Rajaprakash, Meghna; Chakravarty, M Mallar; Lerch, Jason P; Rovet, Joanne
Introduction It is well established that individuals exposed to alcohol in utero have reduced cortical grey matter volumes. However, the candidate determinants of these reductions, cortical thickness (CT) and surface area (SA), have not been investigated exclusively in alcohol-related neurodevelopmental disorder (ARND), the most prevalent fetal alcohol spectrum disorder subgroup that lacks the characteristic facial dysmorphology. Methods T1-weighted magnetic resonance imaging scans were obtained from 88 participants (8–16 years), 36 diagnosed with ARND and 52 typically developing controls. Scans were submitted to the CIVET pipeline (version 1.1.10). Deformable models were used to construct the inner white matter surfaces and pial surfaces from which CT and SA measures were derived. Group differences in cortical volume, CT, and SA were computed using a general linear model covaried for age, sex, and handedness. Results Global cortical volume reductions in ARND did not reflect CT, which did not differ between groups. Instead, volume decreases were consistent with global SA reductions in bilateral frontal and temporal as well as right occipital regions. Local reductions in SA were observed in the right superior temporal gyrus and the right occipital-temporal region. Conclusion Results suggest that in ARND, prenatal alcohol exposure perturbs global SA to a greater degree than CT, particularly in the right temporal lobe. PMID:24653953
Thapar, Anita; Cooper, Miriam; Rutter, Michael
Neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder, although most commonly considered in childhood, can be lifelong conditions. In this Personal View that is shaped by clinical experience and research, we adopt a conceptual approach. First, we discuss what disorders are neurodevelopmental and why such a grouping is useful. We conclude that both distinction and grouping are helpful and that it is important to take into account the strong overlap across neurodevelopmental disorders. Then we highlight some challenges in bridging research and clinical practice. We discuss the complexity of clinical phenotypes and the importance of the social context. We also argue the importance of viewing neurodevelopmental disorders as traits but highlight that this is not the only approach to use. Finally, we consider developmental change across the life-span. Overall, we argue strongly for a flexible approach in clinical practice that takes into consideration the high level of heterogeneity and overlap in neurodevelopmental disorders and for research to link more closely to what is observed in real-life practice.
Information about children reported to have ever been diagnosed with four different neurodevelopmental disorders: attention-deficit/hyperactivity disorder (ADHD), learning disabilities, autism, and intellectual disability.
Robinson-Shelton, Althea; Malow, Beth A
Sleep disturbances are extremely prevalent in children with neurodevelopmental disorders compared to typically developing children. The diagnostic criteria for many neurodevelopmental disorders include sleep disturbances. Sleep disturbance in this population is often multifactorial and caused by the interplay of genetic, neurobiological and environmental overlap. These disturbances often present either as insomnia or hypersomnia. Different sleep disorders present with these complaints and based on the clinical history and findings from diagnostic tests, an appropriate diagnosis can be made. This review aims to provide an overview of causes, diagnosis, and treatment of sleep disturbances in neurodevelopmental disorders that present primarily with symptoms of hypersomnia and/or insomnia.
In this review we examine the current understanding of how genetic deficits associated with neurodevelopmental disorders may impact synapse assembly. We then go on to discuss how the critical periods for these genetic deficits will shape the nature of future clinical interventions. PMID:24990427
With approximately 67 million individuals affected worldwide, autism spectrum disorder (ASD) is the fastest growing neurodevelopmental disorder (United Nations, 2011), with a prevalence estimated to be 1/100. In France ASD affects approximately 600,000 individuals (from childhood to adulthood, half of whom are also mentally retarded), who thus have a major handicap in communication and in adapting to daily life, which leads autism to be recognized as a national public health priority. ASD is a neurodevelopmental disorder that affects several domains (i.e., socio-emotional, language, sensori-motor, executive functioning). These disorders are expressed early in life with an age of onset around 18 months. Despite evidence suggesting a strong genetic link with ASD, the genetic determinant remains unclear. The clinical picture is characterized by impairments in social interaction and communication and the presence of restrictive and repetitive behaviors (DSM-5, ICD-10). However, in addition to these two main dimensions there is significant comorbidity between ASD and other neurodevelopmental disorders such as attention deficit hyperactivity disorder or with genetic and medical conditions. One of the diagnostic features of ASD is its early emergence: symptoms must begin in early childhood for a diagnosis to be given. Due to brain plasticity, early interventions are essential to facilitate clinical improvement. Therefore, general practitioners and pediatricians are on the front line to detect early signs of ASD and to guide both medical explorations and early rehabilitation.
Mastrototaro, Giuseppina; Zaghi, Mattia; Sessa, Alessandro
Epigenetics is the array of the chromatin modifications that customize in cell-, stage-, or condition-specific manner the information encloses in plain DNA molecules. Increasing evidences suggest the importance of epigenetic mechanisms for development and maintenance of central nervous system. In fact, a large number of newly discovered genetic causes of neurodevelopmental disorders such as intellectual disability, autism spectrum disorders, and many other syndromes are mutations within genes encoding for chromatin remodeling enzymes. Here, we review recent findings on the epigenetic origin of human diseases, with emphasis on disorders that affect development of the nervous system, and discuss novel therapeutic avenues that target epigenetic mechanisms.
Wetmore, Daniel Z.; Garner, Craig C.
A growing and interdisciplinary translational neuroscience research effort for neurodevelopmental disorders (NDDs) is investigating the mechanisms of dysfunction and testing effective treatment strategies in animal models and, when possible, in the clinic. NDDs with a genetic basis have received particular attention. Transgenic animals that mimic genetic insults responsible for disease in man have provided insight about mechanisms of dysfunction, and, surprisingly, have shown that cognitive deficits can be addressed in adult animals. This review will present recent translational research based on animal models of genetic NDDs, as well as pharmacotherapeutic strategies under development to address deficits of brain function for Down syndrome, fragile X syndrome, Rett syndrome, neurofibromatosis-1, tuberous sclerosis, and autism. Although these disorders vary in underlying causes and clinical presentation, common pathways and mechanisms for dysfunction have been observed. These include abnormal gene dosage, imbalance among neurotransmitter systems, and deficits in the development, maintenance and plasticity of neuronal circuits. NDDs affect multiple brain systems and behaviors that may be amenable to drug therapies that target distinct deficits. A primary goal of translational research is to replace symptomatic and supportive drug therapies with pharmacotherapies based on a principled understanding of the causes of dysfunction. Based on this principle, several recently developed therapeutic strategies offer clear promise for clinical development in man. PMID:20814256
Contributing reviewers The editors of Journal of Neurodevelopmental Disorders would like to thank all of our reviewers who have contributed to the journal in volume 4 (2012). High quality and timely reviews are critical to the overall quality of the journal. We are committed to providing a unique and important outlet for scholarship regarding neurodevelopmental disorders and are indebted to the outstanding reviewers who have contributed their time over the last year in helping us to reach this goal. PMID:23517765
Racine, Eric; Bell, Emily; Di Pietro, Nina C; Wade, Lucie; Illes, Judy
Many neurodevelopmental disorders affect early brain development in ways that are still poorly understood; yet, these disorders can place an enormous toll on patients, families, and society as a whole and affect all aspects of daily living for patients and their families. We describe a pragmatic, evidence-based framework for engaging in empiric ethics inquiry for a large consortium of researchers in neurodevelopmental disorders and provide relevant case studies of pragmatic neuroethics. The 3 neurodevelopmental disorders that are at the focus of our research, cerebral palsy (CP), autism spectrum disorder (ASD), and fetal alcohol spectrum disorder (FASD), bring unique and intersecting challenges of translating ethically research into clinical care for children and neonates. We identify and discuss challenges related to health care delivery in CP; neonatal neurological decision making; alternative therapies; and identity, integrity, and personhood.
Decker, Scott L.
The role of school psychologists with training in neuropsychology is examined within the context of multitiered models of service delivery and educational reform policies. An expanded role is suggested that builds on expertise in the assessment of neurodevelopmental disorders and extends to broader tiers through consultation practice. Changes in…
Valente, Enza Maria; Rosti, Rasim O.; Gibbs, Elizabeth; Gleeson, Joseph G.
Primary cilia are generally solitary organelles that emanate from the surface of almost all vertebrate cell types. Until recently, details regarding the function of these structures were lacking; however, extensive evidence now suggests that primary cilia have critical roles in sensing the extracellular environment, and in coordinating developmental and homeostatic signalling pathways. Furthermore, disruption of these functions seems to underlie a diverse spectrum of disorders, known as primary ciliopathies. These disorders are characterized by wide-ranging clinical and genetic heterogeneity, but with substantial overlap among distinct conditions. Indeed, ciliopathies are associated with a large variety of manifestations that often include distinctive neurological findings. Herein, we review neurological features associated with primary ciliopathies, highlight genotype–phenotype correlations, and discuss potential mechanisms underlying these findings. PMID:24296655
Verkhratsky, Alexei; Parpura, Vladimir
Astroglial cells represent a main element in the maintenance of homeostasis and providing defense to the brain. Consequently, their dysfunction underlies many, if not all, neurological, neuropsychiatric and neurodegenerative disorders. General astrogliopathy is evident in diametrically opposing morpho-functional changes in astrocytes, i.e. their hypertrophy along with reactivity or atrophy with asthenia. Neurological disorders with astroglial participation can be genetic, of which Alexander disease is a primary sporadic astrogliopathy, environmentally caused, such as heavy metal encephalopathies, or neurodevelopmental in origin. Astroglia also play a role in major neuropsychiatric disorders, ranging from schizophrenia to depression, as well as in additive disorders. Furthermore, astroglia contribute to neurodegenerative processes seen in amyotrophic lateral sclerosis, Alzheimer’s and Huntington’s diseases. PMID:25843667
Award Number: W81XWH-11-1-0365 TITLE: Defining Early Markers of Neurodevelopmental Disorders in Infants With TSC PRINCIPAL...SUBTITLE Defining Early Markers of Neurodevelopmental Disorders in Infants With TSC 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-1-0365 5c...the “Defining Early Markers of Neurodevelopmental Disorders in Infants with TSC” project, administrative set-up of the collaborative project and IRB
Dirani, Leyla Akoury; Salamoun, Mariana
Children with neurodevelopmental disorders who receive early therapeutic interventions present a better developmental pathway than children who do not. Early assessment of neurodevelopmental disorders is the first step in this process. This study aims at describing the variables that are in play in the first assessment of children with autism…
van Loo, K.M.J; Martens, G.J.M
Complex neurodevelopmental disorders, such as schizophrenia, autism, attention deficit (hyperactivity) disorder, (manic) depressive illness and addiction, are thought to result from an interaction between genetic and environmental factors. Association studies on candidate genes and genome-wide linkage analyses have identified many susceptibility chromosomal regions and genes, but considerable efforts to replicate association have been surprisingly often disappointing. Here, we summarize the current knowledge of the genetic contribution to complex neurodevelopmental disorders, focusing on the findings from association and linkage studies. Furthermore, the contribution of the interaction of the genetic with environmental and epigenetic factors to the aetiology of complex neurodevelopmental disorders as well as suggestions for future research are discussed. PMID:19412416
Cioni, Giovanni; Inguaggiato, Emanuela; Sgandurra, Giuseppina
Neurodevelopmental disorders affect motor, cognitive, language, learning, and behavioural development with lifelong consequences. Early identification of infants at risk for neurodevelopmental disorders is a major prerequisite for intervention programmes. This ensures that interventions which aim to positively modify the natural history of these disorders can start in the first weeks or months of life. As indicated by recent scientific evidence, gene abnormalities or congenital brain lesions are not the sole determinants for the neurodevelopmental outcome of affected infants. In fact, environment and experience may modify brain development and improve the outcome in infants at risk for neurodevelopmental disorders. In this review, we analyse the complexity and sensitivity of the brain to environmental stimuli, highlighting clinical effects of early intervention, mainly reported so far in preterm infants, and summarizing the effects of enriched environment on human and animal models. Finally, we discuss some new approaches to early intervention, based on recent neurophysiological theories and new breakthroughs in biotechnologies for diagnosis and rehabilitation.
Tics are repetitive, sharp, rapid, non-rhythmic movements or utterances that are the result of sudden, abrupt and involuntary muscular contractions. Stereotypies are repetitive, apparently impulsive, rhythmic, purposeless movements that follow an individual repertoire that is specific to each individual and that occur under a variable time pattern, which may be either transient or persistent. Both are included in the Diagnostic and statistical manual of mental disorders, fifth edition (DSM-5), among the neurodevelopmental disorders, and together with coordination development disorder go to make up the group of motor disorders. For tics, the categories of 'Tourette's disorder', 'chronic motor or vocal tic disorder' and 'unspecified tic disorder' have been maintained, whereas the category 'transient tics' has disappeared and 'provisional tic disorder' and 'other specified tic disorders' have been incorporated. Within stereotypic movement disorder, the DSM-5 replaces 'non-functional' by 'apparently purposeless'; the thresholds of the need for medical care are withdrawn and replaced with the manual's standard involvement criterion; mental retardation is no longer mentioned and emphasis is placed on the severity of the stereotypic movement; and a criterion concerning the onset of symptoms and specifiers of the existence or not of self-injurious behaviours have been added, together with the association with genetic or general medical diseases or extrinsic factors. Moreover, a categorisation depending on severity has also been included.
Gauffin, Karl; Vinnerljung, Bo; Hjern, Anders
Background Alcohol misuse is an important global health determinant and a major contributor to health inequalities. We aimed to investigate the association between school performance and alcohol-related disorders in early adulthood in a longitudinal register-based national cohort study. Methods We followed a register-based national cohort of Swedish citizens born 1973–1984 (N = 948 440) from compulsory school graduation at age 15–16 to 2009. We divided the population into five groups: high school marks (> mean + 1 SD); high average (between mean and mean + 1 SD); low average (between mean and mean − 1 SD); low (< mean – 1SD); and missing. Cox proportional hazard models were used to investigate the relation between school marks at time of graduation and hospital care for alcohol-related disorders in early adulthood. Results There was a steep gradient in the risk of alcohol-related disorders related to school performance. In comparison with peers in the top category of school marks, students with low marks had adjusted hazard ratios of 8.02 [95% confidence interval (CI) 7.20 to 8.91], low average 3.02 (2.72 to 3.35) and high average 1.55 (1.39 to 1.73). The risk associated with low school marks was stronger in the male population and in the group from high socioeconomic background. Conclusions The study demonstrated a strong graded relation between low school performance and alcohol-related disorders in young adulthood. School performance should be taken into account when developing prevention programmes/policies targeting alcohol misuse among teenagers and young adults, especially if the aim is to reach high-risk groups. PMID:25797580
Children with neurodevelopmental disorders are at risk of sleep problems, typically difficulty getting to sleep, sleep/wake rhythm disturbances and reduced duration of sleep (insomnia). This may be associated with abnormally timed or inadequate secretion of melatonin, a naturally-occurring hormone involved in coordinating the body's sleep-wake cycle. Previously, we reviewed the use of a melatonin product licensed for primary insomnia in adults aged over 55 years. Here we review off-label and unlicensed use of melatonin in children with attention-deficit hyperactivity disorder (ADHD) or autism spectrum disorder or related neurodevelopmental disorders.
Chattopadhyaya, Bidisha; Cristo, Graziella Di
GABAergic interneurons control neuronal excitability, integration, and plasticity. Further, they regulate the generation of temporal synchrony and oscillatory behavior among networks of pyramidal neurons. Such oscillations within and across neural systems are believed to serve various complex functions, such as perception, movement initiation, and memory. Alterations in the development of GABAergic circuits have been implicated in various brain diseases with neurodevelopmental origin. Here, we highlight recent studies suggesting a role for alterations of GABA transmission in the pathophysiology of two neurodevelopmental diseases, schizophrenia, and autism. We further discuss how manipulations of GABA signaling may be used for novel therapeutic interventions.
Sullivan, Peter B.
Children with neurodevelopmental disabilities such as cerebral palsy (CP), spina bifida, or inborn errors of metabolism frequently have associated gastrointestinal problems. These include oral motor dysfunction leading to feeding difficulties, risk of aspiration, prolonged feeding times, and malnutrition with its attendant physical compromise.…
Mouga, Susana; Café, Cátia; Almeida, Joana; Marques, Carla; Duque, Frederico; Oliveira, Guiomar
The influence of specific autism spectrum disorder (ASD) deficits in Intelligence Quotients (IQ), Indexes and subtests from the Wechsler Intelligence Scale for Children-III was investigated in 445 school-aged children: ASD (N = 224) and other neurodevelopmental disorders (N = 221), matched by Full-Scale IQ and chronological age. ASD have lower…
Mouga, Susana; Almeida, Joana; Café, Cátia; Duque, Frederico; Oliveira, Guiomar
We investigated the influence of specific autism spectrum disorder (ASD) deficits in learning adaptive behaviour, besides intelligence quotient (IQ). Participated 217 school-aged: ASD (N = 115), and other neurodevelopmental disorders (OND) groups (N = 102) matched by Full-Scale IQ. We compared standard scores of Vineland Adaptive Behaviour Scale…
Silva, Alcino J; Ehninger, Dan
Recent findings in mice suggest that it is possible to reverse certain neurodevelopmental disorders in adults. Changes in development, previously thought to be irreparable in adults, were believed to underlie the neurological and psychiatric phenotypes of a range of common mental health problems with a clear developmental component. As a consequence, most researchers have focused their efforts on understanding the molecular and cellular processes that alter development with the hope that early intervention could prevent the emergent pathology. Unexpectedly, several different animal model studies published recently, including animal models of autism, suggest that it may be possible to reverse neurodevelopmental disorders in adults: Addressing the underlying molecular and cellular deficits in adults could in several cases dramatically improve the neurocognitive phenotypes in these animal models. The findings reviewed here provide hope to millions of individuals afflicted with a wide range of neurodevelopmental disorders, including autism, since they suggest that it may be possible to treat or even cure them in adults.
Background Inpatient care for alcohol intoxication is increasing in Sweden, especially among young women. Since it is well known that alcohol disorder is a chronic relapsing illness, this study examines the extent to which people return for more care. Method All inpatients with alcohol-related diagnoses in Stockholm County during 1997 were followed prospectively to 2007 through registers. The proportion reappearing for the same diagnosis, other alcohol-related inpatient, or outpatient care each year after baseline, as well as the number of years the inpatients reappeared were calculated (n = 2735). Three diagnoses were examined separately; alcohol dependence, harmful use of alcohol, and alcohol intoxication. Results Three out of five inpatients with an alcohol diagnoses reappeared for more alcohol-related inpatient care during the following decade. The proportion returning was largest the year after baseline and then decreased curvilinearly over time. The inclusion of outpatient care increased proportions, but did not change patterns. Of those with an alcohol dependence diagnosis at baseline 42 percent returned for more alcohol-related inpatient care the first, 28 percent the fifth, and 25 percent the tenth year. Corresponding proportions for harmful use and intoxication were smaller. One in five among those with an alcohol dependence returned for more than five of the ten years. Ordered logistic regressions confirmed that besides diagnosis, age and gender were independently related to the number of years returning to care. Conclusions While middle-aged males with alcohol dependence were in a revolving door, young female inpatients with intoxication diagnosis returned to a comparably lower degree. PMID:21771291
Ullman, Michael T.; Pullman, Mariel Y.
Most research on neurodevelopmental disorders has focused on their abnormalities. However, what remains intact may also be important. Increasing evidence suggests that declarative memory, a critical learning and memory system in the brain, remains largely functional in a number of neurodevelopmental disorders. Because declarative memory remains functional, and because this system can learn and retain numerous types of information, functions, and tasks, it should be able to play compensatory roles for multiple types of impairments across the disorders. Here, we examine this hypothesis for specific language impairment, dyslexia, autism spectrum disorder, Tourette syndrome, and obsessive-compulsive disorder. We lay out specific predictions for the hypothesis and review existing behavioral, electrophysiological, and neuroimaging evidence. Overall, the evidence suggests that declarative memory indeed plays compensatory roles for a range of impairments across all five disorders. Finally, we discuss diagnostic, therapeutic and other implications. PMID:25597655
Fernández-Jaén, Alberto; Cigudosa, Juan C; Martín Fernández-Mayoralas, Daniel; Suela, Javier; Fernández-Perrone, Ana L; Calleja-Pérez, Beatriz; López-Martín, Sara
The medical literature contains a wide body of evidence supporting genetic involvement in neurodevelopmental disorders. Advances made in genetics and technology have increased the diagnostic cost-effectiveness of current studies from 3-5% to 30-40% in patients with intellectual disability or autism spectrum disorders. In this regard, chromosomal microarray studies display greater diagnostic power than conventional techniques (karyotype, subtelomeric analyses, etc.). The latest protocols in the biomedical field of the genetic study of these disorders cite chromosomal microarrays as the first-line analysis, while also recommending other specific studies depending on the patient's clinical features (fragile X syndrome, PTEN mutation, etc.). In the evaluation of other neurodevelopmental disorders (attention deficit hyperactivity disorder, learning disorders, etc.), the number of genetic tests carried out is limited and conditioned by the clinical characteristics or the patient's familial or personal history. Even in these situations, there are no genetic referral or evaluation protocols.
Di Pietro, Nina C.; Whiteley, Louise; Mizgalewicz, Ania; Illes, Judy
The Internet is a major source of health-related information for parents of sick children despite concerns surrounding quality. For neurodevelopmental disorders, the websites of advocacy groups are a largely unexamined source of information. We evaluated treatment information posted on nine highly-trafficked advocacy websites for autism, cerebral…
Boivin, Michael J; Kakooza, Angelina M; Warf, Benjamin C; Davidson, Leslie L; Grigorenko, Elena L
We define neurodevelopment as the dynamic inter-relationship between genetic, brain, cognitive, emotional and behavioural processes across the developmental lifespan. Significant and persistent disruption to this dynamic process through environmental and genetic risk can lead to neurodevelopmental disorders and disability. Research designed to ameliorate neurodevelopmental disorders in low- and middle-income countries, as well as globally, will benefit enormously from the ongoing advances in understanding their genetic and epigenetic causes, as modified by environment and culture. We provide examples of advances in the prevention and treatment of, and the rehabilitation of those with, neurodevelopment disorders in low- and middle-income countries, along with opportunities for further strategic research initiatives. Our examples are not the only possibilities for strategic research, but they illustrate problems that, when solved, could have a considerable impact in low-resource settings. In each instance, research in low- and middle-income countries led to innovations in identification, surveillance and treatment of a neurodevelopmental disorder. These innovations have also been integrated with genotypic mapping of neurodevelopmental disorders, forming important preventative and rehabilitative interventions with the potential for high impact. These advances will ultimately allow us to understand how epigenetic influences shape neurodevelopmental risk and resilience over time and across populations. Clearly, the most strategic areas of research opportunity involve cross-disciplinary integration at the intersection between the environment, brain or behaviour neurodevelopment, and genetic and epigenetic science. At these junctions a robust integrative cross-disciplinary scientific approach is catalysing the creation of technologies and interventions for old problems. Such approaches will enable us to achieve and sustain the United Nations moral and legal mandate for
Billstedt, Eva; Anckarsäter, Henrik; Wallinius, Märta; Hofvander, Björn
Neurodevelopmental disorders (Attention-Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), tic disorder, intellectual disability (ID)), in prison populations have received increased attention but the focus has generally been on one single condition leaving out the global picture. This study assessed the prevalence and overlap of neurodevelopmental disorders (NDD) in a consecutive cohort (n=270) of young adult male offenders (age 18-25 years), sentenced for "hands-on" violent offences and serving prison time in Swedish prisons. Seventy-one percent of all who met inclusion criteria participated. Comprehensive clinical assessments were carried out including history of early antisocial behavior and maladjustment, self-report questionnaires and an intelligence test. Sixty-three percent of the study group met DSM-IV criteria for childhood ADHD, 43% for ADHD in adulthood, 10% met criteria for an ASD, 6% for Tourette syndrome, and 1% for ID. Twenty-two percent had borderline intellectual functioning. A substantial rate of overlap between the NDDs was found. The combined NDD group had an earlier onset of antisocial behavior, had more aggressive behavior and lower school achievements than the non-NDD group. The results highlight the need for prison and probation services to be attentive of and screen for neurodevelopmental disorders in young violent offenders.
Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.
Hsiao, Elaine Y; McBride, Sara W; Hsien, Sophia; Sharon, Gil; Hyde, Embriette R; McCue, Tyler; Codelli, Julian A; Chow, Janet; Reisman, Sarah E; Petrosino, Joseph F; Patterson, Paul H; Mazmanian, Sarkis K
Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.
De Leersnyder, Hélène; Zisapel, Nava; Laudon, Moshe
Previous studies demonstrated the efficacy and safety of prolonged-release melatonin in children and adolescents with neurodevelopmental and behavioral disorders. The long-term effectiveness and safety of prolonged-release melatonin treatment were assessed in 88 children (42 girls and 46 boys) with neurodevelopmental disorders. These patients participated in a compassionate-use program with the drug Circadin (2 mg; Neurim Pharmaceuticals, Tel Aviv, Israel) in France, and received treatment in the context of regular care by a specialized physician. The study involved a structured questionnaire for the parents, comprising a combination of multiple-choice and numeric questions addressing sleep onset/offset, sleep quality problems, and mood. The dose of melatonin ranged from 4-6 mg, and treatment duration ranged from 6-72 months. Within 3 months, sleep latency with prolonged-release melatonin decreased by 44.0% (P < 0.001), sleep duration increased by 10.1% (P < 0.001), the number of awakenings decreased by 75% (P < 0.001), and sleep quality improved by 75%, compared with baseline (P < 0.001). No serious adverse events or treatment-related comorbidities were reported. Prolonged-release melatonin remains a safe, effective therapy for the long-term treatment of sleep disorders in children with neurodevelopmental disorders.
