low doses or associated to ethanol binge drinking produced psychiatric-like disorders and cognitive impairment. Peripherally, MeHg altered oxidative parameters when associated to ethanol. Ethanol administration reduced brain mercury deposit. We proposed that ethanol reduces the necessity of mercury tissue levels to display psychiatric-like disorders/cognitive impairment. Copyright © 2018. Published by Elsevier B.V.

Neonatal neuroimaging: going beyond the pictures.

PubMed

Ramenghi, Luca A; Rutherford, Mary; Fumagalli, Monica; Bassi, Laura; Messner, Hubert; Counsell, Serena; Mosca, Fabio

2009-10-01

The cerebral ultrasound has been used many years for the diagnosis of brain lesions in term and preterm newborns. Major improvements were obtained by the combination of different imaging modalities such as Magnetic Resonance Imaging with the Diffusion Weighted Imaging (DWI) and the new quantitative Diffusion Tensor Imaging (DTI). The clinical use of MRI has been validated over some years especially to depict the perinatal asphyxia lesions in term newborns, but its use in order to diagnose the typical diseases of preterm babies is very recent and useful in identifying a marker able to predict neurological outcome. The imaging correlates for motor impairment are well recognized (periventricular white matter cavitations), but no any imaging correlate for cognitive impairment and neurobehavioral disorders. While DWI has been used in term newborns to identify the ischemic areas with restricted diffusion, it may be also used to characterize brain development in preterm infants with the Apparent Diffusion Coefficient (ADC) and may allow us to detect abnormalities responsible for the non-motor impairments. Recent datas showed that in infants without focal lesions higher ADC values in WM were associated with poorer neurodevelopmental assessment at 2 years. The DTI also allows to detect the Fractional Anisotropy (FA) that measures the microstructure. DTI can also be used to map the WM tracts in the immature brain and may be applied to understand the normal development or the response of the brain to injury. Some WM regions in the preterm brain have a lower FA suggesting that widespread WM abnormalities are present in preterms even in the absence of focal lesions. The complexity of the developing brain can be explained by the new tractography that can assess the connectivity of different WM regions and the association between structure and function, such as optic radiations microstructure and visual assessment score. Technological advances in neonatal brain imaging have made a major contribution to understand the neurobehavioral disorders of the developing brain that have the origin in the early structural cerebral organization and maturation.

Are the Gut Bacteria Telling Us to Eat or Not to Eat? Reviewing the Role of Gut Microbiota in the Etiology, Disease Progression and Treatment of Eating Disorders

PubMed Central

Lam, Yan Y.; Maguire, Sarah; Palacios, Talia; Caterson, Ian D.

2017-01-01

Traditionally recognized as mental illnesses, eating disorders are increasingly appreciated to be biologically-driven. There is a growing body of literature that implicates a role of the gut microbiota in the etiology and progression of these conditions. Gut bacteria may act on the gut–brain axis to alter appetite control and brain function as part of the genesis of eating disorders. As the illnesses progress, extreme feeding patterns and psychological stress potentially feed back to the gut ecosystem that can further compromise physiological, cognitive, and social functioning. Given the established causality between dysbiosis and metabolic diseases, an altered gut microbial profile is likely to play a role in the co-morbidities of eating disorders with altered immune function, short-chain fatty acid production, and the gut barrier being the key mechanistic links. Understanding the role of the gut ecosystem in the pathophysiology of eating disorders will provide critical insights into improving current treatments and developing novel microbiome-based interventions that will benefit patients with eating disorders. PMID:28613252

Are the Gut Bacteria Telling Us to Eat or Not to Eat? Reviewing the Role of Gut Microbiota in the Etiology, Disease Progression and Treatment of Eating Disorders.

PubMed

Lam, Yan Y; Maguire, Sarah; Palacios, Talia; Caterson, Ian D

2017-06-14

Traditionally recognized as mental illnesses, eating disorders are increasingly appreciated to be biologically-driven. There is a growing body of literature that implicates a role of the gut microbiota in the etiology and progression of these conditions. Gut bacteria may act on the gut-brain axis to alter appetite control and brain function as part of the genesis of eating disorders. As the illnesses progress, extreme feeding patterns and psychological stress potentially feed back to the gut ecosystem that can further compromise physiological, cognitive, and social functioning. Given the established causality between dysbiosis and metabolic diseases, an altered gut microbial profile is likely to play a role in the co-morbidities of eating disorders with altered immune function, short-chain fatty acid production, and the gut barrier being the key mechanistic links. Understanding the role of the gut ecosystem in the pathophysiology of eating disorders will provide critical insights into improving current treatments and developing novel microbiome-based interventions that will benefit patients with eating disorders.

Animal models of speech and vocal communication deficits associated with psychiatric disorders

PubMed Central

Konopka, Genevieve; Roberts, Todd F.