A dysfunction of cortical and limbic GABAergic circuits has been postulated to contribute to multiple neurodevelopmental disorders in humans, including schizophrenia, autism, and epilepsy. In the current paper, I summarize the characteristics that underlie the great diversity of cortical GABAergic interneurons and explore how the multiple roles of these cells in developing and mature circuits might contribute to the aforementioned disorders. Furthermore, I review the tightly controlled genetic cascades that determine the fate of cortical interneurons and summarize how the dysfunction of genes important for the generation, specification, maturation, and function of cortical interneurons might contribute to these disorders. PMID:21876820
Tenorio, Marcela; Campos, Ruth; Karmiloff-Smith, Annette
In this article we critique the use of traditional standardized tests for the cognitive assessment of children with neurodevelopmental disorders. Limitations stem from the lack of integrating (a) results from research into the psychological functioning of these populations, and (b) the main arguments underlying models of human development. We identify four secondary issues in this discussion: (1) these instruments cannot be used with children who have particularly low cognitive functioning; (2) little or no variance in the scores obtained by individuals with neurodevelopmental disorders, because all are at floor, prevent adequate interpretations; (3) measurements do not provide information useful for the design of intervention strategies; and (4) different cognitive and/or neural processes may underlie behavioural scores ‘in the normal range’. Rethinking traditional assessment methods in favour of technologically-mediated games yields new cognitive assessment possibilities. PMID:26778874
Schatz, Jeffrey; McClellan, Catherine B.
Sickle cell disease (SCD) is a blood disorder; however, the central nervous system (CNS) is one of the organs frequently affected by the disease. Brain disease can begin early in life and often leads to neurocognitive dysfunction. Approximately one-fourth to one-third of children with SCD have some form of CNS effects from the disease, which…
Hu, Chun; Chen, Wenjuan; Myers, Scott J.; Yuan, Hongjie; Traynelis, Stephen F.
The development of whole exome/genome sequencing technologies has given rise to an unprecedented volume of data linking patient genomic variability to brain disorder phenotypes. A surprising number of variants have been found in the N-methyl-D-aspartate receptor (NMDAR) gene family, with the GRIN2B gene encoding the GluN2B subunit being implicated in many cases of neurodevelopmental disorders, which are psychiatric conditions originating in childhood and include language, motor, and learning disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay, epilepsy, and schizophrenia. The GRIN2B gene plays a crucial role in normal neuronal development and is important for learning and memory. Mutations in human GRIN2B were distributed throughout the entire gene in a number of patients with various neuropsychiatric and developmental disorders. Studies that provide functional analysis of variants are still lacking, however current analysis of de novo variants that segregate with disease cases such as intellectual disability, developmental delay, ASD or epileptic encephalopathies reveal altered NMDAR function. Here, we summarize the current reports of disease-associated variants in GRIN2B from patients with multiple neurodevelopmental disorders, and discuss implications, highlighting the importance of functional analysis and precision medicine therapies. PMID:27818011
Dykens, Elisabeth M.
Purpose of review Developmental disabilities are increasingly recognized, and remarkable progress is being made on the genetic and neurobiological underpinnings of many disorders. Yet, only a tiny percentage of the disability literature addresses families of children with disabilities. A review of recently published family studies reveals salient trends and gaps. Recent findings Consistent with previous work, high levels of parent stress, illness, anxiety, and depression are apparent. Studies in the USA focused on parents of children with autism; in contrast, studies on parents of children with intellectual disabilities were almost always conduced abroad. Compared to other disabilities, families of children with psychiatric disorders and genetic syndromes are understudied. The majority of family studies are descriptive, with very few trials or interventions aimed at reducing parental stress. Of these, mindfulness practices and a peer-mentor model of treatment delivery hold much promise for effective stress reduction. Psychoeducational programs and respite care are differentially beneficial. Summary A new era of family intervention research is in order. This work can take advantage of many advances in telemedicine, peer-mentor models, smart technology, and biomarkers as indices of change. Benefit could also stem from group interventions with parents who share similar concerns, regardless of their child’s diagnostic label. PMID:25594421
Crawley, Jacqueline N
Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.
Lundström, Sebastian; Forsman, Mats; Larsson, Henrik; Kerekes, Nora; Serlachius, Eva; Långström, Niklas; Lichtenstein, Paul
The longitudinal relationship between attention deficit hyperactivity disorder (ADHD) and violent criminality has been extensively documented, while long-term effects of autism spectrum disorders (ASDs), tic disorders (TDs), and obsessive compulsive disorder (OCD) on criminality have been scarcely studied. Using population-based registers of all child and adolescent mental health services in Stockholm, we identified 3,391 children, born 1984-1994, with neurodevelopmental disorders, and compared their risk for subsequent violent criminality with matched controls. Individuals with ADHD or TDs were at elevated risk of committing violent crimes, no such association could be seen for ASDs or OCD. ADHD and TDs are risk factors for subsequent violent criminality, while ASDs and OCD are not associated with violent criminality.
Levin, Michael E.; Lillis, Jason; Seeley, John; Hayes, Steven C.; Pistorello, Jacqueline; Biglan, Anthony
Objective: This study explored the relationship of experiential avoidance (eg, the tendency to avoid, suppress, or otherwise control internal experiences even when doing so causes behavioral harm) to alcohol use disorders and alcohol-related problems. Participants: Cross-sectional data were collected from 240 undergraduate college students in…
Cristino, A S; Williams, S M; Hawi, Z; An, J-Y; Bellgrove, M A; Schwartz, C E; Costa, L da F; Claudianos, C
Many putative genetic factors that confer risk to neurodevelopmental disorders such as autism spectrum disorders (ASDs) and X-linked intellectual disability (XLID), and to neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and schizophrenia (SZ) have been identified in individuals from diverse human populations. Although there is significant aetiological heterogeneity within and between these conditions, recent data show that genetic factors contribute to their comorbidity. Many studies have identified candidate gene associations for these mental health disorders, albeit this is often done in a piecemeal fashion with little regard to the inherent molecular complexity. Here, we sought to abstract relationships from our knowledge of systems level biology to help understand the unique and common genetic drivers of these conditions. We undertook a global and systematic approach to build and integrate available data in gene networks associated with ASDs, XLID, ADHD and SZ. Complex network concepts and computational methods were used to investigate whether candidate genes associated with these conditions were related through mechanisms of gene regulation, functional protein-protein interactions, transcription factor (TF) and microRNA (miRNA) binding sites. Although our analyses show that genetic variations associated with the four disorders can occur in the same molecular pathways and functional domains, including synaptic transmission, there are patterns of variation that define significant differences between disorders. Of particular interest is DNA variations located in intergenic regions that comprise regulatory sites for TFs or miRNA. Our approach provides a hypothetical framework, which will help discovery and analysis of candidate genes associated with neurodevelopmental and neuropsychiatric disorders.
Parikshak, Neelroop N.; Gandal, Michael J.; Geschwind, Daniel H.
Genetic and genomic approaches have implicated hundreds of genetic loci in neurodevelopmental disorders and neurodegeneration, but mechanistic understanding continues to lag behind the pace of gene discovery. Understanding the role of specific genetic variants in the brain involves dissecting a functional hierarchy that encompasses molecular pathways, diverse cell types, neural circuits and, ultimately, cognition and behaviour. With a focus on transcriptomics, this Review discusses how high-throughput molecular, integrative and network approaches inform disease biology by placing human genetics in a molecular systems and neurobiological context. We provide a framework for interpreting network biology studies and leveraging big genomics data sets in neurobiology. PMID:26149713
Jawaid, A.; Riby, D. M.; Owens, J.; White, S. W.; Tarar, T.; Schulz, P. E.
In some neuro-developmental disorders, the combined effect of intellectual disability and atypicalities of social cognition may put individuals at increased vulnerability in their social environment. The neuro-developmental disorders Williams syndrome, characterised by "hypersociability", and autism spectrum disorders, characterised by "social…
Kundakovic, Marija; Jaric, Ivana
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
Mouga, Susana; Café, Cátia; Almeida, Joana; Marques, Carla; Duque, Frederico; Oliveira, Guiomar
The influence of specific autism spectrum disorder (ASD) deficits in Intelligence Quotients (IQ), Indexes and subtests from the Wechsler Intelligence Scale for Children-III was investigated in 445 school-aged children: ASD (N = 224) and other neurodevelopmental disorders (N = 221), matched by Full-Scale IQ and chronological age. ASD have lower scores in the VIQ than PIQ. The core distinctive scores between groups are Processing Speed Index and "Comprehension" and "Coding" subtests with lower results in ASD. ASD group with normal/high IQ showed highest score on "Similarities" subtest whereas the lower IQ group performed better on "Object Assembly". The results replicated our previous work on adaptive behaviour, showing that adaptive functioning is positively correlated with intellectual profile, especially with the Communication domain in ASD.
Schmitt, L. Ian; Halassa, Michael M.
While localizing sensory and motor deficits is one of the cornerstones of clinical neurology, behavioral and cognitive deficits in psychiatry remain impervious to this approach. In psychiatry, major challenges include the relative subtlety by which neural circuits are perturbed, and the limited understanding of how basic circuit functions relate to thought and behavior. Neurodevelopmental disorders offer a window to addressing the first challenge given their strong genetic underpinnings, which can be linked to biological mechanisms. Such links have benefited from genetic modeling in the mouse, and in this review we highlight how this small mammal is now allowing us to crack neural circuits as well. We review recent studies of mouse thalamus, discussing how they revealed general principles that may underlie human perception and attention. Controlling the magnitude (gain) of thalamic sensory responses is a mechanism of attention, and the mouse has enabled its functional dissection at an unprecedented resolution. Further, modeling human genetic neurodevelopmental disease in the mouse has shown how diminished thalamic gain control can lead to attention deficits. This breaks new ground in how we untangle the complexity of psychiatric diseases; by making thalamic circuits accessible to mechanistic dissection, the mouse has not only taught us how they fundamentally work, but also how their dysfunction can be precisely mapped onto behavioral and cognitive deficits. Future studies promise even more progress, with the hope that principled targeting of identified thalamic circuits can be uniquely therapeutic. PMID:27725660
Venker, Courtney E.; Kover, Sara T.
Purpose: Eye-gaze methods have the potential to advance the study of neurodevelopmental disorders. Despite their increasing use, challenges arise in using these methods with individuals with neurodevelopmental disorders and in reporting sufficient methodological detail such that the resulting research is replicable and interpretable. Method: This…
Bozkurt, Muge; Evren, Cuneyt; Umut, Gokhan; Evren, Bilge
Purpose Attention-deficit/hyperactivity disorder (ADHD) has been shown to be related to a higher risk of developing psychiatric problems such as depressive disorders, substance use disorder, and impulsivity. Adults who have comorbid ADHD and alcohol use disorder (AUD) are at greater risk of negative outcomes. Thus, it is important to evaluate the relationship of ADHD symptoms and the severity of alcohol-related problems among patients with AUD. The aim of the present study was to evaluate the effect of ADHD symptoms on severity of alcohol-related problems, while controlling the effects of depression and impulsivity in a sample of inpatients with AUD. Patients and methods Participants (n=190) were evaluated with the Beck Depression Inventory, the Short Form Barratt Impulsiveness Scale, the Michigan Alcohol Screening Test, and the Adult ADHD Self-Report Scale. Results Severity of the scale scores was positively correlated with each other. Although severity of depression and impulsivity (particularly non-planning impulsivity) predicted the severity of alcohol-related problems in a linear regression model, when severity of ADHD symptoms was included in the analysis, the inattentive subscale score, in particular, predicted the severity of alcohol-related problems together with non-planning impulsivity, whereas depression was no longer a predictor. Conclusion These findings suggest that, together with non-planning impulsivity, symptoms of ADHD (particularly inattentive factor) are an important factor that predict alcohol-related problems, while controlling the severity of depressive symptoms among inpatients with AUD. PMID:27462159
Vinet, É; Pineau, C A; Clarke, A E; Fombonne, É; Platt, R W; Bernatsky, S
Children born to women with systemic lupus erythematosus seem to have a potentially increased risk of neurodevelopmental disorders compared to children born to healthy women. Recent experimental data suggest in utero exposure to maternal antibodies and cytokines as important risk factors for neurodevelopmental disorders. Interestingly, women with systemic lupus erythematosus display high levels of autoantibodies and cytokines, which have been shown, in animal models, to alter fetal brain development and induce behavioral anomalies in offspring. Furthermore, subjects with systemic lupus erythematosus and neurodevelopmental disorders share a common genetic predisposition, which could impair the fetal immune response to in utero immunologic insults. Moreover, systemic lupus erythematosus pregnancies are at increased risk of adverse obstetrical outcomes and medication exposures, which have been implicated as potential risk factors for neurodevelopmental disorders. In this article, we review the current state of knowledge on neurodevelopmental disorders and their potential determinants in systemic lupus erythematosus offspring.
Brandler, William M; Paracchini, Silvia
Handedness and brain asymmetry have been linked to neurodevelopmental disorders such as dyslexia and schizophrenia. The genetic nature of this correlation is not understood. Recent discoveries have shown handedness is determined in part by the biological pathways that establish left/right (LR) body asymmetry during development. Cilia play a key role in this process, and candidate genes for dyslexia have also been recently shown to be involved in cilia formation. Defective cilia result not only in LR body asymmetry phenotypes but also brain midline phenotypes such as an absent corpus callosum. These findings suggest that the mechanisms for establishing LR asymmetry in the body are reused for brain midline development, which in turn influences traits such as handedness and reading ability.
Ohshima, Makiko; Coq, Jacques-Olivier; Otani, Kentaro; Hattori, Yorito; Ogawa, Yuko; Sato, Yoshiaki; Harada-Shiba, Mariko; Ihara, Masafumi; Tsuji, Masahiro
Severe intrauterine ischemia is detrimental to the developing brain. The impact of mild intrauterine hypoperfusion on neurological development, however, is still unclear. We induced mild intrauterine hypoperfusion in rats on embryonic day 17 via arterial stenosis with metal microcoils wrapped around the uterine and ovarian arteries. All pups were born with significantly decreased birth weights. Decreased gray and white matter areas were observed without obvious tissue damage. Pups presented delayed newborn reflexes, muscle weakness, and altered spontaneous activity. The levels of proteins indicative of inflammation and stress in the vasculature, i.e., RANTES, vWF, VEGF, and adiponectin, were upregulated in the placenta. The levels of mRNA for proteins associated with axon and astrocyte development were downregulated in fetal brains. The present study demonstrates that even mild intrauterine hypoperfusion can alter neurological development, which mimics the clinical signs and symptoms of children with neurodevelopmental disorders born prematurely or with intrauterine growth restriction. PMID:27996031
Borre, Yuliya E; O'Keeffe, Gerard W; Clarke, Gerard; Stanton, Catherine; Dinan, Timothy G; Cryan, John F
Gut microbiota is essential to human health, playing a major role in the bidirectional communication between the gastrointestinal tract and the central nervous system. The microbiota undergoes a vigorous process of development throughout the lifespan and establishes its symbiotic rapport with the host early in life. Early life perturbations of the developing gut microbiota can impact neurodevelopment and potentially lead to adverse mental health outcomes later in life. This review compares the parallel early development of the intestinal microbiota and the nervous system. The concept of parallel and interacting microbial-neural critical windows opens new avenues for developing novel microbiota-modulating based therapeutic interventions in early life to combat neurodevelopmental deficits and brain disorders.
Bermejo, I; Frank, F
In migrants alcohol-related problems increase with increasing age. This group, in particular, is hardly reached by alcohol-specific care offers. Thus our project aimed at the identification of target group-specific barriers to health-care use by means of a cross-sectional study (n=435). Based on these results a trans-cultural concept for alcohol prevention among elderly migrants was developed and evaluated in a cluster-randomised controlled trial (n=176).
Twin and family studies have demonstrated that most cognitive traits are moderately to highly heritable. Neurodevelopmental disorders such as dyslexia, autism, and specific language impairment (SLI) also show strong genetic influence. Nevertheless, it has proved difficult for researchers to identify genes that would explain substantial amounts of variance in cognitive traits or disorders. Although this observation may seem paradoxical, it fits with a multifactorial model of how complex human traits are influenced by numerous genes that interact with one another, and with the environment, to produce a specific phenotype. Such a model can also explain why genetic influences on cognition have not vanished in the course of human evolution. Recent linkage and association studies of SLI and dyslexia are reviewed to illustrate these points. The role of nonheritable genetic mutations (sporadic copy number variants) in causing autism is also discussed. Finally, research on phenotypic correlates of allelic variation in the genes ASPM and microcephalin is considered; initial interest in these as genes for brain size or intelligence has been dampened by a failure to find phenotypic differences in people with different versions of these genes. There is a current vogue for investigators to include measures of allelic variants in studies of cognition and cognitive disorders. It is important to be aware that the effect sizes associated with these variants are typically small and hard to detect without extremely large sample sizes. PMID:19338500
Dajani, Dina R; Llabre, Maria M; Nebel, Mary Beth; Mostofsky, Stewart H; Uddin, Lucina Q
Executive functions (EFs) are used to set goals, plan for the future, inhibit maladaptive responses, and change behavior flexibly. Although some studies point to specific EF profiles in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) - prevalent and often highly comorbid neurodevelopmental disorders - others have not differentiated them. The objective of the current study was to identify distinct profiles of EF across typically developing (TD) children and children with ASD and ADHD. We employed a latent profile analysis using indicators of EF (e.g., working memory, inhibition, and flexibility) in a mixed group of 8-13 year-olds including TD children (n = 128), children with ASD without ADHD (n = 30), children with ADHD (n = 93), and children with comorbid ASD and ADHD (n = 66). Three EF classes emerged: "above average," "average," and "impaired." EF classes did not reproduce diagnostic categories, suggesting that differences in EF abilities are present within the ASD and ADHD groups. Further, greater EF dysfunction predicted more severe socioemotional problems, such as anxiety/depression. These results highlight the heterogeneity of current diagnostic groups and identify an "impaired" EF group, consisting of children with both ASD and ADHD, which could specifically be targeted for EF intervention.
Dajani, Dina R.; Llabre, Maria M.; Nebel, Mary Beth; Mostofsky, Stewart H.; Uddin, Lucina Q.
Executive functions (EFs) are used to set goals, plan for the future, inhibit maladaptive responses, and change behavior flexibly. Although some studies point to specific EF profiles in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) — prevalent and often highly comorbid neurodevelopmental disorders — others have not differentiated them. The objective of the current study was to identify distinct profiles of EF across typically developing (TD) children and children with ASD and ADHD. We employed a latent profile analysis using indicators of EF (e.g., working memory, inhibition, and flexibility) in a mixed group of 8–13 year-olds including TD children (n = 128), children with ASD without ADHD (n = 30), children with ADHD (n = 93), and children with comorbid ASD and ADHD (n = 66). Three EF classes emerged: “above average,” “average,” and “impaired.” EF classes did not reproduce diagnostic categories, suggesting that differences in EF abilities are present within the ASD and ADHD groups. Further, greater EF dysfunction predicted more severe socioemotional problems, such as anxiety/depression. These results highlight the heterogeneity of current diagnostic groups and identify an “impaired” EF group, consisting of children with both ASD and ADHD, which could specifically be targeted for EF intervention. PMID:27827406
Francis, S.M.; Sagar, A.; Levin-Decanini, T.; Liu, W.; Carter, C.S.; Jacob, S.
Oxytocin (OT) and arginine vasopressin (AVP) are two small, related neuropeptide hormones found in many mammalian species, including humans. Dysregulation of these neuropeptides have been associated with changes in behavior, especially social interactions. We review how the OT and AVP systems have been investigated in Autism Spectrum Disorder (ASD), Prader–Willi Syndrome (PWS), Williams Syndrome (WS) and Fragile X syndrome (FXS). All of these neurodevelopmental disorders (NDD) are marked by social deficits. While PWS, WS and FXS have identified genetic mutations, ASD stems from multiple genes with complex interactions. Animal models of NDD are invaluable for studying the role and relatedness of OT and AVP in the developing brain. We present data from a FXS mouse model affecting the fragile X mental retardation 1 (Fmr1) gene, resulting in decreased OT and AVP staining cells in some brain regions. Reviewing the research about OT and AVP in these NDD suggests that altered OT pathways may be downstream from different etiological factors and perturbations in development. This has implications for ongoing studies of the therapeutic application of OT in NDD. PMID:24462936
Rubenstein, John L.R.
The cerebral cortex has a central role in cognitive and emotional processing. As such, understanding the mechanisms that govern its development and function will be central to understanding the bases of severe neuropsychiatric disorders, particularly those that first appear in childhood. In this review, I highlight recent progress in elucidating genetic, molecular and cellular mechanisms that control cortical development. I discuss basic aspects of cortical developmental anatomy, and mechanisms that regulate cortical size and area formation, with an emphasis on the roles of fibroblast growth factor (Fgf) signaling and specific transcription factors. I then examine how specific types of cortical excitatory projection neurons are generated, and how their axons grow along stereotyped pathways to their targets. Next, I address how cortical inhibitory (GABAergic) neurons are generated, and point out the role of these cells in controlling cortical plasticity and critical periods. The paper concludes with an examination of four possible developmental mechanisms that could contribute to some forms of neurodevelopmental disorders, such as autism. PMID:20735793
Kubota, Takeo; Miyake, Kunio; Hariya, Natsuyo; Mochizuki, Kazuki
Neurodevelopmental disorders, such as autism, are complex entities that can be caused by biological and social factors. In a subset of patients with congenital neurodevelopmental disorders, clear diagnosis can be achieved using DNA sequence-based analysis to identify changes in the DNA sequence (genetic variation). However, it has recently become clear that changes to the secondary modifications of DNA and histone structures (epigenetic variation) can also cause neurodevelopmental disorders via alteration of neural gene function. Moreover, it has recently been demonstrated that epigenetic modifications are more susceptible to alterations induced by environmental factors than are DNA sequences, and that some drugs commonly used reverse mental-stress induced alterations to histone modifications in neural genes. Therefore, application of diagnostic assays to detect epigenetic alterations will provide new insight into the characterization and treatment of neurodevelopmental disorders.
Schubert, D; Martens, G J M; Kolk, S M
The prefrontal cortex (PFC), seat of the highest-order cognitive functions, constitutes a conglomerate of highly specialized brain areas and has been implicated to have a role in the onset and installation of various neurodevelopmental disorders. The development of a properly functioning PFC is directed by transcription factors, guidance cues and other regulatory molecules and requires the intricate and temporal orchestration of a number of developmental processes. Disturbance or failure of any of these processes causing neurodevelopmental abnormalities within the PFC may contribute to several of the cognitive deficits seen in patients with neurodevelopmental disorders. In this review, we elaborate on the specific processes underlying prefrontal development, such as induction and patterning of the prefrontal area, proliferation, migration and axonal guidance of medial prefrontal progenitors, and their eventual efferent and afferent connections. We furthermore integrate for the first time the available knowledge from genome-wide studies that have revealed genes linked to neurodevelopmental disorders with experimental molecular evidence in rodents. The integrated data suggest that the pathogenic variants in the neurodevelopmental disorder-associated genes induce prefrontal cytoarchitectonical impairments. This enhances our understanding of the molecular mechanisms of prefrontal (mis)development underlying the four major neurodevelopmental disorders in humans, that is, intellectual disability, autism spectrum disorders, attention deficit hyperactivity disorder and schizophrenia, and may thus provide clues for the development of novel therapies.
Brion, Mélanie; de Timary, Philippe; Vander Stappen, Caroline; Guettat, Lamia; Lecomte, Benoît; Rombaux, Philippe; Maurage, Pierre
Chemosensory (olfaction-taste) dysfunctions are considered as reliable biomarkers in many neurological and psychiatric states. However, experimental measures of chemosensory abilities are lacking in alcohol-dependence (AD) and Korsakoff Syndrome (KS, a neurological complication of AD), despite the role played by alcohol-related odors and taste in the emergence and maintenance of AD. This study thus investigated chemosensory impairments in AD and KS. Olfactory-gustatory measures were taken among 20 KS, 20 AD, and 20 control participants. Olfaction (odor detection-discrimination-identification) was assessed using the "Sniffin Sticks" battery and taste was measured using the "Taste Strips" task. Impairments were found for high-level olfaction in AD (odor discrimination) and KS (odor discrimination-identification), even after controlling for psychopathological comorbidities. Gustatory deficits were also observed in both groups, indexing a global deficit for chemosensory perception. Finally, the gradient of impairment between the successive disease stages for odor identification suggests that the hypothesis of a continuum between AD and KS regarding cognitive deficits can be generalized to chemosensory perception. AD and KS are thus characterized by deficits in chemosensory abilities, which could constitute a marker of the AD-KS transition. In view of its deleterious influence on everyday life, chemosensory dysfunction should also be taken into account in clinical settings.
Ibi, Daisuke; Yamada, Kiyofumi
Increasing epidemiological evidence indicates that perinatal infection with various viral pathogens enhances the risk for several psychiatric disorders. The pathophysiological significance of astrocyte interactions with neurons and/or gut microbiomes has been reported in neurodevelopmental disorders triggered by pre- and postnatal immune insults. Recent studies with the maternal immune activation or neonatal polyriboinosinic polyribocytidylic acid models of neurodevelopmental disorders have identified various candidate molecules that could be responsible for brain dysfunction. Here, we review the functions of several candidate molecules in neurodevelopment and brain function and discuss their potential as therapeutic targets for psychiatric disorders. PMID:26633355
Gillberg, I Carina; Helles, Adam; Billstedt, Eva; Gillberg, Christopher
We examined comorbid psychiatric and neurodevelopmental disorders in fifty adult males (mean age 30 years) with Asperger syndrome (AS) diagnosed in childhood and followed up prospectively for almost two decades (13-26 years). Only three of the 50 men had never met criteria for an additional psychiatric/neurodevelopmental diagnosis and more than half had ongoing comorbidity (most commonly either ADHD or depression or both). Any psychiatric comorbidity increased the risk of poorer outcome. The minority of the AS group who no longer met criteria for a full diagnosis of an autism spectrum disorder were usually free of current psychiatric comorbidity. The high rate of psychiatric/neurodevelopmental comorbidities underscores the need for a full psychiatric/neurodevelopmental assessment at follow-up of males with AS.
Research in genetics of neurodevelopmental disorders such as autism suggests that several hundred genes are likely risk factors for these disorders. This heterogeneity presents a challenge and an opportunity at the same time. While the exact identity of many of the genes remains to be discovered, genes identified to date encode for proteins that play roles in certain conserved pathways: protein synthesis, transcriptional/epigenetic regulation and synaptic signaling. Next generation of research in neurodevelopmental disorders needs to address the neural circuitry underlying the behavioral symptoms and co-morbidities, the cell types playing critical roles in these circuits and common intercellular signaling pathways that link diverse genes. Results from clinical trials have been mixed so far. Only when we are able to leverage the heterogeneity of neurodevelopmental disorders into precision medicine, will the mechanism-based therapeutics for these disorders start to unlock success. PMID:26472761
Sahin, Mustafa; Sur, Mriganka
Research in the genetics of neurodevelopmental disorders such as autism suggests that several hundred genes are likely risk factors for these disorders. This heterogeneity presents a challenge and an opportunity at the same time. Although the exact identity of many of the genes remains to be discovered, genes identified to date encode proteins that play roles in certain conserved pathways: protein synthesis, transcriptional and epigenetic regulation, and synaptic signaling. The next generation of research in neurodevelopmental disorders must address the neural circuitry underlying the behavioral symptoms and comorbidities, the cell types playing critical roles in these circuits, and common intercellular signaling pathways that link diverse genes. Results from clinical trials have been mixed so far. Only when we can leverage the heterogeneity of neurodevelopmental disorders into precision medicine will the mechanism-based therapeutics for these disorders start to unlock success.