2015-01-01

Disruptions in speech, language and vocal communication are hallmarks of several neuropsychiatric disorders, most notably autism spectrum disorders. Historically, the use of animal models to dissect molecular pathways and connect them to behavioral endophenotypes in cognitive disorders has proven to be an effective approach for developing and testing disease-relevant therapeutics. The unique aspects of human language when compared to vocal behaviors in other animals make such an approach potentially more challenging. However, the study of vocal learning in species with analogous brain circuits to humans may provide entry points for understanding this human-specific phenotype and diseases. Here, we review animal models of vocal learning and vocal communication, and specifically link phenotypes of psychiatric disorders to relevant model systems. Evolutionary constraints in the organization of neural circuits and synaptic plasticity result in similarities in the brain mechanisms for vocal learning and vocal communication. Comparative approaches and careful consideration of the behavioral limitations among different animal models can provide critical avenues for dissecting the molecular pathways underlying cognitive disorders that disrupt speech, language and vocal communication. PMID:26232298

A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies.

PubMed

Chang, Lun-Ching; Jamain, Stephane; Lin, Chien-Wei; Rujescu, Dan; Tseng, George C; Sibille, Etienne

2014-01-01

Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases. In support of the superior discriminative power of this novel approach, we observed no significant enrichment for GWAS-related genes in coexpression modules extracted from single studies or in meta-modules using gene expression data from non-psychiatric control subjects. Genes in the identified module encode proteins implicated in neuronal signaling and structure, including glutamate metabotropic receptors (GRM1, GRM7), GABA receptors (GABRA2, GABRA4), and neurotrophic and development-related proteins [BDNF, reelin (RELN), Ephrin receptors (EPHA3, EPHA5)]. These results are consistent with the current understanding of molecular mechanisms of MDD and provide a set of putative interacting molecular partners, potentially reflecting components of a functional module across cells and biological pathways that are synchronously recruited in MDD, other brain disorders and MDD-related illnesses. Collectively, this study demonstrates the importance of integrating transcriptome data, gene coexpression modules and GWAS results for providing novel and complementary approaches to investigate the molecular pathology of MDD and other complex brain disorders.

Investigation of brain structure in the 1-month infant.

PubMed

Dean, Douglas C; Planalp, E M; Wooten, W; Schmidt, C K; Kecskemeti, S R; Frye, C; Schmidt, N L; Goldsmith, H H; Alexander, A L; Davidson, R J

2018-05-01

The developing brain undergoes systematic changes that occur at successive stages of maturation. Deviations from the typical neurodevelopmental trajectory are hypothesized to underlie many early childhood disorders; thus, characterizing the earliest patterns of normative brain development is essential. Recent neuroimaging research provides insight into brain structure during late childhood and adolescence; however, few studies have examined the infant brain, particularly in infants under 3 months of age. Using high-resolution structural MRI, we measured subcortical gray and white matter brain volumes in a cohort (N = 143) of 1-month infants and examined characteristics of these volumetric measures throughout this early period of neurodevelopment. We show that brain volumes undergo age-related changes during the first month of life, with the corresponding patterns of regional asymmetry and sexual dimorphism. Specifically, males have larger total brain volume and volumes differ by sex in regionally specific brain regions, after correcting for total brain volume. Consistent with findings from studies of later childhood and adolescence, subcortical regions appear more rightward asymmetric. Neither sex differences nor regional asymmetries changed with gestation-corrected age. Our results complement a growing body of work investigating the earliest neurobiological changes associated with development and suggest that asymmetry and sexual dimorphism are present at birth.

Involvement of Programmed Cell Death in Neurotoxicity of Metallic Nanoparticles: Recent Advances and Future Perspectives

NASA Astrophysics Data System (ADS)

Song, Bin; Zhou, Ting; Liu, Jia; Shao, LongQuan

2016-11-01

The widespread application of metallic nanoparticles (NPs) or NP-based products has increased the risk of exposure to NPs in humans. The brain is an important organ that is more susceptible to exogenous stimuli. Moreover, any impairment to the brain is irreversible. Recently, several in vivo studies have found that metallic NPs can be absorbed into the animal body and then translocated into the brain, mainly through the blood-brain barrier and olfactory pathway after systemic administration. Furthermore, metallic NPs can cross the placental barrier to accumulate in the fetal brain, causing developmental neurotoxicity on exposure during pregnancy. Therefore, metallic NPs become a big threat to the brain. However, the mechanisms underlying the neurotoxicity of metallic NPs remain unclear. Programmed cell death (PCD), which is different from necrosis, is defined as active cell death and is regulated by certain genes. PCD can be mainly classified into apoptosis, autophagy, necroptosis, and pyroptosis. It is involved in brain development, neurodegenerative disorders, psychiatric disorders, and brain injury. Given the pivotal role of PCD in neurological functions, we reviewed relevant articles and tried to summarize the recent advances and future perspectives of PCD involvement in the neurotoxicity of metallic NPs, with the purpose of comprehensively understanding the neurotoxic mechanisms of NPs.

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.

Previous Exposure to Anesthesia and Autism Spectrum Disorder (ASD): A Puerto Rican Population-Based Sibling Cohort Study.