Newton, Charles R.
In "Global Perspective on Early Diagnosis and Intervention for Children with Developmental Delays and Disabilities" (p1079-1084, this issue), Scherzer et al. highlighted the potential increase in neurodevelopmental impairments and disabilities affecting an increasing number of children in low- and middle-income countries (LMIC). In this…
Vallianatos, Christina N; Iwase, Shigeki
MethylationofhistoneH3lysine4(H3K4me)isanintricatelyregulatedposttranslational modification, which is broadly associated with enhancers and promoters of actively transcribed genomic loci. Recent advances in next-generation sequencing have identified a number of H3K4me regulators mutated in neurodevelopmental disorders including intellectual disabilities, autism spectrum disorders, and schizophrenia. Here, we aim to summarize the molecular function of H3K4me-regulating enzymes in brain development and function. We describe four H3K4me methyltransferases (KMT2A, KMT2C, KMT2D, KMT2F), four demethylases (KDM1A, KDM5A, KDM5B, KDM5C), and two reader proteins (PHF21A, PHF8) mutated in neurodevelopmental disorders. Understanding the role of these chromatin regulators in the development and maintenance of neural connections will advance therapeutic opportunities for prevention and treatment of these lifelong neurodevelopmental disorders. PMID:26077434
Arnsten, Amy F. T.; Rubia, Katya
Objective: This article aims to review basic and clinical studies outlining the roles of prefrontal cortical (PFC) networks in the behavior and cognitive functions that are compromised in childhood neurodevelopmental disorders and how these map into the neuroimaging evidence of circuit abnormalities in these disorders. Method: Studies of animals,…
Kakooza-Mwesige, Angelina; Ssebyala, Keron; Karamagi, Charles; Kiguli, Sarah; Smith, Karen; Anderson, Meredith C.; Croen, Lisa A.; Trevathan, Edwin; Hansen, Robin; Smith, Daniel; Grether, Judith K.
Neurodevelopmental disorders are recognized to be relatively common in developing countries but little data exist for planning effective prevention and intervention strategies. In particular, data on autism spectrum disorders are lacking. For application in Uganda, we developed a 23-question screener (23Q) that includes the Ten Questions screener…
Li, Junlin; Zhao, Guifang; Gao, Xiaocai
Neurodevelopmental disorders are classified as diseases that cause abnormal functions of the brain or central nervous system. Children with neurodevelopmental disorders show impaired language and speech abilities, learning and memory damage, and poor motor skills. However, we still know very little about the molecular etiology of these disorders. Recent evidence implicates the bromodomain-containing proteins (BCPs) in the initiation and development of neurodevelopmental disorders. BCPs have a particular domain, the bromodomain (Brd), which was originally identified as specifically binding acetyl-lysine residues at the N-terminus of histone proteins in vitro and in vivo. Other domains of BCPs are responsible for binding partner proteins to form regulatory complexes. Once these complexes are assembled, BCPs alter chromosomal states and regulate gene expression. Some BCP complexes bind nucleosomes, are involved in basal transcription regulation, and influence the transcription of many genes. However, most BCPs are involved in targeting. For example, some BCPs function as a recruitment platform or scaffold through their Brds-binding targeting sites. Others are recruited to form a complex to bind the targeting sites of their partners. The regulation mediated by these proteins is especially critical during normal and abnormal development. Mutant BCPs or dysfunctional BCP-containing complexes are implicated in the initiation and development of neurodevelopmental disorders. However, the pathogenic molecular mechanisms are not fully understood. In this review, we focus on the roles of regulatory BCPs associated with neurodevelopmental disorders, including mental retardation, Fragile X syndrome (FRX), Williams syndrome (WS), Rett syndrome and Rubinstein-Taybi syndrome (RTS). A better understanding of the molecular pathogenesis, based upon the roles of BCPs, will lead to screening of targets for the treatment of neurodevelopmental disorders.
The locations of cell death and resulting malformations in embryos following teratogen exposure vary depending on the teratogen used, the genotype of the conceptus, and the developmental stage of the embryo at time of exposure. To date, ethanol-induced cell death has been charac...
Doernberg, Ellen; Hollander, Eric
Neurodevelopmental disorders, specifically autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have undergone considerable diagnostic evolution in the past decade. In the United States, the current system in place is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), whereas worldwide, the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) serves as a general medical system. This review will examine the differences in neurodevelopmental disorders between these two systems. First, we will review the important revisions made from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) to the DSM-5, with respect to ASD and ADHD. Next, we will cover the similarities and differences between ASD and ADHD classification in the DSM-5 and the ICD-10, and how these differences may have an effect on neurodevelopmental disorder diagnostics and classification. By examining the changes made for the DSM-5 in 2013, and critiquing the current ICD-10 system, we can help to anticipate and advise on the upcoming ICD-11, due to come online in 2017. Overall, this review serves to highlight the importance of progress towards complementary diagnostic classification systems, keeping in mind the difference in tradition and purpose of the DSM and the ICD, and that these systems are dynamic and changing as more is learned about neurodevelopmental disorders and their underlying etiology. Finally this review will discuss alternative diagnostic approaches, such as the Research Domain Criteria (RDoC) initiative, which links symptom domains to underlying biological and neurological mechanisms. The incorporation of new diagnostic directions could have a great effect on treatment development and insurance coverage for neurodevelopmental disorders worldwide.
Ho, Karen S; Twede, Hope; Vanzo, Rena; Harward, Erin; Hensel, Charles H; Martin, Megan M; Page, Stephanie; Peiffer, Andreas; Mowery-Rushton, Patricia; Serrano, Moises; Wassman, E Robert
Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.8-million probe custom CMA optimized for the detection of CNVs associated with neurodevelopmental disorders. We report an overall detection rate of 29.4% in our neurodevelopmental cohort, which rises to nearly 33% when cases with DD/ID and/or MCA only are considered. The detection rate for the ASD cohort is also significant, at 25%. Additionally, we find that detection rate and pathogenic yield of CMA vary significantly depending on the primary indications for testing, the age of the individuals tested, and the specialty of the ordering doctor. We also report a significant difference between the detection rate on the ultrahigh resolution optimized array in comparison to the array from which it originated. This increase in detection can significantly contribute to the efficient and effective medical management of neurodevelopmental conditions in the clinic.
Kibby, Michelle Y.; Kroese, Judith M.; Morgan, Allison E.; Hiemenz, Jennifer R.; Cohen, Morris J.; Hynd, George W.
Although children with neurodevelopmental disorders frequently present with reduced short-term memory functioning, the relationship between perisylvian morphology and verbal short-term memory functioning has received limited attention. Thus, examining this relationship in children with neurodevelopmental disorders was the focus of this exploratory…
Bill, Brent R; Lowe, Jennifer K; Dybuncio, Christina T; Fogel, Brent L
Neurodevelopmental and neuropsychiatric disorders result from complex interactions between critical genetic factors and as-yet-unknown environmental components. To gain clinical insight, it is critical to develop a comprehensive understanding of these genetic components. RBFOX1, an RNA splicing factor, regulates expression of large genetic networks during early neuronal development, and haploinsufficiency causes severe neurodevelopmental phenotypes including autism spectrum disorder (ASD), intellectual disability, and epilepsy. Genomic testing in individuals and large patient cohorts has identified phenotypically similar cases possessing copy number variations in RBFOX1, implicating the gene as an important cause of neurodevelopmental disease. However, a significant proportion of the observed structural variation is inherited from phenotypically normal individuals, raising questions regarding overall pathogenicity of variation at the RBFOX1 locus. In this chapter, we discuss the molecular, cellular, and clinical evidence supporting the role of RBFOX1 in neurodevelopment and present a comprehensive model for the contribution of structural variation in RBFOX1 to ASD.
Kakooza-Mwesige, Angelina; Ssebyala, Keron; Karamagi, Charles; Kiguli, Sarah; Smith, Karen; Anderson, Meredith C; Croen, Lisa A; Trevathan, Edwin; Hansen, Robin; Smith, Daniel; Grether, Judith K
Neurodevelopmental disorders are recognized to be relatively common in developing countries but little data exist for planning effective prevention and intervention strategies. In particular, data on autism spectrum disorders are lacking. For application in Uganda, we developed a 23-question screener (23Q) that includes the Ten Questions screener and additional questions on autism spectrum disorder behaviors. We then conducted household screening of 1169 children, 2-9 years of age, followed by clinical assessment of children who screened positive and a sample of those who screened negative to evaluate the validity of the screener. We found that 320 children (27% of the total) screened positive and 68 children received a clinical diagnosis of one or more moderate to severe neurodevelopmental disorders (autism spectrum disorder; cerebral palsy; epilepsy; cognitive, speech and language, hearing, or vision impairment), including 8 children with autism spectrum disorders. Prevalence and validity of the screener were evaluated under different statistical assumptions. Sensitivity of the 23Q ranged from 0.55 to 0.80 and prevalence for ≥1 neurodevelopmental disorders from 7.7/100 children to 12.8/100 children depending on which assumptions were used. The combination of screening positive on both autism spectrum disorders and Ten Questions items was modestly successful in identifying a subgroup of children at especially high risk of autism spectrum disorders. We recommend that autism spectrum disorders and related behavioral disorders be included in studies of neurodevelopmental disorders in low-resource settings to obtain essential data for planning local and global public health responses.
Du, X; Hill, R A
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.
Shehata, Amany I; Hassanein, Faika I; Abdul-Ghani, Rashad
Toxoplasma gondii is an opportunistic parasite with neurotropic characteristics that can mediate neurodevelopmental disorders, including mental, behavioral and personality aspects of their hosts. Therefore, the seroprevalence of anti-Toxoplasma antibodies has been studied in patients with different neurological disorders from different localities. On searching online databases, however, we could not find published studies on the seroprevalence of anti-Toxoplasma antibodies among patients with neurodevelopmental disorders in Egypt. Therefore, the present preliminary study was conducted to determine the serological profile of T. gondii infection among patients with non-schizophrenic neurodevelopmental disorders in Alexandria, Egypt. Data and blood samples were collected from 188 patients recruited for the study from four mental rehabilitation centers in the period from July 2014 to March 2015. The overall seropositivity rates of IgM and IgG among patients were 16.5% (31/188) and 50.0% (94/188), respectively. Of the studied patients' characteristics, only age was significantly associated with anti-Toxoplasma IgG seropositivity, with older patients being about twice more likely exposed to infection. However, no statistically significant association was found with IgM. In addition, seropositivity of anti-Toxoplasma IgG, but not IgM, was significantly associated with non-schizophrenic neurodevelopmental disorders; however, neither IgG nor IgM showed a significant association with cognitive impairment as indicated by the intelligence quotient scores.
Bessa, Carlos; Maciel, Patrícia; Rodrigues, Ana João
Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.
Varshney, Mukesh; Nalvarte, Ivan
Many neurological disorders affect men and women differently regarding prevalence, progression, and severity. It is clear that many of these disorders may originate from defective signaling during fetal or perinatal brain development, which may affect males and females differently. Such sex-specific differences may originate from chromosomal or sex-hormone specific effects. This short review will focus on the estrogen receptor beta (ERβ) signaling during perinatal brain development and put it in the context of sex-specific differences in neurodevelopmental disorders. We will discuss ERβ’s recent discovery in directing DNA de-methylation to specific sites, of which one such site may bear consequences for the susceptibility to the neurological reading disorder dyslexia. We will also discuss how dysregulations in sex-hormone signaling, like those evoked by endocrine disruptive chemicals, may affect this and other neurodevelopmental disorders in a sex-specific manner through ERβ. PMID:28241485
Varshney, Mukesh; Nalvarte, Ivan
Many neurological disorders affect men and women differently regarding prevalence, progression, and severity. It is clear that many of these disorders may originate from defective signaling during fetal or perinatal brain development, which may affect males and females differently. Such sex-specific differences may originate from chromosomal or sex-hormone specific effects. This short review will focus on the estrogen receptor beta (ERβ) signaling during perinatal brain development and put it in the context of sex-specific differences in neurodevelopmental disorders. We will discuss ERβ's recent discovery in directing DNA de-methylation to specific sites, of which one such site may bear consequences for the susceptibility to the neurological reading disorder dyslexia. We will also discuss how dysregulations in sex-hormone signaling, like those evoked by endocrine disruptive chemicals, may affect this and other neurodevelopmental disorders in a sex-specific manner through ERβ.
Lundström, Sebastian; Forsman, Mats; Larsson, Henrik; Kerekes, Nora; Serlachius, Eva; Långström, Niklas; Lichtenstein, Paul
The longitudinal relationship between attention deficit hyperactivity disorder (ADHD) and violent criminality has been extensively documented, while long-term effects of autism spectrum disorders (ASDs), tic disorders (TDs), and obsessive compulsive disorder (OCD) on criminality have been scarcely studied. Using population-based registers of all…
Chilosi, Anna M.; Comparini, Alessandro; Scusa, Maria F.; Berrettini, Stefano; Forli, Francesca; Battini, Roberta; Cipriani, Paola; Cioni, Giovanni
Aim: The effects of sensorineural hearing loss (SNHL) are often complicated by additional disabilities, but the epidemiology of associated disorders is not clearly defined. The aim of this study was to evaluate the frequency and type of additional neurodevelopmental disabilities in a sample of children with SNHL and to investigate the relation…
This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies. PMID:22958744
Blackmer, Allison Beck; Feinstein, James A
Neurodevelopmental disorders (NDDs) are defined as a group of disorders caused by changes in early brain development, resulting in behavioral and cognitive alterations in sensory and motor systems, speech, and language. NDDs affect approximately 1-2% of the general population. Up to 80% of children with NDDs are reported to have disrupted sleep; subsequent deleterious effects on daytime behaviors, cognition, growth, and overall development of the child are commonly reported. Examples of NDDs discussed in this review include autism spectrum disorder, cerebral palsy, Rett syndrome, Angelman syndrome, Williams syndrome, and Smith-Magenis syndrome. The etiology of sleep disorders in children with NDDs is largely heterogeneous and disease specific. The diagnosis and management of sleep disorders in this population are complex, and little high-quality data exist to guide a consistent approach to therapy. Managing sleep disorders in children with NDDs is critical both for the child and for the family but is often frustrating due to the refractory nature of the problem. Sleep hygiene must be implemented as first-line therapy; if sleep hygiene alone fails, it should be combined with pharmacologic management. The available evidence for the use of common pharmacologic interventions, such as iron supplementation and melatonin, as well as less common interventions, such as melatonin receptor agonists, clonidine, gabapentin, hypnotics, trazodone, and atypical antipsychotics is reviewed. Further, parents and caregivers should be provided with appropriate education on the nature of the sleep disorders and the expectation for modest pharmacologic benefit, at best. Additional data from well-designed trials in children with NDDs are desperately needed to gain a better understanding of sleep pharmacotherapy including efficacy and safety implications. Until then, clinicians must rely on the limited available data, as well as clinical expertise, when managing sleep disorders in the
Fung, Lawrence K.; Quintin, Eve-Marie; Haas, Brian W.
Purpose of review The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders. Recent findings Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive–behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well – microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development. Summary Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene–brain–behavior links occurring in neurodevelopmental disorders. PMID:22395002
Ruggieri, Víctor L
The amygdala is related with the recognition of the emotional meaning of stimuli, long-term memory, the orientation of social stimuli and the perception of gaze orientation. It plays a fundamental role in the recognition of faces, especially those expressing fear, and makes it possible to comprehend different emotional states, which will facilitate an appropriate social cognition. Dysfunctions of the amygdala have been associated to a number of different neurodevelopmental disorders as well as neurocognitive and behavioural disorders in specific neurogenetic entities. A number of studies focused on the amygdalic complex have allowed researchers to understand many pathophysiological aspects and to formulate new hypotheses regarding their origins. Given that the disorders or conditions in which the role of the amygdala has been evoked are becoming increasingly more extensive, this article refers the reader to those that have aroused the most interest in recent years. Thus, they can be divided into two groups: developmental and behavioural disorders (autism, anxiety disorders, bipolar disorder, alexithymia and anorexia nervosa) and specific neurogenetic entities (fragile X, Rett, Prader-Willi and Williams syndromes), in which structural or dysfunctional alterations have been observed that may be related with their neurocognitive and behavioural symptoms. It is important to remember that the amygdala is a highly connected structure that forms truly functional networks and has been associated to different disorders with varied explanations and includes several different pathophysiological phenomena. Its role must not, therefore, be simplified in a reductionistic manner, but also placed upon a hierarchy of dysfunctions in other areas that interact with it.
Gillberg, I. Carina; Helles, Adam; Billstedt, Eva; Gillberg, Christopher
We examined comorbid psychiatric and neurodevelopmental disorders in fifty adult males (mean age 30 years) with Asperger syndrome (AS) diagnosed in childhood and followed up prospectively for almost two decades (13-26 years). Only three of the 50 men had "never" met criteria for an additional psychiatric/neurodevelopmental diagnosis and…
Brooks, Alyssa T; Wallen, Gwenyth R
Sleep disturbances are common among alcohol-dependent individuals and are often associated with relapse. The utility of behavioral therapies for sleep disturbances, including cognitive-behavioral therapy for insomnia (CBT-I), among those with alcohol-related disorders is not well understood. This review systematically evaluates the evidence of CBT-I and related behavioral therapies applied to those with alcohol-related disorders and accompanying sleep disturbances. A search of four research databases (PubMed, PsycINFO, Embase, and CINAHL Plus) yielded six studies that met selection criteria. Articles were reviewed using Cochrane’s Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) scoring system. A majority of the studies demonstrated significant improvements in sleep efficiency among behavioral therapy treatment group(s), including but not limited to CBT-I. While behavioral sleep interventions have been successful in varied populations, they may not be utilized to their full potential among those with alcohol-related disorders as evidenced by the low number of studies found. These findings suggest a need for mixed-methods research on individuals’ sleep experience to inform interventions that are acceptable to the target population. PMID:25288884
Wade, Mark; Prime, Heather; Madigan, Sheri
Neurodevelopmental disorders represent a broad class of childhood neurological conditions that have a significant bearing on the wellbeing of children, families, and communities. In this review, we draw on evidence from two common and widely studied neurodevelopmental disorders—autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD)—to demonstrate the utility of genetically informed sibling designs in uncovering the nature and pathogenesis of these conditions. Specifically, we examine how twin, recurrence risk, and infant prospective tracking studies have contributed to our understanding of genetic and environmental liabilities towards neurodevelopmental morbidity through their impact on neurocognitive processes and structural/functional neuroanatomy. It is suggested that the siblings of children with ASD and ADHD are at risk not only of clinically elevated problems in these areas, but also of subthreshold symptoms and/or subtle impairments in various neurocognitive skills and other domains of psychosocial health. Finally, we close with a discussion on the practical relevance of sibling designs and how these might be used in the service of early screening, prevention, and intervention efforts that aim to alleviate the negative downstream consequences associated with disorders of neurodevelopment. PMID:26258141
DENNIS, MAUREEN; FRANCIS, DAVID J.; CIRINO, PAUL T.; SCHACHAR, RUSSELL; BARNES, MARCIA A.; FLETCHER, JACK M.
IQ scores are volatile indices of global functional outcome, the final common path of an individual’s genes, biology, cognition, education, and experiences. In studying neurocognitive outcomes in children with neurodevelopmental disorders, it is commonly assumed that IQ can and should be partialed out of statistical relations or used as a covariate for specific measures of cognitive outcome. We propose that it is misguided and generally unjustified to attempt to control for IQ differences by matching procedures or, more commonly, by using IQ scores as covariates. We offer logical, statistical, and methodological arguments, with examples from three neurodevelopmental disorders (spina bifida meningomyelocele, learning disabilities, and attention deficit hyperactivity disorder) that: (1) a historical reification of general intelligence, g, as a causal construct that measures aptitude and potential rather than achievement and performance has fostered the idea that IQ has special status and that in studying neurocognitive function in neurodevelopmental disorders; (2) IQ does not meet the requirements for a covariate; and (3) using IQ as a matching variable or covariate has produced overcorrected, anomalous, and counterintuitive findings about neurocognitive function. PMID:19402919
Iyer, Janani; Girirajan, Santhosh
Rare copy-number variants (CNVs) are a significant cause of neurodevelopmental disorders. The sequence architecture of the human genome predisposes certain individuals to deletions and duplications within specific genomic regions. While assessment of individuals with different breakpoints has identified causal genes for certain rare CNVs, deriving gene-phenotype correlations for rare CNVs with similar breakpoints has been challenging. We present a comprehensive review of the literature related to genetic architecture that is predisposed to recurrent rearrangements, and functional evaluation of deletions, duplications and candidate genes within rare CNV intervals using mouse, zebrafish and fruit fly models. It is clear that phenotypic assessment and complete genetic evaluation of large cohorts of individuals carrying specific CNVs and functional evaluation using multiple animal models are necessary to understand the molecular genetic basis of neurodevelopmental disorders.
Nichols, Sharon; Jones, Wendy; Roman, Mary J.; Wulfeck, Beverly; Delis, Dean C.; Reilly, Judy; Bellugi, Ursula
Profiles of verbal learning and memory performance were compared for typically developing children and for four developmental disorders characterized by different patterns of language functioning: specific language impairment, early focal brain damage, Williams Syndrome, and Down Syndrome. A list-learning task was used that allowed a detailed…
Frahm, Kathryn A; Barnett, Scott D; Brown, Lisa M; Hickling, Edward J; Olney, Ron; Campbell, Robert R; Lapcevic, William A
The purpose of this study was to document preliminary findings of the association between posttraumatic stress disorder (PTSD), mental health service use, and alcohol related health visits among veterans following 2004-2005 Florida hurricane seasons. A retrospective review of the Veterans Health Administration Medical SAS Outpatient Dataset was conducted to identify veterans residing in Florida during the 2004-2005 hurricane seasons with a history of PTSD and/or PTSD and a substance use disorder. It was found that veterans with PTSD residing in counties affected by hurricanes demonstrated an immediate 28 % increase in use of mental health services following hurricane landfall versus veterans residing in non-hurricane affected counties (+28.0 vs. -6.5 %, p = 0.001). Additionally, veterans residing in affected counties were found to use more group psychotherapy treatment sessions overall (30.3 vs. 27.2 %, p = 0.001). Of note, veterans with PTSD experienced a -0.16 per month (p = 0.114) decrease in alcohol related visits following the 2004 hurricane season. These findings provide insight into the mental health needs of veterans with PTSD following a disaster and can inform delivery of services to veterans with PTSD and alcohol related issues in disaster prone areas.
Mpaka, Davin Mbeya; Okitundu, Daniel Luwa E-Andjafono; Ndjukendi, Ally Omba; N’situ, Adelin Mankubu; Kinsala, Sebastien Yabassi; Mukau, Joachim Ebwel; Ngoma, Valentin Malanda; Kashala-Abotnes, Espérance; Ma-Miezi-Mampunza, Samuel; Vogels, Annick; Steyaert, Jeans
Introduction Autism spectrum disorders (ASD) is a neurodevelopmental disorder that has been rarely diagnosed in Sub-Saharan Africa. Although a proportion of children do present features of ASD in the Democratic Republic of Congo (DRC), little is known about it prevalence. Often, the co-morbidities constitute the upfront symptoms and therefore may it recognition and management difficult, aggravating as such the prognosis. The present study therefore aimed at studying the clinical profile of autism spectrum disorder (ASD) and the associated morbidities among children and adolescents in outpatient clinics in Kinshasa, the Democratic Republic of Congo. Methods We conducted a cross sectional study in the three outpatients centers receiving patients referred for neurodevelopmental disorders in Kinshasa, DRC, from June 2008 to June 2010. A total of 450 subjects aged from 1-18 years old were referred and included in the study. The clinical diagnosis for ASD was made using the DSM-IV-R and the ADIR. Co-morbidities were identified using DSM-IV-R criteria together with an extensive clinical interview and observation. All patients were subject to an intellectual quotient evaluation and an electroencephalogram reporting. Results Of the 450 subjects referred, 120 (29.3%) received the diagnosis of ASD, with boys outnumbering girls (OR 3:1. The mean age was 7.9 years (SD 3.4) (p< 0.001). Intellectual disability (75.83 %) and epilepsy (72.50%) were the main co-morbidities significantly associated with autism (p< 0.001). It was also found that co-morbidities were most frequent in subjects with an IQ<70 (p=0.05). Conclusion ASD is frequent among patients referred for neurodevelopmental disorders in the three outpatients’ centers for neurodevelopmental disorders in Kinshasa. Males seem to be more affected than female. The main co-morbidities were epilepsy and intellectual disabilities. Our findings suggest that it is important to screen for ASD and co-morbidities among all subjects
Yano, Masato; Hayakawa-Yano, Yoshika; Okano, Hideyuki
RNA regulation participates in many aspects of brain development. There is substantial evidence that RNA dysregulation is critical in the pathogenesis of neurodevelopmental disorders, neurological diseases, and cancer. Several gene families encode RNA-binding proteins (RNABPs) that bind directly to RNA and orchestrate the post-transcriptional regulation of gene expression, including pre-mRNA splicing, stability, and poly(A) site usage. Among neural RNABPs, the Elavl and Msi families are the focus of neuronal development research owing to their hierarchical expression pattern: Msi1 is expressed in neural progenitor/stem cells, Elavl2 is expressed in early neuronal progenitors to mature neurons, and Elavl3/4 expression begins slightly later, during cortical neuron development. Traditional biochemical analyses provide mechanistic insight into RNA regulation by these RNABPs, and Drosophila and mouse genetic studies support a relationship between these RNABPs and several neurodevelopmental disorders. In addition, a recent cohort analysis of the human genome shows that genetic mutations and SNPs in these RNABPs are associated with various neurological disorders. Newly emerged technologies assess transcriptome-wide RNA-protein interactions in vivo. These technologies, combined with classical genetics methods, provide new insight into Elavl and Msi, not only with respect to their neurodevelopmental functions, but also their roles in several diseases. We review recent discoveries related to the two RNABP families in brain development and disease.