PubMed

Creagh, O; Torres, H; Rivera, K; Morales-Franqui, M; Altieri-Acevedo, G; Warner, D

2016-01-01

Autism Spectrum Disorder (ASD) is characterized by impaired social interaction and communication, and by restricted and repetitive behavior, that begins usually before a child is three years old.(1) Researchers have shown that prevalence rates in the U.S. may be as high as 1 in 68.(52) A number of studies have examined the effects of early exposure to anesthesia on brain development and subsequent impairment in neurocognitive function; yet, little is known about the possible effects of anesthetic agents on social-behavioral functioning. The association between exposure to anesthesia either in uterus, during the first years of life, or later and development of Autistic Spectrum Disorder (ASD) or its severity was determined in a retrospective population based cohort study. Identify if children who had previous exposure to anesthesia either in uterus, first years of life during their developing brain years, or later, are at risk of developing ASD and its severe form of the disease. Data was obtained from structured interviews administered to a sample of 515 parents/guardians distributed in two groups: ASD = 262 children diagnosed with this condition and Non-ASD: 253 children (siblings of ASD group) without diagnosis (95% confidence interval) that freely decided to participate and agreed to a consent form. Variables studied include: demographics, diagnosis and severity of ASD, exposure to anesthesia, method of childbirth, and age of exposure Children less than 2 years of age were considered into have developing brain period. Data was analyzed using Chi-square or Fisher exact test. In contrast to non-ASD group, most of the children within ASD group were male, 76% (p=0.0001). With regards to methods of childbirth, 64% of the ASD population were vaginal delivery (VD; Non-anesthesia exposure group) and 36% cesarean delivery (CD) compared to non-autistic population with 71% VD and 29% CD, which demonstrates no statistical difference between both groups (p=0.1113). Out of the 36% of ASD population that underwent CD, 7% were performed using general anesthesia and 93% regional anesthesia, while the 29% of the CD of non-ASD, 5% were performed using general anesthesia and 95% regional anesthesia. This reveals no statistical significance (p=0.7569) with the development of ASD and the type of anesthesia used when comparing ASD with non-ASD patients. In view of severity of autism, in VD, 56% of ASD population had mild form of the disorder, 34% moderate, and 10% severe; while CD had a 54% mild form of the disorder, 33% moderate, and 13% severe. This shows no statistical association (p=0.8069) when comparing exposure to anesthesia in uterus to subsequent severe form of ASD. Of the 262 ASD patients, 99 had exposure to anesthetics before their diagnosis, while in Non-ASD population, 110 had exposure to anesthesia, demonstrating no statistically significant association between both groups (p=0.2091). Out of 99 ASD patients exposed to anesthesia prior to their diagnosis, 72 were exposed before age 2. When compared to the 110 Non-ASD patients exposed to anesthesia, 86 had exposure during this developing brain period, which indicates no statistically significant association (p=0.4207). In addition, most of the ASD children exposed to anesthesia during developing brain were diagnosed with mild degree of the disorder when compared to ASD children without any previous exposure to anesthesia (p=0.9700) during the same period. When the exposure occurred after age 2, ASD children developed mild form of the disorder as compared with ASD children without any previous exposure to anesthesia (p=0.1699) in that period. Children under early exposure to anesthesia in uterus, first 2 years of life, or later are not more likely to develop neither ASD nor severe form of the disorder.

Brain disorders and the biological role of music.

PubMed

Clark, Camilla N; Downey, Laura E; Warren, Jason D

2015-03-01

Despite its evident universality and high social value, the ultimate biological role of music and its connection to brain disorders remain poorly understood. Recent findings from basic neuroscience have shed fresh light on these old problems. New insights provided by clinical neuroscience concerning the effects of brain disorders promise to be particularly valuable in uncovering the underlying cognitive and neural architecture of music and for assessing candidate accounts of the biological role of music. Here we advance a new model of the biological role of music in human evolution and the link to brain disorders, drawing on diverse lines of evidence derived from comparative ethology, cognitive neuropsychology and neuroimaging studies in the normal and the disordered brain. We propose that music evolved from the call signals of our hominid ancestors as a means mentally to rehearse and predict potentially costly, affectively laden social routines in surrogate, coded, low-cost form: essentially, a mechanism for transforming emotional mental states efficiently and adaptively into social signals. This biological role of music has its legacy today in the disordered processing of music and mental states that characterizes certain developmental and acquired clinical syndromes of brain network disintegration. © The Author (2014). Published by Oxford University Press.

Brain disorders and the biological role of music

PubMed Central

Clark, Camilla N.; Downey, Laura E.

2015-01-01

Despite its evident universality and high social value, the ultimate biological role of music and its connection to brain disorders remain poorly understood. Recent findings from basic neuroscience have shed fresh light on these old problems. New insights provided by clinical neuroscience concerning the effects of brain disorders promise to be particularly valuable in uncovering the underlying cognitive and neural architecture of music and for assessing candidate accounts of the biological role of music. Here we advance a new model of the biological role of music in human evolution and the link to brain disorders, drawing on diverse lines of evidence derived from comparative ethology, cognitive neuropsychology and neuroimaging studies in the normal and the disordered brain. We propose that music evolved from the call signals of our hominid ancestors as a means mentally to rehearse and predict potentially costly, affectively laden social routines in surrogate, coded, low-cost form: essentially, a mechanism for transforming emotional mental states efficiently and adaptively into social signals. This biological role of music has its legacy today in the disordered processing of music and mental states that characterizes certain developmental and acquired clinical syndromes of brain network disintegration. PMID:24847111

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.