Chamberlain, Stormy J; Lalande, Marc
Human chromosome 15q11-q13 is subject to regulation by genomic imprinting, an epigenetic process by which genes are expressed in a parent-of-origin specific manner. Three neurodevelopmental disorders, Prader-Willi syndrome, Angelman syndrome, and 15q duplication syndrome, result from aberrant expression of imprinted genes in this region. Here, we review the current literature pertaining to mouse models and recently identified patients with atypical deletions, which shed light on the epigenetic regulation of the chromosome 15q11-q13 subregion and the genes that are responsible for the phenotypic outcomes of these disorders.
Duquette, Cheryll; Stodel, Emma; Fullarton, Stephanie; Hagglund, Karras
Fetal Alcohol Spectrum Disorder (FASD) is a term that encompasses the various neurodevelopmental disorders experienced by individuals with prenatal alcohol exposure. FASD incorporates the terms Fetal Alcohol Syndrome (FAS), Fetal Alcohol Effects (FAE), and Alcohol-Related Neurodevelopmental Disorder (ARND). Early studies showed that students with…
Di Cristo, G
GABAergic interneurons powerfully control the function of cortical networks. In addition, they strongly regulate cortical development by modulating several cellular processes such as neuronal proliferation, migration, differentiation and connectivity. Not surprisingly, aberrant development of GABAergic circuits has been implicated in many neurodevelopmental disorders including schizophrenia, autism and Tourette's syndrome. Unfortunately, efforts directed towards the comprehension of the mechanisms regulating GABAergic circuits formation and function have been impaired by the strikingly heterogeneity, both at the morphological and functional level, of GABAergic interneurons. Recent technical advances, including the improvement of interneurons-specific labelling techniques, have started to reveal the basic principles underlying this process. This review summarizes recent findings on the mechanisms underlying the construction of GABAergic circuits in the cortex, with a particular focus on potential implications for brain diseases with neurodevelopmental origin.
Homberg, Judith R; Kyzar, Evan J; Nguyen, Michael; Norton, William H; Pittman, Julian; Poudel, Manoj K; Gaikwad, Siddharth; Nakamura, Shun; Koshiba, Mamiko; Yamanouchi, Hideo; Scattoni, Maria Luisa; Ullman, Jeremy F P; Diamond, David M; Kaluyeva, Aleksandra A; Parker, Matthew O; Klimenko, Victor M; Apryatin, Sergey A; Brown, Richard E; Song, Cai; Gainetdinov, Raul R; Gottesman, Irving I; Kalueff, Allan V
Neurodevelopmental disorders (NDDs) are highly prevalent and severely debilitating brain illnesses caused by aberrant brain growth and development. Resulting in cognitive, social, motor, language and affective disabilities, common NDDs include autism spectrum disorder (ASD), intellectual disability, communication/speech disorders, motor/tic disorders and attention deficit hyperactivity disorder. Affecting neurogenesis, glia/neuronal proliferation and migration, synapse formation and myelination, aberrant neural development occurs over a substantial period of time. Genetic, epigenetic, and environmental factors play a key role in NDD pathogenesis. Animal models are an indispensable tool to study NDDs. Paralleling clinical findings, we comprehensively evaluate various preclinical tests and models which target key (social, cognitive, motor) neurobehavioral domains of ASD and other common NDDs. Covering both traditional (rodent) and alternative NDD models, we outline the emerging areas of research and emphasize how preclinical models play a key role in gaining translational and mechanistic insights into NDDs and their therapy.
Stachowiak, M K; Kucinski, A; Curl, R; Syposs, C; Yang, Y; Narla, S; Terranova, C; Prokop, D; Klejbor, I; Bencherif, M; Birkaya, B; Corso, T; Parikh, A; Tzanakakis, E S; Wersinger, S; Stachowiak, E K
Schizophrenia is a neurodevelopmental disorder featuring complex aberrations in the structure, wiring, and chemistry of multiple neuronal systems. The abnormal developmental trajectory of the brain appears to be established during gestation, long before clinical symptoms of the disease appear in early adult life. Many genes are associated with schizophrenia, however, altered expression of no one gene has been shown to be present in a majority of schizophrenia patients. How does altered expression of such a variety of genes lead to the complex set of abnormalities observed in the schizophrenic brain? We hypothesize that the protein products of these genes converge on common neurodevelopmental pathways that affect the development of multiple neural circuits and neurotransmitter systems. One such neurodevelopmental pathway is Integrative Nuclear FGFR1 Signaling (INFS). INFS integrates diverse neurogenic signals that direct the postmitotic development of embryonic stem cells, neural progenitors and immature neurons, by direct gene reprogramming. Additionally, FGFR1 and its partner proteins link multiple upstream pathways in which schizophrenia-linked genes are known to function and interact directly with those genes. A th-fgfr1(tk-) transgenic mouse with impaired FGF receptor signaling establishes a number of important characteristics that mimic human schizophrenia - a neurodevelopmental origin, anatomical abnormalities at birth, a delayed onset of behavioral symptoms, deficits across multiple domains of the disorder and symptom improvement with typical and atypical antipsychotics, 5-HT antagonists, and nicotinic receptor agonists. Our research suggests that altered FGF receptor signaling plays a central role in the developmental abnormalities underlying schizophrenia and that nicotinic agonists are an effective class of compounds for the treatment of schizophrenia.
Trent, Simon; Dean, Rachel; Veit, Bonnie; Cassano, Tommaso; Bedse, Gaurav; Ojarikre, Obah A; Humby, Trevor; Davies, William
Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,X(Y*)O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,X(Y*)O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding acetylserotonin-O-methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,X(Y*)O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a 'foraging' task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or 'ability to wait', it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,X(Y*)O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,X(Y*)O model.
Corvin, Aiden P
The major mental disorders, schizophrenia and bipolar disorder are substantially heritable. Recent genomic studies have identified a small number of common and rare risk genes contributing to both disorders and support epidemiological evidence that genetic susceptibility overlaps between them. Prompted by the question of whether risk genes cluster in specific molecular pathways or implicate discrete mechanisms we and others have developed hypothesis-free methods of investigating genome-wide association datasets at a pathway-level. The application of our method to the 212 experimentally-derived pathways in the Kyoto Encycolpaedia of Genes and Genomes (KEGG) database identified significant association between the cell adhesion molecule (CAM) pathway and both schizophrenia and bipolar disorder susceptibility across three GWAS datasets. Interestingly, a similar approach applied to an autistic spectrum disorders (ASDs) sample identified a similar pathway and involved many of the same genes. Disruption of a number of these genes (including NRXN1, CNTNAP2 and CASK) are known to cause diverse neurodevelopmental brain disorder phenotypes including schizophenia, autism, learning disability and specific language disorder. Taken together these studies bring the CAM pathway sharply into focus for more comprehensive DNA sequencing to identify the critical genes, and investigate their relationships and interaction with environmental risk factors in the expression of many seemingly different neurodevelopmental disorders.
Olagunju, Andrew T.; Oyelohunnu, Motunrayo. A.; Campbell, Elizabeth A.; Umeh, Charles S.; Aina, Olatunji F.; Oyibo, Wellington; Lesi, Folusho E.A.; Adeyemi, Joseph D.
Autism Spectrum Disorder (ASD) is a globally prevalent neurodevelopmental disorder for which early diagnosis and intervention is the mainstay of management. In the African continent, limited data is available regarding the non-clinic based samples. Lack of information available to caregivers and inadequate skilled manpower often limit early detection and access to the few available though under resourced services in the community. Community based screening can be an important drive to create awareness and improve information dissemination regarding services available for those living with this disorder. This is a descriptive cross-sectional study utilizing data obtained from participants of a community-based autism screening exercise. The surveillance exercise was part of the annual Orange Ribbon initiative for autism awareness and screening held in 2014. Data was obtained from 85 participants involved in the Autism Surveillance screening exercise within the Lagos community. Community public service radio announcements state wide and word of mouth were used to invite and enroll eligible participants to the screening and consultation exercise. A second stage screening and a brief sociodemographic questionnaire followed by a third stage clinical interview and evaluation using the Diagnostic and Statistical Manual of Mental Disorders - 5 Edition (DSM 5) were used. Appropriate consultation and referrals to services in the community were given. Participants had a mean age of 7.53 years (SD 4.35). Twenty-nine (34.5%) met the diagnosis of ASD. Other diagnosis included attention deficit hyperactivity disorder (ADHD), language and speech disorder, intellectual disability (8.3%) and learning disorders (9.5%). Main health concerns to caregivers were poor language development in all (100%), of which 11 (40.7%) were non-verbal; gaze avoidance was seen in 14 (48.3%) and challenging behavior in 12 (42.9%). Comorbidities included seizure disorders (3.4%) and ADHD (6.9%). Persons
Gumpricht, Eric; Rockway, Susie
The incidence of childhood neurodevelopmental disorders, which include autism, attention-deficit hyperactivity disorders, and apraxia, are increasing worldwide and have a profound effect on the behaviors, cognitive skills, mood, and self-esteem of these children. Although the etiologies of these disorders are unclear, they often accompany genetic and biochemical abnormalities resulting in cognitive and communication difficulties. Because cognitive and neural development require essential fatty acids (particularly long-chain ω-3 fatty acids often lacking in mother's and children's diets) during critical growth periods, the potential behavior-modifying effects of these fatty acids as "brain nutrients" has attracted considerable attention. Additionally, there is compelling evidence for increased oxidative stress, altered antioxidant defenses, and neuroinflammation in these children. The purpose of this review is to provide a scientific rationale based on cellular, experimental animal model, observational, and clinical intervention studies for incorporating the combination of ω-3 fatty acids and tocotrienol-rich vitamin E as complementary nutritional therapies in children with neurodevelopmental disorders. Should this nutritional combination correct key clinical or biochemical outcomes and/or improve behavioral patterns, it would provide a safe, complementary option for these children.
Jan, James E; Bax, Martin C O; Owens, Judith A; Ipsiroglu, Osman S; Wasdell, Michael B
This article reviews circadian rhythm sleep disorders (CRSDs) of children with neurodevelopmental disabilities. These sleep disturbances frequently occur in this population but they are misunderstood and under diagnosed. The causes and features of CRSD in children with brain disorders differ in many ways from those seen in typically developing children. It is the brain, including the eyes, which regulates sleep and circadian rhythmicity by modulating pineal melatonin production/secretion and when there is significant brain damage, the sleep/wake patterns may be modified. In most instances CRSD are not disorders of the suprachiasmatic nuclei because these small hypothalamic structures only adjust their functions to the changing photic and non-photic modulatory influences. Each form of CRSD is accompanied by characteristic changes in serum melatonin levels and clinical features. When nocturnal melatonin production/secretion is inappropriately timed or impaired in relation to the environment, timed melatonin replacement therapy will often be beneficial. In this review an attempt is made to clarify the neurophysiological mechanisms underlying the various forms of CRSD because without understanding the photic and non-photic influences on sleep, these sleep disorders can not be fully characterized, defined or even appropriately treated. In the future, the existing definitions for the different forms of CRSD should be modified by experts in pediatric sleep medicine in order to include children with neurodevelopmental disabilities.
Ingrassia, Antonina; Turk, Jeremy
This paper reports on the use of clonidine for the treatment of severe sleep problems associated with behavioural difficulties in children with neurodevelopmental disabilities. Data were obtained from reviewing the case notes of a series of six children with neurodevelopmental disorders of different nature and severity, presenting with problematic sleep. All children in this group showed maintained improvements in their sleep pattern following the use of clonidine with only mild side-effects reported.
Byrne, Susan; Jansen, Lara; U-King-Im, Jean-Marie; Siddiqui, Ata; Lidov, Hart G W; Bodi, Istvan; Smith, Luke; Mein, Rachael; Cullup, Thomas; Dionisi-Vici, Carlo; Al-Gazali, Lihadh; Al-Owain, Mohammed; Bruwer, Zandre; Al Thihli, Khalid; El-Garhy, Rana; Flanigan, Kevin M; Manickam, Kandamurugu; Zmuda, Erik; Banks, Wesley; Gershoni-Baruch, Ruth; Mandel, Hanna; Dagan, Efrat; Raas-Rothschild, Annick; Barash, Hila; Filloux, Francis; Creel, Donnell; Harris, Michael; Hamosh, Ada; Kölker, Stefan; Ebrahimi-Fakhari, Darius; Hoffmann, Georg F; Manchester, David; Boyer, Philip J; Manzur, Adnan Y; Lourenco, Charles Marques; Pilz, Daniela T; Kamath, Arveen; Prabhakar, Prab; Rao, Vamshi K; Rogers, R Curtis; Ryan, Monique M; Brown, Natasha J; McLean, Catriona A; Said, Edith; Schara, Ulrike; Stein, Anja; Sewry, Caroline; Travan, Laura; Wijburg, Frits A; Zenker, Martin; Mohammed, Shehla; Fanto, Manolis; Gautel, Mathias; Jungbluth, Heinz
Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed
Byrne, Susan; Jansen, Lara; U-King-Im, Jean-Marie; Siddiqui, Ata; Lidov, Hart G. W.; Bodi, Istvan; Smith, Luke; Mein, Rachael; Cullup, Thomas; Dionisi-Vici, Carlo; Al-Gazali, Lihadh; Al-Owain, Mohammed; Bruwer, Zandre; Al Thihli, Khalid; El-Garhy, Rana; Flanigan, Kevin M.; Manickam, Kandamurugu; Zmuda, Erik; Banks, Wesley; Gershoni-Baruch, Ruth; Mandel, Hanna; Dagan, Efrat; Raas-Rothschild, Annick; Barash, Hila; Filloux, Francis; Creel, Donnell; Harris, Michael; Hamosh, Ada; Kölker, Stefan; Ebrahimi-Fakhari, Darius; Hoffmann, Georg F.; Manchester, David; Boyer, Philip J.; Manzur, Adnan Y.; Lourenco, Charles Marques; Pilz, Daniela T.; Kamath, Arveen; Prabhakar, Prab; Rao, Vamshi K.; Rogers, R. Curtis; Ryan, Monique M.; Brown, Natasha J.; McLean, Catriona A.; Said, Edith; Schara, Ulrike; Stein, Anja; Sewry, Caroline; Travan, Laura; Wijburg, Frits A.; Zenker, Martin; Mohammed, Shehla; Fanto, Manolis; Gautel, Mathias
Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed
Chao, Hsiao-Tuan; Davids, Mariska; Burke, Elizabeth; Pappas, John G; Rosenfeld, Jill A; McCarty, Alexandra J; Davis, Taylor; Wolfe, Lynne; Toro, Camilo; Tifft, Cynthia; Xia, Fan; Stong, Nicholas; Johnson, Travis K; Warr, Coral G; Yamamoto, Shinya; Adams, David R; Markello, Thomas C; Gahl, William A; Bellen, Hugo J; Wangler, Michael F; Malicdan, May Christine V
Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.
Küry, Sébastien; Besnard, Thomas; Ebstein, Frédéric; Khan, Tahir N; Gambin, Tomasz; Douglas, Jessica; Bacino, Carlos A; Sanders, Stephan J; Lehmann, Andrea; Latypova, Xénia; Khan, Kamal; Pacault, Mathilde; Sacharow, Stephanie; Glaser, Kimberly; Bieth, Eric; Perrin-Sabourin, Laurence; Jacquemont, Marie-Line; Cho, Megan T; Roeder, Elizabeth; Denommé-Pichon, Anne-Sophie; Monaghan, Kristin G; Yuan, Bo; Xia, Fan; Simon, Sylvain; Bonneau, Dominique; Parent, Philippe; Gilbert-Dussardier, Brigitte; Odent, Sylvie; Toutain, Annick; Pasquier, Laurent; Barbouth, Deborah; Shaw, Chad A; Patel, Ankita; Smith, Janice L; Bi, Weimin; Schmitt, Sébastien; Deb, Wallid; Nizon, Mathilde; Mercier, Sandra; Vincent, Marie; Rooryck, Caroline; Malan, Valérie; Briceño, Ignacio; Gómez, Alberto; Nugent, Kimberly M; Gibson, James B; Cogné, Benjamin; Lupski, James R; Stessman, Holly A F; Eichler, Evan E; Retterer, Kyle; Yang, Yaping; Redon, Richard; Katsanis, Nicholas; Rosenfeld, Jill A; Kloetzel, Peter-Michael; Golzio, Christelle; Bézieau, Stéphane; Stankiewicz, Paweł; Isidor, Bertrand
Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.
Cruchet et al. attempt to tease out the myths and facts surrounding the growing popularity of certain dietary approaches in the management of neurodevelopmental disorders, like attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs). The authors identify a particular exclusionary-type approach that seeks to eliminate dietary gluten. Although the relationship between celiac disease (CD) and ADHD/ASD is not well established, a repeated clinical feature noted in CD is the elevated levels of nitric oxide in serum and urine. Elevated oxidative stress has also been observed in neurodevelopmental conditions, and the author of this correspondence has been the first to propose that chronic, environmental exposure to the air pollutant, nitrous oxide may contribute to these oxidative stress profiles through neural cholinergic perturbation. Therefore, the purpose of this correspondence is to highlight this biochemical connection between these conditions so as to identify the clinical populations who may realize the greatest benefit of these dietary approaches, while minimizing any potential risk of nutrient deficiencies.
Reinhard, Sarah M.; Razak, Khaleel; Ethell, Iryna M.
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
Raine, Adrian; Lee, Lydia; Yang, Yaling; Colletti, Patrick
Background Antisocial personality disorder and psychopathy have been hypothesised to have a neurodevelopmental basis, but this proposition has not been formally tested. Aims This study tests the hypothesis that individuals with cavum septum pellucidum (CSP), a marker of limbic neural maldevelopment, will show higher levels of psychopathy and antisocial personality. Method Cavum septum pellucidum was assessed using anatomical magnetic resonance imaging in a community sample. Those with CSP (n = 19) were compared with those lacking CSP (n = 68) on antisocial personality, psychopathy and criminal offending. Results Those with CSP had significantly higher levels of antisocial personality, psychopathy, arrests and convictions compared with controls. The pervasiveness of this association was indicated by the fact that those lacking a diagnosis of antisocial personality disorder, but who were charged or convicted for an offence, had a more extensive CSP than non-antisocial controls. Results could not be attributed to prior trauma exposure, head injury, demographic factors or comorbid psychiatric conditions. Conclusions Our findings appear to be the first to provide evidence for a neurodevelopmental brain abnormality in those with antisocial personality disorder and psychopathy, and support the hypothesis that early maldevelopment of limbic and septal structures predisposes to the spectrum of antisocial behaviours. PMID:20807962
Mizoguchi, Yoshito; Monji, Akira
Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by deficits in social interaction, difficulties with language and repetitive/restricted behaviors. Microglia are resident innate immune cells which release many factors including proinflammatory cytokines, nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) when they are activated in response to immunological stimuli. Recent in vivo imaging has shown that microglia sculpt and refine the synaptic circuitry by removing excess and unwanted synapses and be involved in the development of neural circuits or synaptic plasticity thereby maintaining the brain homeostasis. BDNF, one of the neurotrophins, has various important roles in cell survival, neurite outgrowth, neuronal differentiation, synaptic plasticity and the maintenance of neural circuits in the CNS. Intracellular Ca2+ signaling is important for microglial functions including ramification, de-ramification, migration, phagocytosis and release of cytokines, NO and BDNF. BDNF induces a sustained intracellular Ca2+ elevation through the upregulation of the surface expression of canonical transient receptor potential 3 (TRPC3) channels in rodent microglia. BDNF might have an anti-inflammatory effect through the inhibition of microglial activation and TRPC3 could play important roles in not only inflammatory processes but also formation of synapse through the modulation of microglial phagocytic activity in the brain. This review article summarizes recent findings on emerging dual, inflammatory and non-inflammatory, roles of microglia in the brain and reinforces the importance of intracellular Ca2+ signaling for microglial functions in both normal neurodevelopment and their potential contributing to neurodevelopmental disorders such as ASDs. PMID:28367116
Chechi, Tasleem; Siyahian, Salpi; Thairu, Lucy; Hagerman, Randi; Lozano, Reymundo
Summary The purpose of this study was to identify demographic data, motivational factors and barriers for participation in clinical trials (CTs) at the University of California Davis, MIND Institute. We conducted a cross-sectional survey in 100 participants (81 females and 19 males). The participants had high education levels (only 2% had not completed high school), a mean age of 44 years (SD ± 9.899) and had at least one child with a neurodevelopmental disorder. The diagnosis of Fragile X syndrome (FXS) had a significant association with past participation in CTs (p < 0.001). A statistical significance for age of diagnosis and participation in CTs was also found (z = −2.01, p = 0.045). The motivating factors were to help find cures/treatments for neurodevelopmental disorders and to relieve symptoms related to child's diagnosis. Factors explaining lack of participation, unwillingness to participate or unsure of participation were: lack of information/knowledge about the trials, time commitment to participation (screening, appointments, assessments, laboratory tests, etc.) and low annual household income. These results show that a portion of underrepresented minorities (URM) not participating in CTs are willing to participate and suggests that reducing barriers, particularly lack of knowledge/information and time commitment to trials are needed to improve recruitment. PMID:25606364
Scattoni, Maria Luisa; Crawley, Jacqueline; Ricceri, Laura
In neonatal mice ultrasonic vocalizations have been studied both as an early communicative behavior of the pup-mother dyad and as a sign of an aversive affective state. Adult mice of both sexes produce complex ultrasonic vocalization patterns in different experimental/social contexts. All these vocalizations are becoming an increasingly valuable assay for behavioral phenotyping throughout the mouse life-span and alterations of the ultrasound patterns have been reported in several mouse models of neurodevelopmental disorders. Here we also show that the modulation of vocalizations by maternal cues (maternal potentiation paradigm) – originally identified and investigated in rats - can be measured in C57Bl/6 mouse pups with appropriate modifications of the rat protocol and can likely be applied to mouse behavioral phenotyping. In addition we suggest that a detailed qualitative evaluation of neonatal calls together with analysis of adult mouse vocalization patterns in both sexes in social settings, may lead to a greater understanding of the communication value of vocalizations in mice. Importantly, both neonatal and adult USV altered patterns can be determined during the behavioural phenotyping of mouse models of human neurodevelopmental and neuropsychiatric disorders, starting from those in which deficits in communication are a primary symptom. PMID:18771687
Parker, Whitney E; Orlova, Ksenia A; Parker, William H; Birnbaum, Jacqueline F; Krymskaya, Vera P; Goncharov, Dmitry A; Baybis, Marianna; Helfferich, Jelte; Okochi, Kei; Strauss, Kevin A; Crino, Peter B
A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders.
Chauhan, Ved; Chauhan, Abha
Extensive evidence suggests the role of oxidative stress in autism and other neurodevelopmental disorders. In this study, we investigated whether methylmercury (MeHg) and/or alcohol exposure has deleterious effects in Drosophila melanogaster (fruit flies). A diet containing different concentrations of MeHg in Drosophila induced free radical generation and increased lipid peroxidation (markers of oxidative stress) in a dose-dependent manner. This effect of MeHg on oxidative stress was enhanced by further exposure to alcohol. It was observed that alcohol alone could also induce free radical generation in flies. After alcohol exposure, MeHg did not affect the immobilization of flies, but it increased the recovery time in a concentration-dependent manner. MeHg significantly inhibited the activity of alcohol dehydrogenase (ADH) in a dose-dependent manner. Linear regression analysis showed a significant negative correlation between ADH activity and recovery time upon alcohol exposure in the flies fed a diet with MeHg. This relationship between ADH activity and recovery time after alcohol exposure was confirmed by adding 4-methyl pyrazole (an inhibitor of ADH) to the diet for the flies. These results suggest that consumption of alcohol by pregnant mothers who are exposed to MeHg may lead to increased oxidative stress and to increased length of time for alcohol clearance, which may have a direct impact on the development of the fetus, thereby increasing the risk of neurodevelopmental disorders.
Lee, Young-A; Yamaguchi, Yoshie; Goto, Yukiori
Psychiatric disorders are disadvantageous behavioral phenotypes in humans. Accordingly, a recent epidemiological study has reported decreased fecundity in patients with psychiatric disorders, such as schizophrenia and autism spectrum disorders. Moreover, the fecundity of the relatives of these patients is not exceedingly higher compared to the fecundity of the relatives of normal subjects. Collectively, the prevalence of psychiatric disorders among humans is expected to decrease over generations. Nevertheless, in reality, the prevalence rates of psychiatric disorders in humans either have been constant over a long period of time or have even increased more recently. Several attempts to explain this fact have been made using biological mechanisms, such as de novo gene mutations or variants, although none of these explanations is fully comprehensive. Here, we propose a hypothesis towards understanding the biological mechanisms of psychiatric disorders from evolutionary perspectives. This hypothesis considers that behavioral phenotypes associated with psychiatric disorders might have emerged in the evolution of organisms as a neurodevelopmental adaptation against adverse environmental conditions associated with stress. PMID:26060583
Lee, Young-A; Yamaguchi, Yoshie; Goto, Yukiori
Psychiatric disorders are disadvantageous behavioral phenotypes in humans. Accordingly, a recent epidemiological study has reported decreased fecundity in patients with psychiatric disorders, such as schizophrenia and autism spectrum disorders. Moreover, the fecundity of the relatives of these patients is not exceedingly higher compared to the fecundity of the relatives of normal subjects. Collectively, the prevalence of psychiatric disorders among humans is expected to decrease over generations. Nevertheless, in reality, the prevalence rates of psychiatric disorders in humans either have been constant over a long period of time or have even increased more recently. Several attempts to explain this fact have been made using biological mechanisms, such as de novo gene mutations or variants, although none of these explanations is fully comprehensive. Here, we propose a hypothesis towards understanding the biological mechanisms of psychiatric disorders from evolutionary perspectives. This hypothesis considers that behavioral phenotypes associated with psychiatric disorders might have emerged in the evolution of organisms as a neurodevelopmental adaptation against adverse environmental conditions associated with stress.