Perinatal Asphyxia and Brain Development: Mitochondrial Damage Without Anatomical or Cellular Losses.

PubMed

Lima, Jean Pierre Mendes; Rayêe, Danielle; Silva-Rodrigues, Thaia; Pereira, Paula Ribeiro Paes; Mendonca, Ana Paula Miranda; Rodrigues-Ferreira, Clara; Szczupak, Diego; Fonseca, Anna; Oliveira, Marcus F; Lima, Flavia Regina Souza; Lent, Roberto; Galina, Antonio; Uziel, Daniela

2018-03-26

Perinatal asphyxia remains a significant cause of neonatal mortality and is associated with long-term neurodegenerative disorders. In the present study, we evaluated cellular and subcellular damages to brain development in a model of mild perinatal asphyxia. Survival rate in the experimental group was 67%. One hour after the insult, intraperitoneally injected Evans blue could be detected in the fetuses' brains, indicating disruption of the blood-brain barrier. Although brain mass and absolute cell numbers (neurons and non-neurons) were not reduced after perinatal asphyxia immediately and in late brain development, subcellular alterations were detected. Cortical oxygen consumption increased immediately after asphyxia, and remained high up to 7 days, returning to normal levels after 14 days. We observed an increased resistance to mitochondrial membrane permeability transition, and calcium buffering capacity in asphyxiated animals from birth to 14 days after the insult. In contrast to ex vivo data, mitochondrial oxygen consumption in primary cell cultures of neurons and astrocytes was not altered after 1% hypoxia. Taken together, our results demonstrate that although newborns were viable and apparently healthy, brain development is subcellularly altered by perinatal asphyxia. Our findings place the neonate brain mitochondria as a potential target for therapeutic protective interventions.

Combining Non-Pharmacological Treatments with Pharmacotherapies for Neurological Disorders: A Unique Interface of the Brain, Drug–Device, and Intellectual Property

PubMed Central

Bulaj, Grzegorz

2014-01-01

Mobile medical applications (mHealth), music, and video games are being developed and tested for their ability to improve pharmacotherapy outcomes and medication adherence. Pleiotropic mechanism of music and gamification engages an intrinsic motivation and the brain reward system, supporting therapies in patients with neurological disorders, including neuropathic pain, depression, anxiety, or neurodegenerative disorders. Based on accumulating results from clinical trials, an innovative combination treatment of epilepsy seizures, comorbidities, and the medication non-adherence can be designed, consisting of antiepileptic drugs and disease self-management software delivering clinically beneficial music. Since creative elements and art expressed in games, music, and software are copyrighted, therefore clinical and regulatory challenges in developing copyrighted, drug–device therapies may be offset by a value proposition of the exclusivity due to the patent–independent protection, which can last for over 70 years. Taken together, development of copyrighted non-pharmacological treatments (e-therapies), and their combinations with pharmacotherapies, offer incentives to chronically ill patients and outcome-driven health care industries. PMID:25071711

Neurogenetics and Epigenetics in Impulsive Behaviour: Impact on Reward Circuitry

PubMed Central

Archer, Trevor; Oscar-Berman, Marlene; Blum, Kenneth; Gold, Mark

2012-01-01

Adverse, unfavourable life conditions, particularly during early life stages and infancy, can lead to epigenetic regulation of genes involved in stress-response, behavioral disinhibition, and cognitive-emotional systems. Over time, the ultimate final outcome can be expressed through behaviors bedeviled by problems with impulse control, such as eating disorders, alcoholism, and indiscriminate social behavior. While many reward gene polymorphisms are involved in impulsive behaviors, a polymorphism by itself may not translate to the development of a particular behavioral disorder unless it is impacted by epigenetic effects. Brain-derived neurotrophic factor (BDNF) affects the development and integrity of the noradrenergic, dopaminergic, serotonergic, glutamatergic, and cholinergic neurotransmitter systems, and plasma levels of the neurotrophin are associated with both cognitive and aggressive impulsiveness. Epigenetic mechanisms associated with a multitude of environmental factors, including premature birth, low birth weight, prenatal tobacco exposure, non-intact family, young maternal age at birth of the target child, paternal history of antisocial behavior, and maternal depression, alter the developmental trajectories for several neuropsychiatric disorders. These mechanisms affect brain development and integrity at several levels that determine structure and function in resolving the final behavioral expressions. PMID:23264884

MicroRNA's impact on neurotransmitter and neuropeptide systems: small but mighty mediators of anxiety.