LaSalle, Janine M; Reiter, Lawrence T; Chamberlain, Stormy J
The E3 ubiquitin ligase UBE3A, also known as E6-AP, has a multitude of ascribed functions and targets relevant to human health and disease. Epigenetic regulation of the UBE3A gene by parentally imprinted noncoding transcription within human chromosome 15q11.2–q13.3 is responsible for the maternal-specific effects of 15q11.2–q13.3 deletion or duplication disorders. Here, we review the evidence for diverse and emerging roles for UBE3A in the proteasome, synapse and nucleus in regulating protein stability and transcription as well as the current mechanistic understanding of UBE3A imprinting in neurons. Angelman and Dup15q syndromes as well as experimental models of these neurodevelopmental disorders are highlighted as improving understanding of UBE3A and its complex regulation for improving therapeutic strategies. PMID:26585570
Zeliger, Harold I
Many studies have associated environmental exposure to chemicals with neurological impairments (NIs) including neuropathies, cognitive, motor and sensory impairments; neurodevelopmental disorders (NDDs) including autism and attention deficit hyperactivity disorder (ADHD); neurodegenerative diseases (NDGs) including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The environmental chemicals shown to induce all these diseases include persistent organic pollutants (POPs), the plastic exudates bisphenol A and phthalates, low molecular weight hydrocarbons (LMWHCs) and polynuclear aromatic hydrocarbons (PAHs). It is reported here that though these chemicals differ widely in their chemical properties, reactivities and known points of attack in humans, a common link does exist between them. All are lipophilic species found in serum and they promote the sequential absorption of otherwise non-absorbed toxic hydrophilic species causing these diseases.
Many studies have associated environmental exposure to chemicals with neurological impairments (NIs) including neuropathies, cognitive, motor and sensory impairments; neurodevelopmental disorders (NDDs) including autism and attention deficit hyperactivity disorder (ADHD); neurodegenerative diseases (NDGs) including Alzheimer′s disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The environmental chemicals shown to induce all these diseases include persistent organic pollutants (POPs), the plastic exudates bisphenol A and phthalates, low molecular weight hydrocarbons (LMWHCs) and polynuclear aromatic hydrocarbons (PAHs). It is reported here that though these chemicals differ widely in their chemical properties, reactivities and known points of attack in humans, a common link does exist between them. All are lipophilic species found in serum and they promote the sequential absorption of otherwise non-absorbed toxic hydrophilic species causing these diseases. PMID:24678247
... events. Please support us. Donate | Volunteer Alcohol-Related Liver Disease Discussion on Inspire Support Community Join the ... Disease Information > Alcohol-Related Liver Disease Alcohol-Related Liver Disease Explore this section to learn more about ...
Waltereit, Robert; Leimer, Uwe; von Bohlen Und Halbach, Oliver; Panke, Jutta; Hölter, Sabine M; Garrett, Lillian; Wittig, Karola; Schneider, Miriam; Schmitt, Camie; Calzada-Wack, Julia; Neff, Frauke; Becker, Lore; Prehn, Cornelia; Kutscherjawy, Sergej; Endris, Volker; Bacon, Claire; Fuchs, Helmut; Gailus-Durner, Valérie; Berger, Stefan; Schönig, Kai; Adamski, Jerzy; Klopstock, Thomas; Esposito, Irene; Wurst, Wolfgang; de Angelis, Martin Hrabe; Rappold, Gudrun; Wieland, Thomas; Bartsch, Dusan
Mutations in the SRGAP3 gene residing on chromosome 3p25 have previously been associated with intellectual disability. Genome-wide association studies have also revealed SRGAP3, together with genes from the same cellular network, as risk genes for schizophrenia. SRGAP3 regulates cytoskeletal dynamics through the RHO protein RAC1. RHO proteins are known to be involved in cytoskeletal reorganization during brain development to control processes such as synaptic plasticity. To elucidate the importance of SRGAP3 in brain development, we generated Srgap3-knockout mice. Ten percent of these mice developed a hydrocephalus and died before adulthood. Surviving mice showed various neuroanatomical changes, including enlarged lateral ventricles, white matter tracts, and dendritic spines together with molecular changes, including an increased basal activity of RAC1. Srgap3(-/-) mice additionally exhibited a complex behavioral phenotype. Behavioral studies revealed an impaired spontaneous alternation and social behavior, while long-term memory was unchanged. The animals also had tics. Lower locomotor activity was observed in male Srgap3(-/-) only. Srgap3(-/-) mice showed increased methylphenidate stimulation in males and an impaired prepulse inhibition in females. Together, the results show neurodevelopmental aberration in Srgap3(-/-) mice, with many of the observed phenotypes matching several schizophrenia-related intermediate phenotypes. Mutations of SRGAP3 may thus contribute to various neurodevelopmental disorders.
Bell, Scott; Peng, Huashan; Crapper, Liam; Kolobova, Ilaria; Maussion, Gilles; Vasuta, Cristina; Yerko, Volodymyr; Wong, Tak Pan; Ernst, Carl
The development of targeted therapeutics for rare neurodevelopmental disorders (NDDs) faces significant challenges due to the scarcity of subjects and the difficulty of obtaining human neural cells. Here, we illustrate a rapid, simple protocol by which patient derived cells can be reprogrammed to induced pluripotent stem cells (iPSCs) using an episomal vector and differentiated into neurons. Using this platform enables patient somatic cells to be converted to physiologically active neurons in less than two months with minimal labor. This platform includes a method to combine somatic cell reprogramming with CRISPR/Cas9 gene editing at single cell resolution, which enables the concurrent development of clonal knockout or knock-in models that can be used as isogenic control lines. This platform reduces the logistical barrier for using iPSC technology, allows for the development of appropriate control lines for use in rare neurodevelopmental disease research, and establishes a fundamental component to targeted therapeutics and precision medicine. Stem Cells Translational Medicine 2017;6:886-896.
Buoli, Massimiliano; Serati, Marta; Caldiroli, Alice; Cremaschi, Laura; Altamura, Alfredo Carlo
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.
Samango-Sprouse, Carole; Keen, Colleen; Mitchell, Francie; Sadeghin, Teresa; Gropman, Andrea
Fourty eight, XXXX is a rare chromosomal aneuploidy associated with neurocognitive deficits, speech and language disorders and executive dysfunction but the scarcity and variability of reported cases limit our understanding of the 48, XXXX phenotype. To our knowledge, this is the first study to report on the neurodevelopmental profile of three young females with 48, XXXX. Patient 1 (age = 11.0), Patient 2 (age = 10.9), and Patient 3 (age = 6.4) were evaluated using comprehensive neurodevelopmental assessments. Parent questionnaires were completed to assess behavioral and psychosocial domains including executive function, ADHD and anxiety. Nonverbal intelligence quotients were 56, 80, and 91 for Patients 1, 2, and 3, respectively. There were significantly impaired visual motor capacities in graphomotor and perceptual domains below the 5th centile in Patients 1 and 2, and mildly impaired visual perception skills in Patient 3. All three patients had Childhood Apraxia of Speech (CAS) but of varying severity and similar executive dysfunction, externalizing problems and social difficulties. Familial learning disabilities (FLD) in Patient 1 and the co-occurrence of ADHD in Patient's 1 and 2 may contribute to their more impaired cognitive performances relative to Patient 3 who is the second reported case of 48, XXXX to have normal intellect. These distinct and overlapping characteristics expand the phenotypic profile of 48, XXXX and may be used in the counseling of families and treatment of children with 48, XXXX.
Levman, Jacob; Takahashi, Emi
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
Picchioni, Dante; Reith, R. Michelle; Nadel, Jeffrey L.; Smith, Carolyn B.
Sleep is important for neural plasticity, and plasticity underlies sleep-dependent memory consolidation. It is widely appreciated that protein synthesis plays an essential role in neural plasticity. Studies of sleep-dependent memory and sleep-dependent plasticity have begun to examine alterations in these functions in populations with neurological and psychiatric disorders. Such an approach acknowledges that disordered sleep may have functional consequences during wakefulness. Although neurodevelopmental disorders are not considered to be sleep disorders per se, recent data has revealed that sleep abnormalities are among the most prevalent and common symptoms and may contribute to the progression of these disorders. The main goal of this review is to highlight the role of disordered sleep in the pathology of neurodevelopmental disorders and to examine some potential mechanisms by which sleep-dependent plasticity may be altered. We will also briefly attempt to extend the same logic to the other end of the developmental spectrum and describe a potential role of disordered sleep in the pathology of neurodegenerative diseases. We conclude by discussing ongoing studies that might provide a more integrative approach to the study of sleep, plasticity, and neurodevelopmental disorders. PMID:24839550
Harms, Melanie D.
Individuals with neurodevelopmental disorders are challenged with memory and language deficits that impact their skills acquisition (Martin, Klusek, Estigarriba, & Roberts, 2009; Turner & Alborz, 2003). The value of music when applied as an antecedent and a reinforcer has long been established to address such memory and language deficits…
Gatto, Cheryl L.; Broadie, Kendal
Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. The affected genes often encode synaptic components directly, but also include regulators that secondarily mediate the synthesis or assembly of synaptic proteins. The prime example is Fragile X syndrome (FXS), the leading heritable cause of both intellectual disability and autism spectrum disorders. FXS results from loss of mRNA-binding FMRP, which regulates synaptic transcript trafficking, stability and translation in activity-dependent synaptogenesis and plasticity mechanisms. Genetic models of FXS exhibit striking excitatory and inhibitory synapse imbalance, associated with impaired cognitive and social interaction behaviors. Downstream of translation control, a number of specific synaptic proteins regulate excitatory versus inhibitory synaptogenesis, independently or combinatorially, and loss of these proteins is also linked to disrupted neurodevelopment. The current effort is to define the cascade of events linking transcription, translation and the role of specific synaptic proteins in the maintenance of excitatory versus inhibitory synapses during neural circuit formation. This focus includes mechanisms that fine-tune excitation and inhibition during the refinement of functional synaptic circuits, and later modulate this balance throughout life. The use of powerful new genetic models has begun to shed light on the mechanistic bases of excitation/inhibition imbalance for a range of neurodevelopmental disease states. PMID:21423490
Kokurcan, Ahmet; Atbaşoğlu, Eşref Cem
This review focuses on the differentiation of schizophrenia in the setting of adult psychiatry from neurodevelopmental disorders (NDD's) and psychosis due to other medical conditions (PDMC). Psychotic disorders in early adulthood are most frequently diagnosed with the schizophrenia spectrum or mood disorders. However, they may be the manifestation of neurologic, endocrine or immunologic disease. Individuals with NDD's such as the autism spectrum disorder (ASD) or intellectual developmental disorder (IDD) may also present initially in adulthood. Therefore it is not uncommon that the psychiatrist is the first physician to assess a psychotic patient with underlying medical illness or a NDD. Failure to identify the underlying cause will delay appropriate management. Overdiagnosis of primary psychiatric disorders may be misleading in planning the treatment, as evidence-based treatment algorithms relevant to psychosis are intended for primary psychotic disorders like schizophrenia, and symptomatic treatment may result in unnecessary exposure to antipsychotic drugs. Exclusion of other medical conditions and NDD's is essential before establishing a diagnosis of schizophrenia.
Jivraj, Jamil; Sacrey, Lori-Ann; Newton, Amanda; Nicholas, David; Zwaigenbaum, Lonnie
Participatory research aims to increase the relevance and broaden the implementation of health research by involving those affected by the outcomes of health studies. Few studies within the field of neurodevelopmental disorders, particularly autism spectrum disorders, have involved autistic individuals as partners. This study sought to identify…
Waxegård, Gustaf; Thulesius, Hans
Background To establish integrated healthcare pathways for patients with neurodevelopmental disorders (ND) such as autism spectrum disorder and attention-deficit hyperactivity disorder is challenging. This study sets out to investigate the main concerns for healthcare professionals when integrating ND care pathways and how they resolve these concerns. Methods Using classic grounded theory (Glaser), we analysed efforts to improve and integrate an ND care pathway for children and youth in a Swedish region over a period of 6 years. Data from 42 individual interviews with a range of ND professionals, nine group interviews with healthcare teams, participant observation, a 2-day dialogue conference, focus group meetings, regional media coverage, and reports from other Swedish regional ND projects were analysed. Results The main concern for participants was to deal with overwhelming ND complexity by unpacking control, which is control over strategies to define patients’ status and needs. Unpacking control is key to the professionals’ strivings to expand constructive life space for patients, to squeeze health care to reach available care goals, to promote professional ideologies, and to uphold workplace integrity. Control-seeking behaviour in relation to ND unpacking is ubiquitous and complicates integration of ND care pathways. Conclusions The Unpacking control theory expands central aspects of professions theory and may help to improve ND care development. PMID:27609793
Hu, Qing; Franklin, Jason N; Bryan, Ian; Morris, Erin; Wood, Andrew; DeWitt, Jamie C
Immune comorbidities often are reported in subsets of patients with neurodevelopmental disorders, including autism spectrum disorders and attention-deficit hyperactivity disorder. A common immunopathology is an increase in serum autoantibodies against myelin basic protein (MBP) relative to control patients. Increases in autoantibodies suggest possible deficits in self-tolerance that may contribute to the formation of brain-specific autoantibodies and subsequent effects on the central nervous system (CNS). Oppositely, the formation of neuronal autoantibodies may be a reaction to neuronal injury or damage. Perfluorooctanoic acid (PFOA) is an environmental pollutant that induces multisystem toxicity in rodent models, including immunotoxicity and neurotoxicity. We hypothesized that developmental exposure to PFOA may induce immunotoxicity similar to that observed in subsets of patients with neurodevelopmental disorders. To test this hypothesis, we evaluated subsets of T cells from spleens, serum markers of autoreactivity, and levels of MBP and T cell infiltration in the cerebella of adult offspring exposed to 0.02, 0.2, or 2mg/kg of PFOA given to dams from gestation through lactation. Litter weights of offspring from dams exposed to 2mg/kg of PFOA were reduced by 32.6%, on average, from postnatal day one (PND1) through weaning (PND21). The percentage of splenic CD4+CD25+Foxp3+ T cells in male and female offspring from dams exposed to 2mg/kg of PFOA was reduced by 22% relative to the control percentage. Ex vivo co-cultures of splenic CD4+CD25+ T cells and CD4+CD25- T cells from dosed male offspring produced less IL-10 relative to control cells. Anti-ssDNA, a serum marker of autoreactivity, was decreased by 26%, on average, in female offspring from dams exposed to 0.02 and 2mg/kg PFOA. No other endpoints were statistically different by dose. These data suggest that developmental PFOA exposure may impact T cell responses and may be a possible route to downstream effects on
Jivraj, Jamil; Sacrey, Lori-Ann; Newton, Amanda; Nicholas, David; Zwaigenbaum, Lonnie
Participatory research aims to increase the relevance and broaden the implementation of health research by involving those affected by the outcomes of health studies. Few studies within the field of neurodevelopmental disorders, particularly autism spectrum disorders, have involved autistic individuals as partners. This study sought to identify and characterize published participatory research partnerships between researchers and individuals with autism spectrum disorder or other neurodevelopmental disorders and examine the influence of participatory research partnerships on the research process and reported study outcomes. A search of databases and review of gray literature identified seven studies that described participatory research partnerships between academic researchers and individuals with autism spectrum disorder or other neurodevelopmental disorders. A comparative analysis of the studies revealed two key themes: (1) variations in the participatory research design and (2) limitations during the reporting of the depth of the partner's involvement. Both themes potentially limit the application and generalizability of the findings. The results of the review are discussed in relation to the use of evaluative frameworks for such participatory research studies to determine the potential benefits of participatory research partnerships within the neurodevelopmental and autism spectrum disorder populations.
Geraghty, Estella M.; Tancredi, Daniel J.; Delwiche, Lora D.; Schmidt, Rebecca J.; Ritz, Beate; Hansen, Robin L.; Hertz-Picciotto, Irva
Background: Gestational exposure to several common agricultural pesticides can induce developmental neurotoxicity in humans, and has been associated with developmental delay and autism. Objectives: We evaluated whether residential proximity to agricultural pesticides during pregnancy is associated with autism spectrum disorders (ASD) or developmental delay (DD) in the Childhood Autism Risks from Genetics and Environment (CHARGE) study. Methods: The CHARGE study is a population-based case–control study of ASD, DD, and typical development. For 970 participants, commercial pesticide application data from the California Pesticide Use Report (1997–2008) were linked to the addresses during pregnancy. Pounds of active ingredient applied for organophophates, organochlorines, pyrethroids, and carbamates were aggregated within 1.25-km, 1.5-km, and 1.75-km buffer distances from the home. Multinomial logistic regression was used to estimate the odds ratio (OR) of exposure comparing confirmed cases of ASD (n = 486) or DD (n = 168) with typically developing referents (n = 316). Results: Approximately one-third of CHARGE study mothers lived, during pregnancy, within 1.5 km (just under 1 mile) of an agricultural pesticide application. Proximity to organophosphates at some point during gestation was associated with a 60% increased risk for ASD, higher for third-trimester exposures (OR = 2.0; 95% CI: 1.1, 3.6), and second-trimester chlorpyrifos applications (OR = 3.3; 95% CI: 1.5, 7.4). Children of mothers residing near pyrethroid insecticide applications just before conception or during third trimester were at greater risk for both ASD and DD, with ORs ranging from 1.7 to 2.3. Risk for DD was increased in those near carbamate applications, but no specific vulnerable period was identified. Conclusions: This study of ASD strengthens the evidence linking neurodevelopmental disorders with gestational pesticide exposures, particularly organophosphates, and provides novel results of
Vahdatpour, Cyrus; Dyer, Adam H.; Tropea, Daniela
Insulin-Like Growth Factor 1 (IGF-1) is a neurotrophic polypeptide with crucial roles to play in Central Nervous System (CNS) growth, development and maturation. Following interrogation of the neurobiology underlying several neurodevelopmental disorders and Autism Spectrum Disorders (ASD), both recombinant IGF-1 (mecasermin) and related derivatives, such as (1-3)IGF-1, have emerged as potential therapeutic approaches. Clinical pilot studies and early reports have supported the safety/preliminary efficacy of IGF-1 and related compounds in the treatment of Rett Syndrome, with evidence mounting for its use in Phelan McDermid Syndrome and Fragile X Syndrome. In ASD, clinical trials are ongoing. Here, we review the role of IGF-1 in the molecular etiologies of these conditions in addition to the accumulating evidence from early clinical studies highlighting the possibility of IGF-1 and related compounds as potential treatments for these childhood-onset neurodevelopmental disorders. PMID:27746717
Kroon, Tim; Sierksma, Martijn C.; Meredith, Rhiannon M.
Brain function and behavior undergo significant plasticity and refinement, particularly during specific critical and sensitive periods. In autistic and intellectual disability (ID) neurodevelopmental disorders (NDDs) and their corresponding genetic mouse models, impairments in many neuronal and behavioral phenotypes are temporally regulated and in some cases, transient. However, the links between neurobiological mechanisms governing typically normal brain and behavioral development (referred to also as “neurotypical” development) and timing of NDD impairments are not fully investigated. This perspective highlights temporal patterns of synaptic and neuronal impairment, with a restricted focus on autism and ID types of NDDs. Given the varying known genetic and environmental causes for NDDs, this perspective proposes two strategies for investigation: (1) a focus on neurobiological mechanisms underlying known critical periods in the (typically) normal-developing brain; (2) investigation of spatio-temporal expression profiles of genes implicated in monogenic syndromes throughout affected brain regions. This approach may help explain why many NDDs with differing genetic causes can result in overlapping phenotypes at similar developmental stages and better predict vulnerable periods within these disorders, with implications for both therapeutic rescue and ultimately, prevention. PMID:24198768
Almogbel, Yasser S; Goyal, Rohit; Sansgiry, Sujit S
The objective of this study was to examine the association between parenting stress and functional impairment among children with Neurodevelopmental Disorder (NDD). A sample of 150 parents of children diagnosed with NDD were recruited from schools that offer special education services. Parents completed a self-administered survey containing the parenting stress index-short form (PSI-SF) scale and the Columbia Impairment Scale. The multiple logistic regression conducted to compare those with clinically significant PSI-SF scores indicated that the risk of parents with clinically significant scores of parenting stress increased 5.5 times with functionally impaired children with NDD. Further the risk of stress increased 4.6 times when these parents reported having their own disorder/disease. The risk of stress was reduced by 57% for those who had higher than a college level education compared to those with a college level education or below. These findings might help health care providers to initiate early intervention strategies such as peer support and education that can prevent parenting stress and reduce the risk of potential incidence of depression.
Ullrich, Nicole J
Each year in the United States, an average of one to two children per 10,000 develop cancer. The etiology of most childhood cancer remains largely unknown but is likely attributable to random or induced genetic aberrations in somatic tissue. However, a subset of children develops cancer in the setting of an underlying inheritable condition involving a germline genetic mutation or chromosomal aberration. Despite overall improved survival rates for children with cancer over recent decades, many patients experience neurological and neurocognitive complications during the course of their illness and/or as late effects of treatment. Improvements in therapy, longer survival times, and improved imaging techniques have all increased both the time that patients are at risk and the ability to detect such complications. How an underlying inherited disorder influences the incidence, timing, etiology, and treatment of such sequelae has not been extensively documented, but evidence exists for an increased risk for secondary malignancies and in some cases life-threatening sensitivity/toxicity to conventionally dosed cancer treatments, thus emphasizing the need for the early recognition of such syndromes. This review outlines the major tumor- and treatment-related neurodevelopmental sequelae in pediatric cancer patients, with particular attention to children with an underlying inheritable disorder.
Coiro, Pierluca; Padmashri, Ragunathan; Suresh, Anand; Spartz, Elizabeth; Pendyala, Gurudutt; Chou, Shinnyi; Jung, Yoosun; Meays, Brittney; Roy, Shreya; Gautam, Nagsen; Alnouti, Yazen; Li, Ming; Dunaevsky, Anna
Both genetic and environmental factors are thought to contribute to neurodevelopmental and neuropsychiatric disorders with maternal immune activation (MIA) being a risk factor for both autism spectrum disorders and schizophrenia. Although MIA mouse offspring exhibit behavioral impairments, the synaptic alterations in vivo that mediate these behaviors are not known. Here we employed in vivo multiphoton imaging to determine that in the cortex of young MIA offspring there is a reduction in number and turnover rates of dendritic spines, sites of majority of excitatory synaptic inputs. Significantly, spine impairments persisted into adulthood and correlated with increased repetitive behavior, an ASD relevant behavioral phenotype. Structural analysis of synaptic inputs revealed a reorganization of presynaptic inputs with a larger proportion of spines being contacted by both excitatory and inhibitory presynaptic terminals. These structural impairments were accompanied by altered excitatory and inhibitory synaptic transmission. Finally, we report that a postnatal treatment of MIA offspring with the anti-inflammatory drug ibudilast, prevented both synaptic and behavioral impairments. Our results suggest that a possible altered inflammatory state associated with maternal immune activation results in impaired synaptic development that persists into adulthood but which can be prevented with early anti-inflammatory treatment.
Meredith, R M
During sensitive and critical periods, the brain undergoes significant plasticity from the level of individual synapses and neuronal networks up to the level of behaviour. Both sensitive and critical periods during neurotypical development of the young animal provide a framework to the early temporally-regulated modifications that occur in the nervous system. In neurodevelopmental disorders (NDD), notably autistic syndromes and intellectual disability, children exhibit developmental delays in motor, social and sensory processes and often miss key developmental milestones. In corresponding genetic NDD mouse models, recent data reveal temporally-regulated and in some cases, transient impairments in many neuronal and behavioural phenotypes during development. However, the mechanisms underlying these impairments in NDDs and their potential links with neurobiological mechanisms governing neurotypical development are not fully investigated. This article highlights the potential for the use of known critical and sensitive periods during vertebrate development to investigate and advance our understanding of the neural bases underlying impairments in these developmental disorders of the nervous system.
Rubenstein, John L R
The cerebral cortex has a central role in cognitive and emotional processing. As such, understanding the mechanisms that govern its development and function will be central to understanding the bases of severe neuropsychiatric disorders, particularly those that first appear in childhood. In this review, I highlight recent progress in elucidating genetic, molecular and cellular mechanisms that control cortical development. I discuss basic aspects of cortical developmental anatomy, and mechanisms that regulate cortical size and area formation, with an emphasis on the roles of fibroblast growth factor (Fgf) signaling and specific transcription factors. I then examine how specific types of cortical excitatory projection neurons are generated, and how their axons grow along stereotyped pathways to their targets. Next, I address how cortical inhibitory (GABAergic) neurons are generated, and point out the role of these cells in controlling cortical plasticity and critical periods. The paper concludes with an examination of four possible developmental mechanisms that could contribute to some forms of neurodevelopmental disorders, such as autism.
Kimura, Ryuichi; Tucci, Valter; Kaneda, Hideki; Wakana, Shigeharu; Osumi, Noriko
Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD) have increased over the last few decades. These neurodevelopmental disorders are characterized by a complex etiology, which involves multiple genes and gene-environmental interactions. Various genes that control specific properties of neural development exert pivotal roles in the occurrence and severity of phenotypes associated with neurodevelopmental disorders. Moreover, paternal aging has been reported as one of the factors that contribute to the risk of ASD and ADHD. Here we report, for the first time, that paternal aging has profound effects on the onset of behavioral abnormalities in mice carrying a mutation of Pax6, a gene with neurodevelopmental regulatory functions. We adopted an in vitro fertilization approach to restrict the influence of additional factors. Comprehensive behavioral analyses were performed in Sey/+ mice (i.e., Pax6 mutant heterozygotes) born from in vitro fertilization of sperm taken from young or aged Sey/+ fathers. No body weight changes were found in the four groups, i.e., Sey/+ and wild type (WT) mice born to young or aged father. However, we found important differences in maternal separation-induced ultrasonic vocalizations of Sey/+ mice born from young father and in the level of hyperactivity of Sey/+ mice born from aged fathers in the open-field test, respectively, compared to WT littermates. Phenotypes of anxiety were observed in both genotypes born from aged fathers compared with those born from young fathers. No significant difference was found in social behavior and sensorimotor gating among the four groups. These results indicate that mice with a single genetic risk factor can develop different phenotypes depending on the paternal age. Our study advocates for serious considerations on the role of paternal aging in breeding strategies for animal studies. PMID:27855195
Yoshizaki, Kaichi; Furuse, Tamio; Kimura, Ryuichi; Tucci, Valter; Kaneda, Hideki; Wakana, Shigeharu; Osumi, Noriko
Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD) have increased over the last few decades. These neurodevelopmental disorders are characterized by a complex etiology, which involves multiple genes and gene-environmental interactions. Various genes that control specific properties of neural development exert pivotal roles in the occurrence and severity of phenotypes associated with neurodevelopmental disorders. Moreover, paternal aging has been reported as one of the factors that contribute to the risk of ASD and ADHD. Here we report, for the first time, that paternal aging has profound effects on the onset of behavioral abnormalities in mice carrying a mutation of Pax6, a gene with neurodevelopmental regulatory functions. We adopted an in vitro fertilization approach to restrict the influence of additional factors. Comprehensive behavioral analyses were performed in Sey/+ mice (i.e., Pax6 mutant heterozygotes) born from in vitro fertilization of sperm taken from young or aged Sey/+ fathers. No body weight changes were found in the four groups, i.e., Sey/+ and wild type (WT) mice born to young or aged father. However, we found important differences in maternal separation-induced ultrasonic vocalizations of Sey/+ mice born from young father and in the level of hyperactivity of Sey/+ mice born from aged fathers in the open-field test, respectively, compared to WT littermates. Phenotypes of anxiety were observed in both genotypes born from aged fathers compared with those born from young fathers. No significant difference was found in social behavior and sensorimotor gating among the four groups. These results indicate that mice with a single genetic risk factor can develop different phenotypes depending on the paternal age. Our study advocates for serious considerations on the role of paternal aging in breeding strategies for animal studies.