PubMed

Martinetz, Stefanie

2016-06-01

Psychiatric disorders rank among the most common severe diseases worldwide, with millions of people affected worldwide every year. The symptoms are manifold, and the outcome for the patients is often unclear. As a high and yearly rising cost burden for society, anxiety disorders, depression and their related mental disorders are currently a well-researched topic in order to develop new functional pharmacological therapies as alternatives to those that are in use and bear many unpleasant side effects. Brain circuitries, such as those underlying anxiety formations, are mainly driven by the interplay of various neurotransmitter systems and the interaction of different brain loci, as well as the modulating impact of neuropeptides. Targeting those networks is a complex but promising way to regulate mood. Alterations on molecular level of the neuronal cell in response to respective receptor activation, especially at post-transcriptional level via the highly regulatory function of non-coding RNAs such as microRNAs (miRNAs) seem to hold a promising future in the development of novel therapeutic strategies and are therefore under intensified investigation. This review focusses on the impact of miRNAs on the neurotransmitter and neuropeptide systems of the central nervous system relevant for the formation of anxiety disorders and discusses the potential of miRNAs for the development of new therapeutic strategies for anxiety and mood disorders.

Smoking and the developing brain: altered white matter microstructure in attention-deficit/hyperactivity disorder and healthy controls.

PubMed

van Ewijk, Hanneke; Groenman, Annabeth P; Zwiers, Marcel P; Heslenfeld, Dirk J; Faraone, Stephen V; Hartman, Catharina A; Luman, Marjolein; Greven, Corina U; Hoekstra, Pieter J; Franke, Barbara; Buitelaar, Jan; Oosterlaan, Jaap

2015-03-01

Brain white matter (WM) tracts, playing a vital role in the communication between brain regions, undergo important maturational changes during adolescence and young adulthood, a critical period for the development of nicotine dependence. Attention-deficit/hyperactivity disorder (ADHD) is associated with increased smoking and widespread WM abnormalities, suggesting that the developing ADHD brain might be especially vulnerable to effects of smoking. This study aims to investigate the effect of smoking on (WM) microstructure in adolescents and young adults with and without ADHD. Diffusion tensor imaging was performed in an extensively phenotyped sample of nonsmokers (n = 95, 50.5% ADHD), irregular smokers (n = 41, 58.5% ADHD), and regular smokers (n = 50, 82.5% ADHD), aged 14-24 years. A whole-brain voxelwise approach investigated associations of smoking, ADHD and their interaction, with WM microstructure as measured by fractional anisotropy (FA) and mean diffusivity (MD). Widespread alterations in FA and MD were found for regular smokers compared to irregular and nonsmokers, mainly located in the corpus callosum and WM tracts surrounding the basal ganglia. Several regions overlapped with regions of altered FA for ADHD versus controls, albeit in different directions. Irregular and nonsmokers did not differ, and ADHD and smoking did not interact. Results implicate that smoking and ADHD have independent effects on WM microstructure, and possibly do not share underlying mechanisms. Two mechanisms may play a role in the current results. First, smoking may cause alterations in WM microstructure in the maturing brain. Second, pre-existing WM microstructure differences possibly reflect a risk factor for development of a smoking addiction. © 2014 Wiley Periodicals, Inc.

Increased Small-World Network Topology Following Deployment-Acquired Traumatic Brain Injury Associated with the Development of Post-Traumatic Stress Disorder.

PubMed

Rowland, Jared A; Stapleton-Kotloski, Jennifer R; Dobbins, Dorothy L; Rogers, Emily; Godwin, Dwayne W; Taber, Katherine H

2018-05-01

Cross-sectional and longitudinal studies in active duty and veteran cohorts have both demonstrated that deployment-acquired traumatic brain injury (TBI) is an independent risk factor for developing post-traumatic stress disorder (PTSD), beyond confounds such as combat exposure, physical injury, predeployment TBI, and pre-deployment psychiatric symptoms. This study investigated how resting-state brain networks differ between individuals who developed PTSD and those who did not following deployment-acquired TBI. Participants included postdeployment veterans with deployment-acquired TBI history both with and without current PTSD diagnosis. Graph metrics, including small-worldness, clustering coefficient, and modularity, were calculated from individually constructed whole-brain networks based on 5-min eyes-open resting-state magnetoencephalography (MEG) recordings. Analyses were adjusted for age and premorbid IQ. Results demonstrated that participants with current PTSD displayed higher levels of small-worldness, F(1,12) = 5.364, p < 0.039, partial eta squared = 0.309, and Cohen's d = 0.972, and clustering coefficient, F(1, 12) = 12.204, p < 0.004, partial eta squared = 0.504, and Cohen's d = 0.905, than participants without current PTSD. There were no between-group differences in modularity or the number of modules present. These findings are consistent with a hyperconnectivity hypothesis of the effect of TBI history on functional networks rather than a disconnection hypothesis, demonstrating increased levels of clustering coefficient rather than a decrease as might be expected; however, these results do not account for potential changes in brain structure. These results demonstrate the potential pathological sequelae of changes in functional brain networks following deployment-acquired TBI and represent potential neurobiological changes associated with deployment-acquired TBI that may increase the risk of subsequently developing PTSD.