Arnold, Miranda; Cross, Rebecca; Singleton, Kaela S.; Zlatic, Stephanie; Chapleau, Christopher; Mullin, Ariana P.; Rolle, Isaiah; Moore, Carlene C.; Theibert, Anne; Pozzo-Miller, Lucas; Faundez, Victor; Larimore, Jennifer
AGAP1 is an Arf1 GTPase activating protein that interacts with the vesicle-associated protein complexes adaptor protein 3 (AP-3) and Biogenesis of Lysosome Related Organelles Complex-1 (BLOC-1). Overexpression of AGAP1 in non-neuronal cells results in an accumulation of endosomal cargoes, which suggests a role in endosome-dependent traffic. In addition, AGAP1 is a candidate susceptibility gene for two neurodevelopmental disorders, autism spectrum disorder (ASD) and schizophrenia (SZ); yet its localization and function in neurons have not been described. Here, we describe that AGAP1 localizes to axons, dendrites, dendritic spines and synapses, colocalizing preferentially with markers of early and recycling endosomes. Functional studies reveal overexpression and down-regulation of AGAP1 affects both neuronal endosomal trafficking and dendritic spine morphology, supporting a role for AGAP1 in the recycling endosomal trafficking involved in their morphogenesis. Finally, we determined the sensitivity of AGAP1 expression to mutations in the DTNBP1 gene, which is associated with neurodevelopmental disorder, and found that AGAP1 mRNA and protein levels are selectively reduced in the null allele of the mouse ortholog of DTNBP1. We postulate that endosomal trafficking contributes to the pathogenesis of neurodevelopmental disorders affecting dendritic spine morphology, and thus excitatory synapse structure and function. PMID:27713690
Kibby, Michelle Y; Kroese, Judith M; Morgan, Allison E; Hiemenz, Jennifer R; Cohen, Morris J; Hynd, George W
Although children with neurodevelopmental disorders frequently present with reduced short-term memory functioning, the relationship between perisylvian morphology and verbal short-term memory functioning has received limited attention. Thus, examining this relationship in children with neurodevelopmental disorders was the focus of this exploratory study. Results suggested leftward asymmetry in the temporal bank of the planum temporale is related to better coding and storage of semantic material. In contrast, parietal bank morphology is related to coding and storage of phonological material, and presence of an extra gyrus in the parietal region is associated with reduced phonological working memory. Data also supported a relationship between pars triangularis morphology and verbal short-term memory functioning, but this is not material-specific.
Erdodi, Laszlo; Lajiness-O'Neill, Renee; Schmitt, Thomas A.
Visual and auditory verbal learning using a selective reminding format was studied in a mixed clinical sample of children with autism spectrum disorder (ASD) (n = 42), attention-deficit hyperactivity disorder (n = 83), velocardiofacial syndrome (n = 17) and neurotypicals (n = 38) using the Test of Memory and Learning to (1) more thoroughly…
Provenzano, Giovanni; Pangrazzi, Luca; Poli, Andrea; Berardi, Nicoletta; Bozzi, Yuri
Induction of phosphorylated extracellular-regulated kinase (pERK) is a reliable molecular readout of learning-dependent neuronal activation. Here, we describe a pERK immunohistochemistry protocol to study the profile of hippocampal neuron activation following exposure to a spatial learning task in a mouse model characterized by cognitive deficits of neurodevelopmental origin. Specifically, we used pERK immunostaining to study neuronal activation following Morris water maze (MWM, a classical hippocampal-dependent learning task) in Engrailed-2 knockout (En2(-/-)) mice, a model of autism spectrum disorders (ASD). As compared to wild-type (WT) controls, En2(-/-) mice showed significant spatial learning deficits in the MWM. After MWM, significant differences in the number of pERK-positive neurons were detected in specific hippocampal subfields of En2(-/-) mice, as compared to WT animals. Thus, our protocol can robustly detect differences in pERK-positive neurons associated to hippocampal-dependent learning impairment in a mouse model of ASD. More generally, our protocol can be applied to investigate the profile of hippocampal neuron activation in both genetic or pharmacological mouse models characterized by cognitive deficits.
Soden, Sarah E.; Saunders, Carol J.; Willig, Laurel K.; Farrow, Emily G.; Smith, Laurie D.; Petrikin, Josh E.; LePichon, Jean-Baptiste; Miller, Neil A.; Thiffault, Isabelle; Dinwiddie, Darrell L.; Twist, Greyson; Noll, Aaron; Heese, Bryce A.; Zellmer, Lee; Atherton, Andrea M.; Abdelmoity, Ahmed T.; Safina, Nicole; Nyp, Sarah S.; Zuccarelli, Britton; Larson, Ingrid A.; Modrcin, Ann; Herd, Suzanne; Creed, Mitchell; Ye, Zhaohui; Yuan, Xuan; Brodsky, Robert A.; Kingsmore, Stephen F.
Neurodevelopmental disorders (NDDs) affect more than 3% of children and are attributable to single-gene mutations at more than 1000 loci. Traditional methods yield molecular diagnoses in less than one-half of children with NDD. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) can enable diagnosis of NDD, but their clinical and cost-effectiveness are unknown. One hundred families with 119 children affected by NDD received diagnostic WGS and/or WES of parent-child trios, wherein the sequencing approach was guided by acuity of illness. Forty-five percent received molecular diagnoses. An accelerated sequencing modality, rapid WGS, yielded diagnoses in 73% of families with acutely ill children (11 of 15). Forty percent of families with children with nonacute NDD, followed in ambulatory care clinics (34 of 85), received diagnoses: 33 by WES and 1 by staged WES then WGS. The cost of prior negative tests in the nonacute patients was $19,100 per family, suggesting sequencing to be cost-effective at up to $7640 per family. A change in clinical care or impression of the pathophysiology was reported in 49% of newly diagnosed families. If WES or WGS had been performed at symptom onset, genomic diagnoses may have been made 77 months earlier than occurred in this study. It is suggested that initial diagnostic evaluation of children with NDD should include trio WGS or WES, with extension of accelerated sequencing modalities to high-acuity patients. PMID:25473036
Harrington, Adam J; Raissi, Aram; Rajkovich, Kacey; Berto, Stefano; Kumar, Jaswinder; Molinaro, Gemma; Raduazzo, Jonathan; Guo, Yuhong; Loerwald, Kris; Konopka, Genevieve; Huber, Kimberly M; Cowan, Christopher W
Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) – a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice. DOI: http://dx.doi.org/10.7554/eLife.20059.001 PMID:27779093
Grant, William B.; Wimalawansa, Sunil J.; Holick, Michael F.; Cannell, John J.; Pludowski, Pawel; Lappe, Joan M.; Pittaway, Mary; May, Philip
People with neurodevelopmental disorders and intellectual disabilities have much greater health care needs. Mainly staying indoors, such people generally have low 25-hydroxyvitamin D (25(OH)D) concentrations. The Vitamin D Task Force of the American Academy of Developmental Medicine and Dentistry (AADMD) reviewed the evidence of 25(OH)D concentrations that benefit the health of persons with developmental disabilities. Maintaining recommended optimal serum 25(OH)D concentrations year long will benefit skeletal development in infants, children, and adolescents, and benefit musculoskeletal health and neuromuscular coordination in adult patients, and decrease risk of falls. Maintaining optimal concentrations decreases risks and severities of autoimmune diseases, cardiovascular disease, many types of cancer, dementia, types 1 and 2 diabetes mellitus, and respiratory tract infections. Other benefits include improved dental and oral health and improved physical performance. The Task Force recommends that 25(OH)D concentrations for optimal health to be in the range of 75 to 125 nmol/L, which can be achieved using between 800 and 4000 IU/day vitamin D3 and sensible exposure to solar UVB radiation. The paper also discusses the potential risks of higher 25(OH)D concentrations, the evidence from and limitations of randomized controlled trials, and the recommendations by various groups and agencies. PMID:25734565
Wise, Merrill S.
Empirical evidence indicates that sleep spindles facilitate neuroplasticity and “off-line” processing during sleep, which supports learning, memory consolidation, and intellectual performance. Children with neurodevelopmental disorders (NDDs) exhibit characteristics that may increase both the risk for and vulnerability to abnormal spindle generation. Despite the high prevalence of sleep problems and cognitive deficits in children with NDD, only a few studies have examined the putative association between spindle characteristics and cognitive function. This paper reviews the literature regarding sleep spindle characteristics in children with NDD and their relation to cognition in light of what is known in typically developing children and based on the available evidence regarding children with NDD. We integrate available data, identify gaps in understanding, and recommend future research directions. Collectively, studies are limited by small sample sizes, heterogeneous populations with multiple comorbidities, and nonstandardized methods for collecting and analyzing findings. These limitations notwithstanding, the evidence suggests that future studies should examine associations between sleep spindle characteristics and cognitive function in children with and without NDD, and preliminary findings raise the intriguing question of whether enhancement or manipulation of sleep spindles could improve sleep-dependent memory and other aspects of cognitive function in this population. PMID:27478646
Soden, Sarah E; Saunders, Carol J; Willig, Laurel K; Farrow, Emily G; Smith, Laurie D; Petrikin, Josh E; LePichon, Jean-Baptiste; Miller, Neil A; Thiffault, Isabelle; Dinwiddie, Darrell L; Twist, Greyson; Noll, Aaron; Heese, Bryce A; Zellmer, Lee; Atherton, Andrea M; Abdelmoity, Ahmed T; Safina, Nicole; Nyp, Sarah S; Zuccarelli, Britton; Larson, Ingrid A; Modrcin, Ann; Herd, Suzanne; Creed, Mitchell; Ye, Zhaohui; Yuan, Xuan; Brodsky, Robert A; Kingsmore, Stephen F
Neurodevelopmental disorders (NDDs) affect more than 3% of children and are attributable to single-gene mutations at more than 1000 loci. Traditional methods yield molecular diagnoses in less than one-half of children with NDD. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) can enable diagnosis of NDD, but their clinical and cost-effectiveness are unknown. One hundred families with 119 children affected by NDD received diagnostic WGS and/or WES of parent-child trios, wherein the sequencing approach was guided by acuity of illness. Forty-five percent received molecular diagnoses. An accelerated sequencing modality, rapid WGS, yielded diagnoses in 73% of families with acutely ill children (11 of 15). Forty percent of families with children with nonacute NDD, followed in ambulatory care clinics (34 of 85), received diagnoses: 33 by WES and 1 by staged WES then WGS. The cost of prior negative tests in the nonacute patients was $19,100 per family, suggesting sequencing to be cost-effective at up to $7640 per family. A change in clinical care or impression of the pathophysiology was reported in 49% of newly diagnosed families. If WES or WGS had been performed at symptom onset, genomic diagnoses may have been made 77 months earlier than occurred in this study. It is suggested that initial diagnostic evaluation of children with NDD should include trio WGS or WES, with extension of accelerated sequencing modalities to high-acuity patients.
Grant, William B; Wimalawansa, Sunil J; Holick, Michael F; Cannell, John J; Pludowski, Pawel; Lappe, Joan M; Pittaway, Mary; May, Philip
People with neurodevelopmental disorders and intellectual disabilities have much greater health care needs. Mainly staying indoors, such people generally have low 25-hydroxyvitamin D (25(OH)D) concentrations. The Vitamin D Task Force of the American Academy of Developmental Medicine and Dentistry (AADMD) reviewed the evidence of 25(OH)D concentrations that benefit the health of persons with developmental disabilities. Maintaining recommended optimal serum 25(OH)D concentrations year long will benefit skeletal development in infants, children, and adolescents, and benefit musculoskeletal health and neuromuscular coordination in adult patients, and decrease risk of falls. Maintaining optimal concentrations decreases risks and severities of autoimmune diseases, cardiovascular disease, many types of cancer, dementia, types 1 and 2 diabetes mellitus, and respiratory tract infections. Other benefits include improved dental and oral health and improved physical performance. The Task Force recommends that 25(OH)D concentrations for optimal health to be in the range of 75 to 125 nmol/L, which can be achieved using between 800 and 4000 IU/day vitamin D3 and sensible exposure to solar UVB radiation. The paper also discusses the potential risks of higher 25(OH)D concentrations, the evidence from and limitations of randomized controlled trials, and the recommendations by various groups and agencies.
Uzunova, Genoveva; Hollander, Eric; Shepherd, Jason
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
Xiao, Zhou; Qiu, Ting; Ke, Xiaoyan; Xiao, Xiang; Xiao, Ting; Liang, Fengjing; Zou, Bing; Huang, Haiqing; Fang, Hui; Chu, Kangkang; Zhang, Jiuping; Liu, Yijun
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that occurs within the first 3 years of life, which is marked by social skills and communication deficits along with stereotyped repetitive behavior. Although great efforts have been made to clarify the underlying neuroanatomical abnormalities and brain-behavior relationships…
Asadollahi, Reza; Oneda, Beatrice; Joset, Pascal; Azzarello-Burri, Silvia; Bartholdi, Deborah; Steindl, Katharina; Vincent, Marie; Cobilanschi, Joana; Sticht, Heinrich; Baldinger, Rosa; Reissmann, Regina; Sudholt, Irene; Thiel, Christian T; Ekici, Arif B; Reis, André; Bijlsma, Emilia K; Andrieux, Joris; Dieux, Anne; FitzPatrick, David; Ritter, Susanne; Baumer, Alessandra; Latal, Beatrice; Plecko, Barbara; Jenni, Oskar G; Rauch, Anita
Background Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context. Methods By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1–500 kb in a cohort of 714 patients with undiagnosed NDDs. Results We detected 96 rare CNVs <500 kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130 kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear. Conclusions These results verify the diagnostic relevance of genome-wide rare CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions. PMID:25106414
Berkowicz, Susan R.; Featherby, Travis J.; Whisstock, James C.; Bird, Phillip I.
Background: Brinps 1–3, and Astrotactins (Astn) 1 and 2, are members of the Membrane Attack Complex/Perforin (MACPF) superfamily that are predominantly expressed in the mammalian brain during development. Genetic variation at the human BRINP2/ASTN1 and BRINP1/ASTN2 loci has been implicated in neurodevelopmental disorders. We, and others, have previously shown that Brinp1−/− mice exhibit behavior reminiscent of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Method: We created Brinp2−/− mice and Brinp3−/− mice via the Cre-mediated LoxP system to investigate the effect of gene deletion on anatomy and behavior. Additionally, Brinp2−/−Brinp3−/− double knock-out mice were generated by interbreeding Brinp2−/− and Brinp3−/− mice. Genomic validation was carried out for each knock-out line, followed by histological, weight and behavioral examination. Brinp1−/−Brinp2−/−Brinp3−/− triple knock-out mice were also generated by crossing Brinp2/3 double knock-out mice with previously generated Brinp1−/− mice, and examined by weight and histological analysis. Results: Brinp2−/− and Brinp3−/− mice differ in their behavior: Brinp2−/− mice are hyperactive, whereas Brinp3−/− mice exhibit marked changes in anxiety-response on the elevated plus maze. Brinp3−/− mice also show evidence of altered sociability. Both Brinp2−/− and Brinp3−/− mice have normal short-term memory, olfactory responses, pre-pulse inhibition, and motor learning. The double knock-out mice show behaviors of Brinp2−/− and Brinp3−/− mice, without evidence of new or exacerbated phenotypes. Conclusion: Brinp3 is important in moderation of anxiety, with potential relevance to anxiety disorders. Brinp2 dysfunction resulting in hyperactivity may be relevant to the association of ADHD with chromosome locus 1q25.2. Brinp2−/− and Brinp3−/− genes do not compensate in the mammalian brain and likely have
Rajkumar, Ravi Philip
Gender identity disorder (GID), recently renamed gender dysphoria (GD), is a rare condition characterized by an incongruity between gender identity and biological sex. Clinical evidence suggests that schizophrenia occurs in patients with GID at rates higher than in the general population and that patients with GID may have schizophrenia-like personality traits. Conversely, patients with schizophrenia may experience alterations in gender identity and gender role perception. Neurobiological research, including brain imaging and studies of finger length ratio and handedness, suggests that both these disorders are associated with altered cerebral sexual dimorphism and changes in cerebral lateralization. Various mechanisms, such as Toxoplasma infection, reduced levels of brain-derived neurotrophic factor (BDNF), early childhood adversity, and links with autism spectrum disorders, may account for some of this overlap. The implications of this association for further research are discussed.
Rajkumar, Ravi Philip
Gender identity disorder (GID), recently renamed gender dysphoria (GD), is a rare condition characterized by an incongruity between gender identity and biological sex. Clinical evidence suggests that schizophrenia occurs in patients with GID at rates higher than in the general population and that patients with GID may have schizophrenia-like personality traits. Conversely, patients with schizophrenia may experience alterations in gender identity and gender role perception. Neurobiological research, including brain imaging and studies of finger length ratio and handedness, suggests that both these disorders are associated with altered cerebral sexual dimorphism and changes in cerebral lateralization. Various mechanisms, such as Toxoplasma infection, reduced levels of brain-derived neurotrophic factor (BDNF), early childhood adversity, and links with autism spectrum disorders, may account for some of this overlap. The implications of this association for further research are discussed. PMID:25548672
Picinelli, Chiara; Lintas, Carla; Piras, Ignazio Stefano; Gabriele, Stefano; Sacco, Roberto; Brogna, Claudia; Persico, Antonio Maria
Rare and common CNVs can contribute to the etiology of neurodevelopmental disorders. One of the recurrent genomic aberrations associated with these phenotypes and proposed as a susceptibility locus is the 15q11.2 BP1-BP2 CNV encompassing TUBGCP5, CYFIP1, NIPA2, and NIPA1. Characterizing by array-CGH a cohort of 243 families with various neurodevelopmental disorders, we identified five patients carrying the 15q11.2 duplication and one carrying the deletion. All CNVs were confirmed by qPCR and were inherited, except for one duplication where parents were not available. The phenotypic spectrum of CNV carriers was broad but mainly neurodevelopmental, in line with all four genes being implicated in axonal growth and neural connectivity. Phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. This variability may be due to reduced penetrance or altered gene dosage on a particular genetic background. We evaluated the expression levels of the four genes in peripheral blood RNA and found the expected reduction in the deleted case, while duplicated carriers displayed high interindividual variability. These data suggest that differential expression of these genes could partially account for differences in clinical phenotypes, especially among duplication carriers. Furthermore, urinary Mg(2+) levels appear negatively correlated with NIPA2 gene copy number, suggesting they could potentially represent a useful biomarker, whose reliability will need replication in larger samples. © 2016 Wiley Periodicals, Inc.
Hanson, Kari L.; Hrvoj-Mihic, Branka; Semendeferi, Katerina
The evolution of the human brain has been marked by a nearly three-fold increase in size since our divergence from the last common ancestor shared with chimpanzees and bonobos. Despite increased interest in comparative neuroanatomy and phylogenetic methods, relatively little is known regarding the effects that this enlargement has had on its internal organization, and how certain areas of the brain have differentially expanded over evolutionary time. Analyses of the microstructure of several regions of the human cortex and subcortical structures have demonstrated subtle changes at the cellular and molecular level, suggesting that the human brain is more than simply a ‘scaled-up’ primate brain. Ongoing research in comparative neuroanatomy has much to offer our understanding of human brain evolution. Through analysis of the neuroanatomical phenotype at the level of reorganization in cytoarchitecture and cellular morphology, new data continue to highlight changes in cell density and organization associated with volumetric changes in discrete regions. An understanding of the functional significance of variation in neural circuitry can further be approached through studies of atypical human development. Many neurodevelopmental disorders cause disruption in systems associated with uniquely human features of cognition, including language and social cognition. Understanding the genetic and developmental mechanisms that underlie variation in the human cognitive phenotype can help to clarify the functional significance of interspecific variation. By uniting approaches from comparative neuroanatomy and neuropathology, insights can be gained that clarify trends in human evolution. Here, we explore these lines of evidence, and their significance for understanding functional variation between species, and within neuropathological variation in the human brain. PMID:25247986
Valdes-Socin, Hernan; Rubio Almanza, Matilde; Tomé Fernández-Ladreda, Mariana; Debray, François Guillaume; Bours, Vincent; Beckers, Albert
The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology. PMID:25071724
Kril, Jillian J.
Alcohol-related diseases of the nervous system are caused by excessive exposures to alcohol, with or without co-existing nutritional or vitamin deficiencies. Toxic and metabolic effects of alcohol (ethanol) vary with brain region, age/developmental stage, dose, and duration of exposures. In the mature brain, heavy chronic or binge alcohol exposures can cause severe debilitating diseases of the central and peripheral nervous systems, and skeletal muscle. Most commonly, long-standing heavy alcohol abuse leads to disproportionate loss of cerebral white matter and impairments in executive function. The cerebellum (especially the vermis), cortical-limbic circuits, skeletal muscle, and peripheral nerves are also important targets of chronic alcohol-related metabolic injury and degeneration. Although all cell types within the nervous system are vulnerable to the toxic, metabolic, and degenerative effects of alcohol, astrocytes, oligodendrocytes, and synaptic terminals are major targets, accounting for the white matter atrophy, neural inflammation and toxicity, and impairments in synaptogenesis. Besides chronic degenerative neuropathology, alcoholics are predisposed to develop severe potentially life-threatening acute or subacute symmetrical hemorrhagic injury in the diencephalon and brainstem due to thiamine deficiency, which exerts toxic/metabolic effects on glia, myelin, and the microvasculature. Alcohol also has devastating neurotoxic and teratogenic effects on the developing brain in association with fetal alcohol spectrum disorder/fetal alcohol syndrome. Alcohol impairs function of neurons and glia, disrupting a broad array of functions including neuronal survival, cell migration, and glial cell (astrocytes and oligodendrocytes) differentiation. Further progress is needed to better understand the pathophysiology of this exposure-related constellation of nervous system diseases and better correlate the underlying pathology with in vivo imaging and biochemical lesions
Zarnegar, Zohreh; Hambrick, Erin P; Perry, Bruce D; Azen, Stanley P; Peterson, Cassandra
Research on early intervention for young children (infants and toddlers) with fetal alcohol spectrum disorders (FASD), particularly children with comorbid maltreatment experiences, is limited. Existing research has primarily focused on structuring environments to be responsive to the needs experienced by children with FASD rather than improving their functioning. The purpose of this study is to present outcomes from an early psychosocial intervention with 10 adopted, maltreated young children diagnosed with FASD, aged 10-53 months (M = 35 months), and their adoptive parents. The potential for early, targeted interventions to improve developmental outcomes for children with prenatal alcohol exposure was examined, as well as improving the skills of and reducing stress experienced by their adoptive parents. Based on the outcomes of a neurodevelopmentally informed assessment protocol, the 10 children whose data are presented were recommended to receive a range of regulatory, somatosensory, relational, and cognitive enrichments. As part of their treatment, children and caregivers received Child-Parent Psychotherapy (CPP), and caregivers (here, adoptive parents) also received Mindful Parenting Education (MPE). Related-samples Wilcoxon signed-rank tests indicated that scores of several measures of child developmental functioning improved from pre- to post-intervention and that parents' caregiving skills improved while their caregiving stress decreased. Reliable change analyses indicated that change observed from pre- to post-intervention was reliable. The promise of using neurodevelopmentally informed assessment strategies to sequence interventions for young children with diverse neurodevelopmental insults is discussed.
GABAergic interneurons are critical for the normal function and development of neural circuits, and their dysfunction is implicated in a large number of neurodevelopmental disorders. Experience and activity-dependent mechanisms play an important role in GABAergic circuit development, also recent studies involve a number of molecular players involved in the process. Emphasizing the molecular mechanisms of GABAergic synapse formation, in particular basket cell perisomatic synapses, this paper draws attention to the links between critical period plasticity, GABAergic synapse maturation, and the consequences of its dysfunction on the development of the nervous system. PMID:21826279
Torres, Fátima; Barbosa, Mafalda; Maciel, Patrícia
Neurodevelopmental disorders (NDs) encompass a spectrum of neuropsychiatric manifestations. Chromosomal regions 1q21.1, 3q29, 15q11.2, 15q13.3, 16p11.2, 16p13.1 and 22q11 harbour rare but recurrent CNVs that have been uncovered as being important risk factors for several of these disorders. These rearrangements may underlie a broad phenotypical spectrum, ranging from normal development, to learning problems, intellectual disability (ID), epilepsy and psychiatric diseases, such as autism spectrum disorders (ASDs) and schizophrenia (SZ). The highly increased risk of developing neurodevelopmental phenotypes associated with some of these CNVs makes them an unavoidable element in the clinical context in paediatrics, neurology and psychiatry. However, and although finding these risk loci has been the goal of neuropsychiatric genetics for many years, the translation of this recent knowledge into clinical practice has not been trivial. In this article, we will: (1) review the state of the art on recurrent CNVs associated with NDs, namely ASD, ID, epilepsy and SZ; (2) discuss the models used to dissect the underlying neurobiology of disease, (3) discuss how this knowledge can be used in clinical practice.
Oh-Nishi, Arata; Koga, Kaori; Maeda, Tadakazu; Suhara, Tetsuya
Epidemiological studies have shown that maternal infection during early pregnancy increases the risk of neurodevelopmental disorders (i.e., schizophrenia or autism) in offspring. Recently, diagnostic/stratification biomarkers for the maternal immune activation background in patients with neurodevelopmental disorders have been energetically searched for in the patient blood. Here, we report a novel serologic marker candidate for the disorders found in the maternal immune activation (MIA) rat model. Serum proteome analysis of the MIA rat showed that the immunoglobulin (Ig) light chain is reproducibly augmented. The Ig light chain in sera takes two forms - free form or bound to the Ig heavy chain. Only the former is an inflammatory disease marker, but pro-inflammatory cytokine levels in the sera of the MIA rats were below detectable limits of the ELISA protocol we used. We thereby carried out serum assays of Ig light chains and pro-inflammatory cytokines of commercially available schizophrenia patient sera for research. Although the number of samples was limited, we found augmentation of free Ig light chains but not pro-inflammatory cytokines in sporadic schizophrenia patient sera. Our findings suggest that Ig light chain assay of the schizophrenia/autism patient sera would be worthy to be validated in larger scale.