Differential Brain Development with Low and High IQ in Attention-Deficit/Hyperactivity Disorder

PubMed Central

de Zeeuw, Patrick; Schnack, Hugo G.; van Belle, Janna; Weusten, Juliette; van Dijk, Sarai; Langen, Marieke; Brouwer, Rachel M.; van Engeland, Herman; Durston, Sarah

2012-01-01

Attention-Deficit/Hyperactivity Disorder (ADHD) and intelligence (IQ) are both heritable phenotypes. Overlapping genetic effects have been suggested to influence both, with neuroimaging work suggesting similar overlap in terms of morphometric properties of the brain. Together, this evidence suggests that the brain changes characteristic of ADHD may vary as a function of IQ. This study investigated this hypothesis in a sample of 108 children with ADHD and 106 typically developing controls, who participated in a cross-sectional anatomical MRI study. A subgroup of 64 children also participated in a diffusion tensor imaging scan. Brain volumes, local cortical thickness and average cerebral white matter microstructure were analyzed in relation to diagnostic group and IQ. Dimensional analyses investigated possible group differences in the relationship between anatomical measures and IQ. Second, the groups were split into above and below median IQ subgroups to investigate possible differences in the trajectories of cortical development. Dimensionally, cerebral gray matter volume and cerebral white matter microstructure were positively associated with IQ for controls, but not for ADHD. In the analyses of the below and above median IQ subgroups, we found no differences from controls in cerebral gray matter volume in ADHD with below-median IQ, but a delay of cortical development in a number of regions, including prefrontal areas. Conversely, in ADHD with above-median IQ, there were significant reductions from controls in cerebral gray matter volume, but no local differences in the trajectories of cortical development. In conclusion, the basic relationship between IQ and neuroanatomy appears to be altered in ADHD. Our results suggest that there may be multiple brain phenotypes associated with ADHD, where ADHD combined with above median IQ is characterized by small, more global reductions in brain volume that are stable over development, whereas ADHD with below median IQ is associated more with a delay of cortical development. PMID:22536435

Evolving Applications, Technological Challenges and Future Opportunities in Neuromodulation: Proceedings of the Fifth Annual Deep Brain Stimulation Think Tank

PubMed Central

Ramirez-Zamora, Adolfo; Giordano, James J.; Gunduz, Aysegul; Brown, Peter; Sanchez, Justin C.; Foote, Kelly D.; Almeida, Leonardo; Starr, Philip A.; Bronte-Stewart, Helen M.; Hu, Wei; McIntyre, Cameron; Goodman, Wayne; Kumsa, Doe; Grill, Warren M.; Walker, Harrison C.; Johnson, Matthew D.; Vitek, Jerrold L.; Greene, David; Rizzuto, Daniel S.; Song, Dong; Berger, Theodore W.; Hampson, Robert E.; Deadwyler, Sam A.; Hochberg, Leigh R.; Schiff, Nicholas D.; Stypulkowski, Paul; Worrell, Greg; Tiruvadi, Vineet; Mayberg, Helen S.; Jimenez-Shahed, Joohi; Nanda, Pranav; Sheth, Sameer A.; Gross, Robert E.; Lempka, Scott F.; Li, Luming; Deeb, Wissam; Okun, Michael S.

2018-01-01

The annual Deep Brain Stimulation (DBS) Think Tank provides a focal opportunity for a multidisciplinary ensemble of experts in the field of neuromodulation to discuss advancements and forthcoming opportunities and challenges in the field. The proceedings of the fifth Think Tank summarize progress in neuromodulation neurotechnology and techniques for the treatment of a range of neuropsychiatric conditions including Parkinson's disease, dystonia, essential tremor, Tourette syndrome, obsessive compulsive disorder, epilepsy and cognitive, and motor disorders. Each section of this overview of the meeting provides insight to the critical elements of discussion, current challenges, and identified future directions of scientific and technological development and application. The report addresses key issues in developing, and emphasizes major innovations that have occurred during the past year. Specifically, this year's meeting focused on technical developments in DBS, design considerations for DBS electrodes, improved sensors, neuronal signal processing, advancements in development and uses of responsive DBS (closed-loop systems), updates on National Institutes of Health and DARPA DBS programs of the BRAIN initiative, and neuroethical and policy issues arising in and from DBS research and applications in practice. PMID:29416498

Evolving Applications, Technological Challenges and Future Opportunities in Neuromodulation: Proceedings of the Fifth Annual Deep Brain Stimulation Think Tank.

PubMed

Ramirez-Zamora, Adolfo; Giordano, James J; Gunduz, Aysegul; Brown, Peter; Sanchez, Justin C; Foote, Kelly D; Almeida, Leonardo; Starr, Philip A; Bronte-Stewart, Helen M; Hu, Wei; McIntyre, Cameron; Goodman, Wayne; Kumsa, Doe; Grill, Warren M; Walker, Harrison C; Johnson, Matthew D; Vitek, Jerrold L; Greene, David; Rizzuto, Daniel S; Song, Dong; Berger, Theodore W; Hampson, Robert E; Deadwyler, Sam A; Hochberg, Leigh R; Schiff, Nicholas D; Stypulkowski, Paul; Worrell, Greg; Tiruvadi, Vineet; Mayberg, Helen S; Jimenez-Shahed, Joohi; Nanda, Pranav; Sheth, Sameer A; Gross, Robert E; Lempka, Scott F; Li, Luming; Deeb, Wissam; Okun, Michael S

2017-01-01

The annual Deep Brain Stimulation (DBS) Think Tank provides a focal opportunity for a multidisciplinary ensemble of experts in the field of neuromodulation to discuss advancements and forthcoming opportunities and challenges in the field. The proceedings of the fifth Think Tank summarize progress in neuromodulation neurotechnology and techniques for the treatment of a range of neuropsychiatric conditions including Parkinson's disease, dystonia, essential tremor, Tourette syndrome, obsessive compulsive disorder, epilepsy and cognitive, and motor disorders. Each section of this overview of the meeting provides insight to the critical elements of discussion, current challenges, and identified future directions of scientific and technological development and application. The report addresses key issues in developing, and emphasizes major innovations that have occurred during the past year. Specifically, this year's meeting focused on technical developments in DBS, design considerations for DBS electrodes, improved sensors, neuronal signal processing, advancements in development and uses of responsive DBS (closed-loop systems), updates on National Institutes of Health and DARPA DBS programs of the BRAIN initiative, and neuroethical and policy issues arising in and from DBS research and applications in practice.

The human brain—from cells to society

PubMed Central

Hoogland, Eva; Patten, Iain; Berghmans, Stephane

2013-01-01

In December 2011, the European Science Foundation (ESF) brought together experts from a wide range of disciplines to discuss the issues that will influence the development of a healthier, more brain-aware European society. This perspective summarizes the main outcomes of that discussion and highlights important considerations to support improved mental health in Europe, including: The development of integrated neuropsychotherapeutic approaches to the treatment of psychiatric disorders.The development of more valid disease models for research into psychiatric disorders.An improved understanding of the relationship between biology and environment, particularly in relation to developmental plasticity and emerging pathology.More comparative studies to explore how scientific concepts relating to the human brain are received and understood in different sociocultural contexts.Research into the legal and ethical implications of recent developments in the brain sciences, including behavioral screening and manipulation, and emerging neurotechnologies. The broad geographical spread of the consulted experts across the whole of Europe, along with the wide range of disciplines they represent, gives these conclusions a strong scientific and pan-European endorsement. The next step will be to look closely into these five selected topics, in terms of research strategy, science policy, societal implications, and legal and ethical frameworks. PMID:23966920

Vulnerability Imposed by Diet and Brain Trauma for Anxiety-Like Phenotype: Implications for Post-Traumatic Stress Disorders

PubMed Central

Tyagi, Ethika; Agrawal, Rahul; Zhuang, Yumei; Abad, Catalina; Waschek, James A.; Gomez-Pinilla, Fernando

2013-01-01

Mild traumatic brain injury (mTBI, cerebral concussion) is a risk factor for the development of psychiatric illness such as posttraumatic stress disorder (PTSD). We sought to evaluate how omega-3 fatty acids during brain maturation can influence challenges incurred during adulthood (transitioning to unhealthy diet and mTBI) and predispose the brain to a PTSD-like pathobiology. Rats exposed to diets enriched or deficient in omega-3 fatty acids (n-3) during their brain maturation period, were transitioned to a western diet (WD) when becoming adult and then subjected to mTBI. TBI resulted in an increase in anxiety-like behavior and its molecular counterpart NPY1R, a hallmark of PTSD, but these effects were more pronounced in the animals exposed to n-3 deficient diet and switched to WD. The n-3 deficiency followed by WD disrupted BDNF signaling and the activation of elements of BDNF signaling pathway (TrkB, CaMKII, Akt and CREB) in frontal cortex. TBI worsened these effects and more prominently in combination with the n-3 deficiency condition. Moreover, the n-3 deficiency primed the immune system to the challenges imposed by the WD and brain trauma as evidenced by results showing that the WD or mTBI affected brain IL1β levels and peripheral Th17 and Treg subsets only in animals previously conditioned to the n-3 deficient diet. These results provide novel evidence for the capacity of maladaptive dietary habits to lower the threshold for neurological disorders in response to challenges. PMID:23483949

Magnetic resonance elastography (MRE) of the human brain: technique, findings and clinical applications

NASA Astrophysics Data System (ADS)

Hiscox, Lucy V.; Johnson, Curtis L.; Barnhill, Eric; McGarry, Matt D. J.; Huston 3rd, John; van Beek, Edwin J. R.; Starr, John M.; Roberts, Neil