Marques, Andrea Horvath; O'Connor, Thomas G.; Roth, Christine; Susser, Ezra; Bjørke-Monsen, Anne-Lise
The developing immune system and central nervous system in the fetus and child are extremely sensitive to both exogenous and endogenous signals. Early immune system programming, leading to changes that can persist over the life course, has been suggested, and other evidence suggests that immune dysregulation in the early developing brain may play a role in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. The timing of immune dysregulation with respect to gestational age and neurologic development of the fetus may shape the elicited response. This creates a possible sensitive window of programming or vulnerability. This review will explore the effects of maternal prenatal and infant nutritional status (from conception until early childhood) as well as maternal prenatal stress and anxiety on early programming of immune function, and how this might influence neurodevelopment. We will describe fetal immune system development and maternal-fetal immune interactions to provide a better context for understanding the influence of nutrition and stress on the immune system. Finally, we will discuss the implications for prevention of neurodevelopmental disorders, with a focus on nutrition. Although certain micronutrient supplements have shown to both reduce the risk of neurodevelopmental disorders and enhance fetal immune development, we do not know whether their impact on immune development contributes to the preventive effect on neurodevelopmental disorders. Future studies are needed to elucidate this relationship, which may contribute to a better understanding of preventative mechanisms. Integrating studies of neurodevelopmental disorders and prenatal exposures with the simultaneous evaluation of neural and immune systems will shed light on mechanisms that underlie individual vulnerability or resilience to neurodevelopmental disorders and ultimately contribute to the development of primary preventions and early interventions. PMID:23914151
Marques, Andrea Horvath; O'Connor, Thomas G; Roth, Christine; Susser, Ezra; Bjørke-Monsen, Anne-Lise
The developing immune system and central nervous system in the fetus and child are extremely sensitive to both exogenous and endogenous signals. Early immune system programming, leading to changes that can persist over the life course, has been suggested, and other evidence suggests that immune dysregulation in the early developing brain may play a role in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. The timing of immune dysregulation with respect to gestational age and neurologic development of the fetus may shape the elicited response. This creates a possible sensitive window of programming or vulnerability. This review will explore the effects of maternal prenatal and infant nutritional status (from conception until early childhood) as well as maternal prenatal stress and anxiety on early programming of immune function, and how this might influence neurodevelopment. We will describe fetal immune system development and maternal-fetal immune interactions to provide a better context for understanding the influence of nutrition and stress on the immune system. Finally, we will discuss the implications for prevention of neurodevelopmental disorders, with a focus on nutrition. Although certain micronutrient supplements have shown to both reduce the risk of neurodevelopmental disorders and enhance fetal immune development, we do not know whether their impact on immune development contributes to the preventive effect on neurodevelopmental disorders. Future studies are needed to elucidate this relationship, which may contribute to a better understanding of preventative mechanisms. Integrating studies of neurodevelopmental disorders and prenatal exposures with the simultaneous evaluation of neural and immune systems will shed light on mechanisms that underlie individual vulnerability or resilience to neurodevelopmental disorders and ultimately contribute to the development of primary preventions and early interventions.
Barnes, SA; Pinto-Duarte, A; Kappe, A; Zembrzycki, A; Metzler, A; Mukamel, EA; Lucero, J; Wang, X; Sejnowski, TJ; Markou, A; Behrens, MM
Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv+) fast-spiking interneurons, have been proposed as underlying causes of several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv+ GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv+ interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv+ interneurons resulted in reduced numbers of Pv+ neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv+ neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders. PMID:26260494
Barnes, S A; Pinto-Duarte, A; Kappe, A; Zembrzycki, A; Metzler, A; Mukamel, E A; Lucero, J; Wang, X; Sejnowski, T J; Markou, A; Behrens, M M
Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv(+)) fast-spiking interneurons, have been proposed as underlying causes of several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv(+) GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv(+) interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv(+) interneurons resulted in reduced numbers of Pv(+) neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv(+) neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders.
Moffitt, Terrie E.; Houts, Renate; Asherson, Philip; Belsky, Daniel W; Corcoran, David L; Hammerle, Maggie; Harrington, Honalee; Hogan, Sean; Meier, Madeline; Polanczyk, Guilherme V.; Poulton, Richie; Ramrakha, Sandhya; Sugden, Karen; Williams, Benjamin; Rohde, Luis Augusto; Caspi, Avshalom
Objective Despite a prevailing assumption that adult ADHD is a childhood-onset neurodevelopmental disorder, no prospective-longitudinal study has described the childhoods of the adult-ADHD population. We report follow-back analyses of ADHD cases diagnosed in adulthood, alongside follow-forward analyses of ADHD cases diagnosed in childhood, in one cohort. Method Participants belonged to a representative birth cohort of 1,037 individuals born in Dunedin, New Zealand in 1972-73 and followed to age 38, with 95% retention. Symptoms of ADHD, associated clinical features, comorbid disorders, neuropsychological deficits, GWAS-derived polygenic risk, and life impairment indicators were assessed. Data sources were participants, parents, teachers, informants, neuropsychological testing, and administrative records. Adult ADHD diagnoses used DSM5 criteria, apart from onset-age and cross-setting corroboration, which were study outcomes. Results As expected, the childhood-ADHD group showed 6% prevalence, male excess, childhood comorbid disorders, neurocognitive deficits, polygenic risk, and, despite having outgrown their ADHD diagnosis, residual adult life impairment. As expected, the adult-ADHD group showed 3% prevalence, gender balance, adult substance dependence, adult life impairment, and treatment contact. Unexpectedly, the childhood-ADHD and adult-ADHD groups comprised virtually non-overlapping sets; 90% of adult-ADHD cases lacked a history of childhood ADHD. Also unexpectedly, the adult-ADHD group did not show tested neuropsychological deficits in childhood or adulthood, nor did they show polygenic risk for childhood ADHD. Conclusion Findings raise the possibility that adults presenting with the ADHD symptom picture may not have a childhood-onset neurodevelopmental disorder. If this finding is replicated, then the disorder's place in the classification system must be reconsidered, and research must investigate the etiology of adult ADHD. PMID:25998281
The paper discusses the application of fMRI in combination with neuropsychology to neurodevelopmental psychiatric disorders, exemplified on the case of attention deficit hyperactivity disorder (ADHD) in comparison with schizophrenia. The view is presented that ADHD, rather than being a compound of unrelated co-existing deficits, is a pervasive disorder of impulsiveness, which manifests at the motor, emotional, social and cognitive domain. Neuropsychology needs to refine the psychological measurements of these impulsivity symptoms and, in combination with fMRI, provide new insights into the interrelationship between brain and dysfunction and its bi-directional causalities. The suitability of the dynamic technique of functional MRI to assess the dynamic nature of developmental neuropsychiatric disorders is discussed. Brain activation can inform about strategy and compensatory mechanisms at a neuroanatomical level, which are not observable at a psychological level, providing insight into the underlying neurocognitive mechanisms of psychiatric disorders. Data are presented and discussed on opposing neurocognitive activation patterns for patients with ADHD and those with schizophrenia while performing a stop task. Comparisons between patient groups will be essential to address the specificity of neurocognitive mechanisms corresponding to specific neurodevelopmental psychiatric disorders.
Meyer, Urs; Feldon, Joram; Fatemi, S Hossein
Based on the epidemiological association between maternal infection during pregnancy and enhanced risk of neurodevelopmental brain disorders in the offspring, a number of in-vivo models have been established in rats and mice in order to study this link on an experimental basis. These models provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, and to explore the critical neuroimmunological and developmental factors involved in shaping the vulnerability to infection-induced neurodevelopmental disturbances in humans. Here, we summarize the findings derived from numerous in-vivo models of prenatal infection and/or immune activation in rats and mice, including models of exposure to influenza virus, bacterial endotoxin, viral-like acute phase responses and specific pro-inflammatory cytokines. Furthermore, we discuss the methodological aspects of these models in relation to their practical implementation and their translatability to the human condition. We highlight that these models can successfully examine the influence of the precise timing of maternal immune activation, the role of pro- and anti-inflammatory cytokines, and the contribution of gene-environment interactions in the association between prenatal immune challenge and postnatal brain dysfunctions. Finally, we discuss that in-vivo models of prenatal immune activation offer a unique opportunity to establish and evaluate early preventive interventions aiming to reduce the risk of long-lasting brain dysfunctions following prenatal exposure to infection.
Geier, David A.; Hooker, Brian S.; Kern, Janet K.; King, Paul G.; Sykes, Lisa K.; Geier, Mark R.
A hypothesis testing case-control study evaluated concerns about the toxic effects of organic-mercury (Hg) exposure from thimerosal-containing (49.55% Hg by weight) vaccines on the risk of neurodevelopmental disorders (NDs). Automated medical records were examined to identify cases and controls enrolled from their date-of-birth (1991–2000) in the Vaccine Safety Datalink (VSD) project. ND cases were diagnosed with pervasive developmental disorder (PDD), specific developmental delay, tic disorder or hyperkinetic syndrome of childhood. In addition, putative non-thimerosal-related outcomes of febrile seizure, failure to thrive and cerebral degenerations were examined. The cumulative total dose of Hg exposure from thimerosal-containing hepatitis B vaccine (T-HBV) administered within the first six months of life was calculated. On a per microgram of organic-Hg basis, PDD (odds ratio (OR) = 1.054), specific developmental delay (OR = 1.035), tic disorder (OR = 1.034) and hyperkinetic syndrome of childhood (OR = 1.05) cases were significantly more likely than controls to receive increased organic-Hg exposure. By contrast, none of the non-thimerosal related outcomes were significantly more likely than the controls to have received increased organic-Hg exposure. Routine childhood vaccination may be an important public health tool to reduce infectious disease-associated morbidity/mortality, but the present study significantly associates organic-Hg exposure from T-HBV with an increased risk of an ND diagnosis. PMID:25198681
Geier, David A; Hooker, Brian S; Kern, Janet K; King, Paul G; Sykes, Lisa K; Geier, Mark R
A hypothesis testing case-control study evaluated concerns about the toxic effects of organic-mercury (Hg) exposure from thimerosal-containing (49.55% Hg by weight) vaccines on the risk of neurodevelopmental disorders (NDs). Automated medical records were examined to identify cases and controls enrolled from their date-of-birth (1991-2000) in the Vaccine Safety Datalink (VSD) project. ND cases were diagnosed with pervasive developmental disorder (PDD), specific developmental delay, tic disorder or hyperkinetic syndrome of childhood. In addition, putative non-thimerosal-related outcomes of febrile seizure, failure to thrive and cerebral degenerations were examined. The cumulative total dose of Hg exposure from thimerosal-containing hepatitis B vaccine (T-HBV) administered within the first six months of life was calculated. On a per microgram of organic-Hg basis, PDD (odds ratio (OR) = 1.054), specific developmental delay (OR = 1.035), tic disorder (OR = 1.034) and hyperkinetic syndrome of childhood (OR = 1.05) cases were significantly more likely than controls to receive increased organic-Hg exposure. By contrast, none of the non-thimerosal related outcomes were significantly more likely than the controls to have received increased organic-Hg exposure. Routine childhood vaccination may be an important public health tool to reduce infectious disease-associated morbidity/mortality, but the present study significantly associates organic-Hg exposure from T-HBV with an increased risk of an ND diagnosis.
Bell, Emily; Wallace, Tessa; Chouinard, Isabelle; Shevell, Michael; Racine, Eric
Faced with the limitations of currently available mainstream medical treatments and interventions, parents of children with neurodevelopmental disorders often seek information about unproven interventions. These interventions frequently have undetermined efficacy and uncertain safety profiles. In this article, we present a general background and…
Holland, A.; Whittington, J.; Cohen, O.; Curfs, L.; Delahaye, F.; Dudley, O.; Horsthemke, B.; Lindgren, A. -C.; Nourissier, C.; Sharma, N.; Vogels, A.
Background: Prader-Willi Syndrome (PWS) is a rare genetically determined neurodevelopmental disorder with a complex phenotype that changes with age. The rarity of the syndrome and the need to control for different variables such as genetic sub-type, age and gender limits clinical studies of sufficient size in any one country. A clinical research…
Plummer, Jasmine T.; Gordon, Alexis J.; Levitt, Pat
Most psychiatric disorders are considered neurodevelopmental, and the associated genes often are expressed in tissues outside of the brain. This suggests a biological relatedness with medical co-occurrences that could have broad clinical implications for diagnosis and patient management over a lifetime. A qualitative integration of public data from genetic consortia of psychiatric disorders and medical comorbidities explores the question of whether genetically associated psychiatric illnesses present with co-occurring disturbances can be used to define specific mental–physical health relations. Novel patterns of gene-disorder relations appear with approximately one-third of conservatively defined, consortia-generated candidate risk genes with multiple psychiatric diagnoses. Moreover, nearly as many genes overlap with non-psychiatric phenotypes, including cardiovascular, renal, respiratory, and metabolic disturbances. While the landscape of genetic risk will change as study populations are expanded and biological confirmations accrue, the current relationships suggest that a mostly siloed perspective of gene relatedness to one categorical psychiatric diagnosis is not clinically useful. The future holds the promise that once candidates are fully validated, genome screening and mutation identification will bring more precision for predicting the risk for complex health conditions. Our view is that as genetic data are refined, continuing to decipher a shared pattern of genetic risk for brain and peripheral organ pathophysiology is not simply an academic exercise. Rather, determining relatedness will impact predictions of multifaceted health risks, patient treatment, and management. PMID:27597832
Lopez-Atalaya, Jose P; Valor, Luis M; Barco, Angel
The number of genetic syndromes associated with intellectual disability that are caused by mutations in genes encoding chromatin-modifying enzymes has sharply risen in the last decade. We discuss here a neurodevelopmental disorder, the Rubinstein-Taybi syndrome (RSTS), originated by mutations in the genes encoding the lysine acetyltransferases CBP and p300. We first describe clinical and genetic aspects of the syndrome to later focus on the insight provided by the research in animal models of this disease. These studies have not only clarified the molecular etiology of RSTS and helped to dissect the developmental and adult components of the syndrome but also contributed to outline some important connections between epigenetics and cognition. We finally discuss how this body of research has opened new venues for the therapeutic intervention of this currently untreatable disease and present some of the outstanding questions in the field. We believe that the progress in the understanding of this rare disorder also has important implications for other intellectual disability disorders that share an epigenetic origin.
Sollis, Elliot; Graham, Sarah A; Vino, Arianna; Froehlich, Henning; Vreeburg, Maaike; Dimitropoulou, Danai; Gilissen, Christian; Pfundt, Rolph; Rappold, Gudrun A; Brunner, Han G; Deriziotis, Pelagia; Fisher, Simon E
De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.
... clinical diagnosis. It refers to conditions such as fetal alcohol syndrome (FAS), alcohol- related neurodevelopmental disorder (ARND), and alcohol- ... Gossage, J.P. 2001. Estimating the prevalence of fetal alcohol syndrome: A summary. Alcohol Research & Health 25(3):159– ...
disorders such as ASD. 15. SUBJECT TERMS Autism , placenta, tryptophan, serotonin, kynurenine, maternal immune activation, fetal brain 16...14 3 INTRODUCTION Maternal infections in humans increase the risk for autism spectrum disorders (ASD) in the offspring. In rodents...fetal brain development. KEYWORDS Autism , placenta, tryptophan, serotonin, kynurenine, maternal immune activation, fetal brain. OVERALL PROJECT
Chapleau, Christopher A; Larimore, Jennifer L; Theibert, Anne; Pozzo-Miller, Lucas
The process of axonal and dendritic development establishes the synaptic circuitry of the central nervous system (CNS) and is the result of interactions between intrinsic molecular factors and the external environment. One growth factor that has a compelling function in neuronal development is the neurotrophin brain-derived neurotrophic factor (BDNF). BDNF participates in axonal and dendritic differentiation during embryonic stages of neuronal development, as well as in the formation and maturation of dendritic spines during postnatal development. Recent studies have also implicated vesicular trafficking of BDNF via secretory vesicles, and both secretory and endosomal trafficking of vesicles containing synaptic proteins, such as neurotransmitter and neurotrophin receptors, in the regulation of axonal and dendritic differentiation, and in dendritic spine morphogenesis. Several genes that are either mutated or deregulated in neurodevelopmental disorders associated with mental retardation have now been identified, and several mouse models of these disorders have been generated and characterized. Interestingly, abnormalities in dendritic and synaptic structure are consistently observed in human neurodevelopmental disorders associated with mental retardation, and in mouse models of these disorders as well. Abnormalities in dendritic and synaptic differentiation are thought to underlie altered synaptic function and network connectivity, thus contributing to the clinical outcome. Here, we review the roles of BDNF and vesicular trafficking in axonal and dendritic differentiation in the context of dendritic and axonal morphological impairments commonly observed in neurodevelopmental disorders associated with mental retardation.
Mikhail, Fady M; Lose, Edward J; Robin, Nathaniel H; Descartes, Maria D; Rutledge, Katherine D; Rutledge, S Lane; Korf, Bruce R; Carroll, Andrew J
Recent studies suggest that copy number variations (CNVs) encompassing several genes involved in neurodevelopmental pathways are associated with a variety of neuropsychiatric phenotypes, including developmental delay (DD), mental retardation (MR), and autism spectrum disorders (ASDs). Here we present eight patients in a cohort of approximately 1,200 patients referred for clinical array CGH testing for various neurodevelopmental phenotypes,whowere identified to carry small (<1.0Mb with the majority <500 kb) either total gene or intragenic deletions encompassing critical synaptic and other neurodevelopmental genes. The presentations of these patients included variable degrees of DD, speech problems, learning disabilities, MR, autistic-like features, and mild non-specific dysmorphic features. These genes belong to four functional categories, including neuronal transcription factor genes (NFIA at 1p31.3, MEF2C at 5q14.3, andCAMAT1at 1p36.23p36.31), neuron-specific splicing factor genes (RBFOX1 at 16p13.2p13.3), genes involved in synapse formation and maintenance (CNTNAP2 at 7q35 and LRFN5 at 14q21.2), and genes involved in neurotransmission (CHRNA7 at 15q13.3 and IL1RAPL1 at Xp21.2p21.3). Our report expands the list of neurodevelopmental genes deleted in various neurobehavioral phenotypes, expands the phenotypes caused by haploinsufficiency of previously reported critical neurodevelopmental genes, and elucidates the clinical relevance and need for careful clinical interpretation of some small CNVs<500 kb. This report also suggests that small clinically relevant deletions encompassing critical synaptic and other neurodevelopmental genes can present clinically with various neurobehavioral phenotypes, which implies the existence of overlapping neuronal pathways in the pathogenesis of these phenotypes.
Demjaha, Arsime; MacCabe, James H; Murray, Robin M
The debate endures as to whether schizophrenia and bipolar disorder are separate entities or different manifestations of a single underlying pathological process. Here, we argue that this sterile argument obscures the fact that the truth lies somewhere in between. Thus, recent studies support a model whereby, on a background of some shared genetic liability for both disorders, patients with schizophrenia have been subject to additional genetic and/or environmental factors that impair neurodevelopment; for example, copy number variants and obstetric complications are associated with schizophrenia but not with bipolar disorder. As a result, children destined to develop schizophrenia show an excess of neuromotor delays and cognitive difficulties while those who later develop bipolar disorder perform at least as well as the general population. In keeping with this model, cognitive impairments and brain structural abnormalities are present at first onset of schizophrenia but not in the early stages of bipolar disorder. However, with repeated episodes of illness, cognitive and brain structural abnormalities accumulate in both schizophrenia and bipolar disorder, thus clouding the picture.
Rubenstein, John L. R.
The cerebral cortex has a central role in cognitive and emotional processing. As such, understanding the mechanisms that govern its development and function will be central to understanding the bases of severe neuropsychiatric disorders, particularly those that first appear in childhood. In this review, I highlight recent progress in elucidating…
Schizophrenia and bipolar disorders share not only clinical features but also some risk factors such as genetic markers and childhood adversity, while other risk factors such as urbanicity and obstetric complications seem to be specific to schizophrenia. An intriguing question is whether the well-established abnormal neurodevelopment present in many children and adolescents who eventually develop schizophrenia is also present in bipolar patients. The literature on adult bipolar patients is controversial. We report data on a subgroup of patients with pediatric-onset psychotic bipolar disorder who seem to share some developmental trajectories with patients with early-onset schizophrenia. These early-onset psychotic bipolar patients have low intelligence quotient, more neurological signs, reduced frontal gray matter at the time of their first psychotic episode, and greater brain changes than healthy controls in a pattern similar to early-onset schizophrenia cases. However, patients with early-onset schizophrenia seem to have more social impairment, developmental abnormalities (eg, language problems), and lower academic achievement in childhood than early-onset bipolar patients. We suggest that some of these abnormal developmental trajectories are more related to the phenotypic features (eg, early-onset psychotic symptoms) of these 2 syndromes than to categorically defined Diagnostic and Statistical Manual of Mental Disorders disorders. PMID:24371326
Deidda, Gabriele; Bozarth, Ignacio F.; Cancedda, Laura
During mammalian ontogenesis, the neurotransmitter GABA is a fundamental regulator of neuronal networks. In neuronal development, GABAergic signaling regulates neural proliferation, migration, differentiation, and neuronal-network wiring. In the adult, GABA orchestrates the activity of different neuronal cell-types largely interconnected, by powerfully modulating synaptic activity. GABA exerts these functions by binding to chloride-permeable ionotropic GABAA receptors and metabotropic GABAB receptors. According to its functional importance during development, GABA is implicated in a number of neurodevelopmental disorders such as autism, Fragile X, Rett syndrome, Down syndrome, schizophrenia, Tourette's syndrome and neurofibromatosis. The strength and polarity of GABAergic transmission is continuously modulated during physiological, but also pathological conditions. For GABAergic transmission through GABAA receptors, strength regulation is achieved by different mechanisms such as modulation of GABAA receptors themselves, variation of intracellular chloride concentration, and alteration in GABA metabolism. In the never-ending effort to find possible treatments for GABA-related neurological diseases, of great importance would be modulating GABAergic transmission in a safe and possibly physiological way, without the dangers of either silencing network activity or causing epileptic seizures. In this review, we will discuss the different ways to modulate GABAergic transmission normally at work both during physiological and pathological conditions. Our aim is to highlight new research perspectives for therapeutic treatments that reinstate natural and physiological brain functions in neuro-pathological conditions. PMID:24904277
Johnels, Jakob Åsberg; Hagberg, Bibbi; Gillberg, Christopher; Miniscalco, Carmela
Oral narrative retelling is often problematic for children with communicative and neurodevelopmental disorders. However, beyond a suggested role of language level, little is known about the basis of narrative performance. In this study we examine whether oral narrative retelling might be associated not just with language level but also with skills related to nonverbal narrative temporal sequencing. A diagnostically heterogeneous sample of Swedish-speaking children with a full scale IQ >70 was included in the study (N = 55; age 6-9 years). Narrative retelling skills were measured using the three subscores from the bus story test (BST). Independent predictors included (1) temporal sequencing skills according to a picture arrangement test and (2) a language skills factor consisting of definitional vocabulary and receptive grammar. Regression analyses show that language skills predicted BST Sentence Length and Subordinate Clauses subscores, while both temporal sequencing and language were independently linked with the BST Information subscore. When subdividing the sample based on nonverbal temporal sequencing level, a significant subgroup difference was found only for BST Information. Finally, a principal component analysis shows that temporal sequencing and BST Information loaded on a common factor, separately from the language measures. It is concluded that language level is an important correlate of narrative performance more generally in this diagnostically heterogeneous sample, and that nonverbal temporal sequencing functions are important especially for conveying story information. Theoretical and clinical implications are discussed.
Imam, Tuhina; Lee, Cheryl E; Chen, Shirley Yu; Herman, Adam; Sharma, Balraj; Johal, Gurinder; Gu, Bobby
Background The Portal for Families Overcoming Neurodevelopmental Disorders (PFOND) provides a structured Internet interface for the sharing of information with individuals struggling with the consequences of rare developmental disorders. Large disease-impacted communities can support fundraising organizations that disseminate Web-based information through elegant websites run by professional staff. Such quality resources for families challenged by rare disorders are infrequently produced and, when available, are often dependent upon the continued efforts of a single individual. Objective The project endeavors to create an intuitive Web-based software system that allows a volunteer with limited technical computer skills to produce a useful rare disease website in a short time period. Such a system should provide access to emerging news and research findings, facilitate community participation, present summary information about the disorder, and allow for transient management by volunteers who are likely to change periodically. Methods The prototype portal was implemented using the WordPress software system with both existing and customized supplementary plug-in software modules. Gamification scoring features were implemented in a module, allowing editors to measure progress. The system was installed on a Linux-based computer server, accessible across the Internet through standard Web browsers. Results A prototype PFOND system was implemented and tested. The prototype system features a structured organization with distinct partitions for background information, recent publications, and community discussions. The software design allows volunteer editors to create a themed website, implement a limited set of topic pages, and connect the software to dynamic RSS feeds providing information about recent news or advances. The prototype was assessed by a fraction of the disease sites developed (8 out of 27), including Aarskog-Scott syndrome, Aniridia, Adams-Oliver syndrome
Durieux, Alice M. S.; Fernandes, Cathy; Murphy, Declan; Labouesse, Marie Anais; Giovanoli, Sandra; Meyer, Urs; Li, Qi; So, Po-Wah; McAlonan, Grainne
An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as autism spectrum disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here, we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviors relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more anxious in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate glutamate acutely and have functional consequences even in adulthood. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders across the life-span. PMID:26696857
Kim, Young Shin; State, Matthew W
Recent advances in the genetics of neurodevelopmental disorder (NDD) have demonstrated that rare mutations play a role not only in Mendelian syndromes, but in complex, common forms of NDDs as well. Strikingly, both common polymorphisms and rare variations in a single gene or genetic locus have been found to carry risk for conditions previously considered to be clinically and aetiologically distinct. Recent developments in the methods and tools available for studying complex NDDs have led to systematic and reliable genome-wide variant discovery. Both common as well as rare, and structural as well as sequence, genetic variations have been identified as contributing to NDDs. There are multiple examples in which the identical variant had been found to contribute to a wide range of formerly distinct diagnoses, including autism, schizophrenia, epilepsy, intellectual disability and language disorders. These include variations in chromosomal structure at 16p11.2, rare de novo point mutations at the gene SCN2A, and common single nucleotide polymorphisms (SNPs) mapping near loci encoding the genes ITIH3, AS3MT, CACNA1C and CACNB2. These selected examples point to the challenges to current diagnostic approaches. Widely used categorical schema have been adequate to provide an entré into molecular mechanisms of NDDs, but there is a need to develop an alternative, more biologically-relevant nosology. Thus recent advances in gene discovery in the area of NDDs are leading to a re-conceptualization of diagnostic boundaries. Findings suggest that epidemiological samples may provide important new insights into the genetics and diagnosis of NDDs and that other areas of medicine may provide useful models for developing a new diagnostic nosology, one that simultaneously integrates categorical diagnoses, biomarkers and dimensional variables.