2016-12-01

Neurological disorders are one of the most important public health concerns in developed countries. Established brain imaging techniques such as magnetic resonance imaging (MRI) and x-ray computerised tomography (CT) have been essential in the identification and diagnosis of a wide range of disorders, although usually are insufficient in sensitivity for detecting subtle pathological alterations to the brain prior to the onset of clinical symptoms—at a time when prognosis for treatment is more favourable. The mechanical properties of biological tissue provide information related to the strength and integrity of the cellular microstructure. In recent years, mechanical properties of the brain have been visualised and measured non-invasively with magnetic resonance elastography (MRE), a particularly sensitive medical imaging technique that may increase the potential for early diagnosis. This review begins with an introduction to the various methods used for the acquisition and analysis of MRE data. A systematic literature search is then conducted to identify studies that have specifically utilised MRE to investigate the human brain. Through the conversion of MRE-derived measurements to shear stiffness (kPa) and, where possible, the loss tangent (rad), a summary of results for global brain tissue and grey and white matter across studies is provided for healthy participants, as potential baseline values to be used in future clinical investigations. In addition, the extent to which MRE has revealed significant alterations to the brain in patients with neurological disorders is assessed and discussed in terms of known pathophysiology. The review concludes by predicting the trends for future MRE research and applications in neuroscience.

Vulnerability imposed by diet and brain trauma for anxiety-like phenotype: implications for post-traumatic stress disorders.

PubMed

Tyagi, Ethika; Agrawal, Rahul; Zhuang, Yumei; Abad, Catalina; Waschek, James A; Gomez-Pinilla, Fernando

2013-01-01

Mild traumatic brain injury (mTBI, cerebral concussion) is a risk factor for the development of psychiatric illness such as posttraumatic stress disorder (PTSD). We sought to evaluate how omega-3 fatty acids during brain maturation can influence challenges incurred during adulthood (transitioning to unhealthy diet and mTBI) and predispose the brain to a PTSD-like pathobiology. Rats exposed to diets enriched or deficient in omega-3 fatty acids (n-3) during their brain maturation period, were transitioned to a western diet (WD) when becoming adult and then subjected to mTBI. TBI resulted in an increase in anxiety-like behavior and its molecular counterpart NPY1R, a hallmark of PTSD, but these effects were more pronounced in the animals exposed to n-3 deficient diet and switched to WD. The n-3 deficiency followed by WD disrupted BDNF signaling and the activation of elements of BDNF signaling pathway (TrkB, CaMKII, Akt and CREB) in frontal cortex. TBI worsened these effects and more prominently in combination with the n-3 deficiency condition. Moreover, the n-3 deficiency primed the immune system to the challenges imposed by the WD and brain trauma as evidenced by results showing that the WD or mTBI affected brain IL1β levels and peripheral Th17 and Treg subsets only in animals previously conditioned to the n-3 deficient diet. These results provide novel evidence for the capacity of maladaptive dietary habits to lower the threshold for neurological disorders in response to challenges.

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.

Glycogen synthase kinase-3 levels and phosphorylation undergo large fluctuations in mouse brain during development

PubMed Central

Beurel, Eléonore; Mines, Marjelo A; Song, Ling; Jope, Richard S

2012-01-01

Objectives Dysregulated glycogen synthase kinase-3 (GSK3) may contribute to the pathophysiology of mood disorders and other diseases, and appears to be a target of certain therapeutic drugs. The growing recognition of heightened vulnerability during development to many psychiatric diseases, including mood disorders, led us to test if there are developmental changes in mouse brain GSK3 and its regulation by phosphorylation and by therapeutic drugs. Methods GSK3 levels and phosphorylation were measured at seven ages of development in mouse cerebral cortex and hippocampus. Results Two periods of rapid transitions in GSK3 levels were identified, a large rise between postnatal day 1 and two to three weeks of age, where GSK3 levels were as high as four-fold adult mouse brain levels, and a rapid decline between two to four and eight weeks of age, when adult levels were reached. Inhibitory serine-phosphorylation of GSK3, particularly GSK3β, was extremely high in one-day postnatal mouse brain, and rapidly declined thereafter. These developmental changes in GSK3 were equivalent in male and female cerebral cortex, and differed from other signaling kinases, including Akt, ERK1/2, JNK, and p38 levels and phosphorylation. In contrast to adult mouse brain, where administration of lithium or fluoxetine rapidly and robustly increased serine-phosphorylation of GSK3, in young mice these responses were blunted or absent. Conclusions High brain levels of GSK3 and large fluctuations in its levels and phosphorylation in juvenile and adolescent mouse brain raise the possibility that they may contribute to destabilized mood regulation induced by environmental and genetic factors. PMID:23167932

Different Neural Patterns Are Associated with Trials Preceding Inhibitory Errors in Children with and without Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Spinelli, Simona; Joel, Suresh; Nelson, Tess E.; Vasa, Roma A.; Pekar, James J.; Mostofsky, Stewart H.

2011-01-01

Objective: Attention-deficit/hyperactivity disorder (ADHD) is associated with difficulty inhibiting impulsive, hyperactive, and off-task behavior. However, no studies have examined whether a distinct pattern of brain activity precedes inhibitory errors in typically developing (TD) children and children with ADHD. In healthy adults, increased…