Kerns, Kimberly A; Macoun, Sarah; MacSween, Jenny; Pei, Jacqueline; Hutchison, Marnie
The current study investigated the efficacy of a game-based process specific intervention for improving attention and working memory in children with Fetal Alcohol Spectrum Disorders (FASD) and Autism Spectrum Disorders (ASD). The Caribbean Quest (CQ) is a 'serious game' that consists of five hierarchically structured tasks, delivered in an adaptive format, targeting different aspects of attention and/or working memory. In addition to game play, the intervention incorporates metacognitive strategies provided by trained educational assistants (EAs), to facilitate generalization and far transfer to academic and daily skills. EAs delivered the intervention to children (ages 6-13) during their regular school day, providing children with instruction in metacognitive strategies to improve game play, with participants completing approximately 12 hours of training over an 8 to 12 school week period. Pre- and post-test analyses revealed significant improvement on measures of working memory and attention, including reduced distractibility and improved divided attention skills. Additionally, children showed significant gains in performance on an academic measure of reading fluency, suggesting that training-related gains in attention and working memory transferred to classroom performance. Exit interviews with EAs revealed that the intervention was easily delivered within the school day, that children enjoyed the intervention, and that children transferred metacognitive strategies learned in game play into the classroom. Preliminary results support this game-based process specific intervention as a potentially effective treatment and useful tool for supporting cognitive improvements in children with FASD or ASD, when delivered as part of an overall treatment plan.
Neira-Fresneda, Juanita; Potocki, Lorraine
Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6 Mb microduplication of 17p11.2, known as PTLS, represents the mechanistically predicted homologous recombination reciprocal of the SMS microdeletion, both resulting in multiple congenital anomalies. Mouse model studies have revealed that the retinoic acid-inducible 1 gene (RAI1) within the SMS and PTLS critical genomic interval is the dosage-sensitive gene responsible for the major phenotypic features in these disorders. Even though PTLS and SMS share the same genomic region, clinical manifestations and behavioral issues are distinct and in fact some mirror traits may be on opposite ends of a given phenotypic spectrum. We describe the neurobehavioral phenotypes of SMS and PTLS patients during different life phases as well as clinical guidelines for diagnosis and a multidisciplinary approach once diagnosis is confirmed by array comparative genomic hybridization or RAI1 gene sequencing. The main goal is to increase awareness of these rare disorders because an earlier diagnosis will lead to more timely developmental intervention and medical management which will improve clinical outcome.
Neira-Fresneda, Juanita; Potocki, Lorraine
Smith–Magenis syndrome (SMS) and Potocki–Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6 Mb microduplication of 17p11.2, known as PTLS, represents the mechanistically predicted homologous recombination reciprocal of the SMS microdeletion, both resulting in multiple congenital anomalies. Mouse model studies have revealed that the retinoic acid–inducible 1 gene (RAI1) within the SMS and PTLS critical genomic interval is the dosage-sensitive gene responsible for the major phenotypic features in these disorders. Even though PTLS and SMS share the same genomic region, clinical manifestations and behavioral issues are distinct and in fact some mirror traits may be on opposite ends of a given phenotypic spectrum. We describe the neurobehavioral phenotypes of SMS and PTLS patients during different life phases as well as clinical guidelines for diagnosis and a multidisciplinary approach once diagnosis is confirmed by array comparative genomic hybridization or RAI1 gene sequencing. The main goal is to increase awareness of these rare disorders because an earlier diagnosis will lead to more timely developmental intervention and medical management which will improve clinical outcome. PMID:27617127
Atladóttir, H. Ó.; Schendel, D. E.; Parner, E. T.; Henriksen, T. B.
The aim of this study was to describe the profile of specific neonatal morbidities in children later diagnosed with autism spectrum disorder (ASD), and to compare this profile with the profile of children with hyperkinetic disorder, cerebral palsy, epilepsy or intellectual disability. This is a Danish population based cohort study, including all…
Ho, Karen S.; Wassman, E. Robert; Baxter, Adrianne L.; Hensel, Charles H.; Martin, Megan M.; Prasad, Aparna; Twede, Hope; Vanzo, Rena J.; Butler, Merlin G.
Copy number variants (CNVs) detected by chromosomal microarray analysis (CMA) significantly contribute to understanding the etiology of autism spectrum disorder (ASD) and other related conditions. In recognition of the value of CMA testing and its impact on medical management, CMA is in medical guidelines as a first-tier test in the evaluation of children with these disorders. As CMA becomes adopted into routine care for these patients, it becomes increasingly important to report these clinical findings. This study summarizes the results of over 4 years of CMA testing by a CLIA-certified clinical testing laboratory. Using a 2.8 million probe microarray optimized for the detection of CNVs associated with neurodevelopmental disorders, we report an overall CNV detection rate of 28.1% in 10,351 consecutive patients, which rises to nearly 33% in cases without ASD, with only developmental delay/intellectual disability (DD/ID) and/or multiple congenital anomalies (MCA). The overall detection rate for individuals with ASD is also significant at 24.4%. The detection rate and pathogenic yield of CMA vary significantly with the indications for testing, age, and gender, as well as the specialty of the ordering doctor. We note discrete differences in the most common recurrent CNVs found in individuals with or without a diagnosis of ASD. PMID:27941670
Fawkes, Diane B.; Malow, Beth A.; Weiss, Shelly K.; Reynolds, Ann; Loh, Alvin; Adkins, Karen; Wofford, Deborah; Wyatt, Amanda D.; Goldman, Suzanne E.
The literature has been highly informative for when to use actigraphy and its validity in pediatric research. However, minimal literature exists on how to perform actigraphy, especially in special populations. We determined whether providing actigraphy training to parents and coordinators increased the nights of actigraphy data that could be scored. We compared two studies in children with autism spectrum disorders, one which provided a basic level of training in a single site trial and the other which provided more detailed training to parents and coordinators in a multisite trial. There was an increase in scorable nights in the multisite trial containing a one-hour structured parent training session. Our results support the use of educational tools in clinical trials that use actigraphy. PMID:24669845
Fawkes, Diane B; Malow, Beth A; Weiss, Shelly K; Reynolds, Ann M; Loh, Alvin; Adkins, Karen W; Wofford, Deborah D; Wyatt, Amanda D; Goldman, Suzanne E
The literature has been highly informative for when to use actigraphy and its validity in pediatric research. However, minimal literature exists on how to perform actigraphy, especially in special populations. We determined whether providing actigraphy training to parents and coordinators increased the nights of actigraphy data that could be scored. We compared two studies in children with autism spectrum disorders, one of which provided a basic level of training in a single-site trial and the other of which provided more detailed training to parents and coordinators in a multisite trial. There was an increase in scorable nights in the multisite trial containing a one-hour structured parent training session. Our results support the use of educational tools in clinical trials that use actigraphy.
Duy, Phan Q.; Budimirovic, Dejan B.
Abstract Fragile X syndrome (FXS) is the leading genetic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID) worldwide. Preclinical successes in understanding the biology of FXS have led to numerous translational attempts in human clinical trials of therapeutics that target the excitatory/inhibitory neural signaling imbalances thought to underlie FXS. Despite the preclinical success story, the negative results of the human clinical trials have been deemed to be at least in part disappointing by the field. In this commentary, we contend that such negative studies results in clinical trials may actually propel the FXS field forward by serving as important lessons for designing and implementing improved future clinical trials such that can objectively assess the full range of responses to new therapeutics.
Herbal mixtures consisting of puerarin and either polyenylphosphatidylcholine or curcumin provide comprehensive protection against alcohol-related disorders in P rats receiving free choice water and 15% ethanol in pure water.
Singh, Ashok K; Jiang, Yin; Benlhabib, Elhabib; Gupta, Shveta
SPCh or CU may provide alternative therapy for alcohol-related disorders.
Perez-Villena, Ana; Soto-Insuga, Victor; Castaño-De la Mota, Cristina; Martin-Del Valle, Fernando; Pons-Rodriguez, Montserrat; Losada-Del Pozo, Rebeca; Moreno-Acero, Noelia; Alarcon-Martinez, Helena; Rodrigo-Moreno, María; Miravet-Fuster, Elena; Monfort-Belenguer, Lucía; Polo-Antunez, Antonio; Martinez-Bermejo, Antonio; Merino-Andreu, Milagros
Introduccion. Los trastornos de sueño son frecuentes en niños con trastornos neurologicos. El objetivo del estudio es conocer la opinion de los neuropediatras y su prevalencia real en España. Pacientes y metodos. Estudio transversal multicentrico (12 hospitales españoles, 15 investigadores). Se administro la encuesta Bedtime, Excesive Daytime Sleepiness, Awakenings, Regularity, Sleep-Disordered Breathing (BEARS) y se definieron tres grupos: A (2-5 años), B (6-12 años) y C (> 12 años). Asimismo, se recogio la opinion de neuropediatras de la Sociedad Española de Neuropediatria mediante una encuesta anonima. Resultados. Se recogieron 939 encuestas. Los principales motivos de consulta en los grupos B y C fueron trastorno por deficit de atencion/hiperactividad (32,4% y 30,1%, respectivamente) y cefalea (25,1% y 27,6%, respectivamente), y en el grupo A, los trastornos del neurodesarrollo (32,4%) y la epilepsia (21,4%). Al menos un area del sueño alterada se encontro en el 92,9% de niños del grupo A (n = 209; media: 3 años), en el 64,2% del grupo B (n = 534; media: 9,4 años) y en el 58,2% del grupo C (n = 196; media: 13,7 años). Se recibieron 61 encuestas respondidas por los neuropediatras (16,75% de las enviadas), quienes estimaban que los trastornos del sueño afectaban a menos de una cuarta parte de sus pacientes (24,5%), y hasta un 23% afirmo que la prevalencia era inferior al 10%. Conclusion. El 58-92% de los padres-pacientes que acuden a consultas de neuropediatria refiere tener algun aspecto del sueño alterado. Aunque la mayoria de los neuropediatras subraya la importancia de un diagnostico y tratamiento de los trastornos de sueño de los niños con trastornos neurologicos, se suele infraestimar su frecuencia e importancia.
Xu, Qiong; Goldstein, Jennifer; Wang, Ping; Gadi, Inder K.; Labreche, Heather; Rehder, Catherine; Wang, Wei-Ping; McConkie, Allyn; Xu, Xiu; Jiang, Yong-hui
Background The pathogenicity of copy number variations (CNV) in neurodevelopmental disorders is well supported by research literature. However, few studies have evaluated the utility and counseling challenges of CNV analysis in the clinic. Methods We analyzed the findings of CNV studies from a cohort referred for clinical genetics evaluation of autism spectrum disorders (ASD), developmental disability (DD), and intellectual disability (ID). Results Twenty-two CNV in 21 out of 115 probands are considered to be pathogenic (18.3%). Five CNV are likely pathogenic and 22 CNV are variants of unknown significance (VUS). We have found 7 cases with more than 2 CNV and 2 with a complex rearrangement of the 22q13.3 Phelan-McDermid syndrome region. We identified a new and de novo 1q21.3 deletion that encompasses SETDB1, a gene encoding methylates histone H3 on lysine-9 (H3K9) methyltransferase, in a case with typical ASD and ID. Conclusions We provide evidence to support the value of CNV analysis in etiological evaluation of neurodevelopmental disorders. However, interpretation of the clinical significance and counseling families are still challenging because of the variable penetrance and pleotropic expressivity of CNVs. In addition, the identification of a 1q21.3 deletion encompassing SETDB1 provides further support for the role of chromatin modifiers in the etiology of ASD. PMID:27119313
Lesch, Klaus-Peter; Araragi, Naozumi; Waider, Jonas; van den Hove, Daniel; Gutknecht, Lise
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.
Lesch, Klaus-Peter; Araragi, Naozumi; Waider, Jonas; van den Hove, Daniel; Gutknecht, Lise
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. PMID:22826343
Staples, Pamela A.
The study of older adults is relatively new for the social sciences. There is a growing awareness of the alcohol-related problems in this population. Between 2 and 10 percent of older social drinkers present severe alcohol-related problems of different kinds. Three terms describe the major consequences of "too much" alcohol: intoxication,…
Sekiguchi, Mari; Katayama, Syouichi; Hatano, Naoya; Shigeri, Yasushi; Sueyoshi, Noriyuki; Kameshita, Isamu
Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase predominantly expressed in brain and mutations of its gene are known to be associated with neurodevelopmental disorders such as X-linked West syndrome and Rett syndrome. However, the physiological substrates of CDKL5 that are directly linked to these neurodevelopmental disorders are currently unknown. In this study, we explored endogenous substrates for CDKL5 in mouse brain extracts fractionated by a liquid-phase isoelectric focusing. In conjunction with CDKL5 phosphorylation assay, this approach detected a protein band with an apparent molecular mass of 120kDa that is remarkably phosphorylated by CDKL5. This 120-kDa protein was identified as amphiphysin 1 (Amph1) by LC-MS/MS analysis, and the site of phosphorylation by CDKL5 was determined to be Ser-293. The phosphorylation mimic mutants, Amph1(S293E) and Amph1(S293D), showed significantly reduced affinity for endophilin, a protein involved in synaptic vesicle endocytosis. Introduction of point mutations in the catalytic domain of CDKL5, which are disease-causing missense mutations found in Rett patients, resulted in the impairment of kinase activity toward Amph1. These results suggest that Amph1 is the cytoplasmic substrate for CDKL5 and that its phosphorylation may play crucial roles in the neuronal development.
The approach to treating alcohol-related problems in primary care settings needs: 1) to recognize the incidence of alcohol-related problems in primary care settings; 2) to know the way of screening; 3) to know how to help patients; and 4) to know enough about treating alcoholism to appropriately refer patients for additional help. This article looks research evidence about the incidence of alcohol-related problems in primary care and recognition of incidence and way of screening of alcohol-related problems by primary care physicians in Japan. Then this article describes evidence-based as well as author's experience-based approach to treat the alcohol-related health problems in primary care settings. In line with the newly introduced law to prevent the alcohol-related health problems and the anticipating introduction of new specialty of general medicine, early intervention to alcohol-related problems in primary care settings will be much appreciated. To do so, enough amounts of education and research are needed.
Hempel, Annmarie; Pagnamenta, Alistair T; Blyth, Moira; Mansour, Sahar; McConnell, Vivienne; Kou, Ikuyo; Ikegawa, Shiro; Tsurusaki, Yoshinori; Matsumoto, Naomichi; Lo-Castro, Adriana; Plessis, Ghislaine; Albrecht, Beate; Battaglia, Agatino; Taylor, Jenny C; Howard, Malcolm F; Keays, David; Sohal, Aman Singh; Kühl, Susanne J; Kini, Usha; McNeill, Alisdair
Background SOX11 is a transcription factor proposed to play a role in brain development. The relevance of SOX11 to human developmental disorders was suggested by a recent report of SOX11 mutations in two patients with Coffin–Siris syndrome. Here we further investigate the role of SOX11 variants in neurodevelopmental disorders. Methods We used array based comparative genomic hybridisation and trio exome sequencing to identify children with intellectual disability who have deletions or de novo point mutations disrupting SOX11. The pathogenicity of the SOX11 mutations was assessed using an in vitro gene expression reporter system. Loss-of-function experiments were performed in xenopus by knockdown of Sox11 expression. Results We identified seven individuals with chromosome 2p25 deletions involving SOX11. Trio exome sequencing identified three de novo SOX11 variants, two missense (p.K50N; p.P120H) and one nonsense (p.C29*). The biological consequences of the missense mutations were assessed using an in vitro gene expression system. These individuals had microcephaly, developmental delay and shared dysmorphic features compatible with mild Coffin–Siris syndrome. To further investigate the function of SOX11, we knocked down the orthologous gene in xenopus. Morphants had significant reduction in head size compared with controls. This suggests that SOX11 loss of function can be associated with microcephaly. Conclusions We thus propose that SOX11 deletion or mutation can present with a Coffin–Siris phenotype. PMID:26543203
Zahr, Natalie M; Kaufman, Kimberley L; Harper, Clive G
One of the sequelae of chronic alcohol abuse is malnutrition. Importantly, a deficiency in thiamine (vitamin B(1)) can result in the acute, potentially reversible neurological disorder Wernicke encephalopathy (WE). When WE is recognized, thiamine treatment can elicit a rapid clinical recovery. If WE is left untreated, however, patients can develop Korsakoff syndrome (KS), a severe neurological disorder characterized by anterograde amnesia. Alcohol-related brain damage (ARBD) describes the effects of chronic alcohol consumption on human brain structure and function in the absence of more discrete and well-characterized neurological concomitants of alcoholism such as WE and KS. Through knowledge of both the well-described changes in brain structure and function that are evident in alcohol-related disorders such as WE and KS and the clinical outcomes associated with these changes, researchers have begun to gain a better understanding of ARBD. This Review examines ARBD from the perspective of WE and KS, exploring the clinical presentations, postmortem brain pathology, in vivo MRI findings and potential molecular mechanisms associated with these conditions. An awareness of the consequences of chronic alcohol consumption on human behavior and brain structure can enable clinicians to improve detection and treatment of ARBD.
We describe a project aimed at studying a large number of individuals (>200) with specific recurrent genetic variations (deletion or duplication of segment 16p11.2) that increase the risk of developing autism spectrum (ASD) and other developmental disorders. The genetics-first approach augmented by web-based recruitment, multisite collaboration and calibration, and robust data-sharing policies could be adopted by other groups studying neuropsychiatric disorders to accelerate the pace of research.
Vannucci, Anna; Nelson, Eric E.; Bongiorno, Diana M.; Pine, Daniel S.; Yanovski, Jack A.; Tanofsky-Kraff, Marian
Background Pediatric loss-of-control eating is a robust behavioral precursor to binge-type eating disorders. Elucidating precursors to loss-of-control eating and binge-type eating disorders may refine developmental risk models of eating disorders and inform interventions. Method We review evidence within constructs of the Negative Valence Systems (NVS)-domain, as specified by the Research Domain Criteria framework. Based on published studies, we propose an integrated NVS model of binge-type eating disorder risk. Results Data implicate altered corticolimbic functioning, neuroendocrine dysregulation, and self-reported negative affect as possible risk-factors. However, neuroimaging and physiological data in children and adolescents are sparse, and most prospective studies are limited to self-report measures. Conclusions We discuss a broad NVS framework for conceptualizing early risk for binge-type eating disorders. Future neural and behavioral research on the developmental trajectory of loss-of-control and binge-type eating disorders is required. PMID:26040923
Kaur, Kulbir; Simon, Anne F; Chauhan, Ved; Chauhan, Abha
Developmental disorders such as autism and attention deficit hyperactivity disorder (ADHD) appear to have a complex etiology implicating both genetic and environmental factors. Bisphenol A (BPA), a widely used chemical in the plastic containers and in the linings of food and beverage cans, has been suggested to play a possible causative role in some developmental disorders. Here, we report behavioral modifications in Drosophila melanogaster following early exposure to BPA, which may suggest BPA as an environmental risk factor for the behavioral impairments that are the basis of diagnosis of autism and ADHD. In an open field assay with perinatally BPA-exposed and vehicle-treated control Drosophila, different parameters of locomotion (distance traveled, walking speed, spatial movement, mobility, turn angle, angular velocity and meander) were analyzed using the ethovision software. We also examined the repetitive and social interaction behaviors in these flies. In an open field assay, we identified disturbances in the locomotion patterns of BPA-exposed Drosophila that may relate to the decision-making and the motivational state of the animal. An increase in repetitive behavior was observed as an increase in the grooming behavior of Drosophila following BPA exposure. Furthermore, we also observed abnormal social interaction by the BPA-exposed flies in a social setting. These results demonstrate the effect of the environmentally prevalent risk agent BPA on the behavior of Drosophila, and suggest the practicability and the ease of using Drosophila as a model in the studies of neurobehavioral developmental disorders.
Xu, Xiangjun; Jaehne, Emily J; Greenberg, Zarina; McCarthy, Peter; Saleh, Eiman; Parish, Clare L; Camera, Daria; Heng, Julian; Haas, Matilda; Baune, Bernhard T; Ratnayake, Udani; van den Buuse, Maarten; Lopez, Angel F; Ramshaw, Hayley S; Schwarz, Quenten
Sequencing and expression analyses implicate 14-3-3ζ as a genetic risk factor for neurodevelopmental disorders such as schizophrenia and autism. In support of this notion, we recently found that 14-3-3ζ(-/-) mice in the Sv/129 background display schizophrenia-like defects. As epistatic interactions play a significant role in disease pathogenesis we generated a new congenic strain in the BALB/c background to determine the impact of genetic interactions on the 14-3-3ζ(-/-) phenotype. In addition to replicating defects such as aberrant mossy fibre connectivity and impaired spatial memory, our analysis of 14-3-3ζ(-/-) BALB/c mice identified enlarged lateral ventricles, reduced synaptic density and ectopically positioned pyramidal neurons in all subfields of the hippocampus. In contrast to our previous analyses, 14-3-3ζ(-/-) BALB/c mice lacked locomotor hyperactivity that was underscored by normal levels of the dopamine transporter (DAT) and dopamine signalling. Taken together, our results demonstrate that dysfunction of 14-3-3ζ gives rise to many of the pathological hallmarks associated with the human condition. 14-3-3ζ-deficient BALB/c mice therefore provide a novel model to address the underlying biology of structural defects affecting the hippocampus and ventricle, and cognitive defects such as hippocampal-dependent learning and memory.
Ronca, April E.
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
Ballendine, Stephanie A; Greba, Quentin; Dawicki, Wojciech; Zhang, Xiaobei; Gordon, John R; Howland, John G
Research suggests that maternal immune activation (MIA) during pregnancy increases the risk of neurodevelopmental disorders including schizophrenia and autism in the offspring. Current theories suggest that inflammatory mediators including cytokines and chemokines may underlie the increased risk of these disorders in humans. For example, elevated maternal interleukin-8 (IL-8) during pregnancy is associated with increased risk of schizophrenia in the offspring. Given this association, the present experiments examined ELR-CXC chemokines CXCL1 and CXCL2, rodent homologues of human IL-8, and activation of their receptors (CXCR1 and CXCR2) in an established rodent model of MIA. Pregnant Long Evans rats were treated with the viral mimetic polyinosinic-polycytidylic acid (polyI:C; 4 mg/kg, i.v.) on gestational day 15. Protein analysis using multiplex assays and ELISA showed that polyI:C significantly increased maternal serum concentrations of interleukin-1β, tumor necrosis factor, and CXCL1 3h after administration. Subsequent experiments tested the role of elevated maternal CXCL1 on behavior of the offspring by administering a CXCR1/CXCR2 antagonist (G31P; 500 μg/kg, i.p.; 1h before, 48 and 96 h after polyI:C treatment). The male offspring of dams treated with polyI:C demonstrated subtle impairments in prepulse inhibition (PPI), impaired associative and crossmodal recognition memory, and altered behavioral flexibility in an operant test battery. While G31P did not completely reverse the behavioral impairments caused by polyI:C, it enhanced PPI during adolescence and strategy set-shifting and reversal learning during young adulthood. These results suggest that while polyI:C treatment significantly increases maternal CXCL1, elevations of this chemokine are not solely responsible for the effects of polyI:C on the behavior of the offspring.
Ballendine, Stephanie A.; Greba, Quentin; Dawicki, Wojciech; Zhang, Xiaobei; Gordon, John R.; Howland, John G.
Research suggests that maternal immune activation (MIA) during pregnancy increases the risk of neurodevelopmental disorders including schizophrenia and autism in the offspring. Current theories suggest that inflammatory mediators including cytokines and chemokines may underlie the increased risk of these disorders in humans. For example, elevated maternal interleukin-8 (IL-8) during pregnancy is associated with increased risk of schizophrenia in the offspring. Given this association, the present experiments examined ELR-CXC chemokines CXCL1 and CXCL2, rodent homologues of human IL-8, and activation of their receptors (CXCR1 and CXCR2) in an established rodent model of MIA. Pregnant Long Evans rats were treated with the viral mimetic polyinosinic–polycytidylic acid (polyI:C; 4 mg/kg, i.v.) on gestational day 15. Protein analysis using multiplex assays and ELISA showed that polyI:C significantly increased maternal serum concentrations of interleukin-1β, tumor necrosis factor, and CXCL1 3 h after administration. Subsequent experiments tested the role of elevated maternal CXCL1 on behavior of the offspring by administering a CXCR1/CXCR2 antagonist (G31P; 500 μg/kg, i.p.; 1 h before, 48 and 96 h after polyI:C treatment). The male offspring of dams treated with polyI:C demonstrated subtle impairments in prepulse inhibition (PPI), impaired associative and crossmodal recognition memory, and altered behavioral flexibility in an operant test battery. While G31P did not completely reverse the behavioral impairments caused by polyI:C, it enhanced PPI during adolescence and strategy set-shifting and reversal learning during young adulthood. These results suggest that while polyI:C treatment significantly increases maternal CXCL1, elevations of this chemokine are not solely responsible for the effects of polyI:C on the behavior of the offspring. PMID:25445065
Cappi, C; Brentani, H; Lima, L; Sanders, S J; Zai, G; Diniz, B J; Reis, V N S; Hounie, A G; Conceição do Rosário, M; Mariani, D; Requena, G L; Puga, R; Souza-Duran, F L; Shavitt, R G; Pauls, D L; Miguel, E C; Fernandez, T V
Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein-protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10(-8) per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular
Cappi, C; Brentani, H; Lima, L; Sanders, S J; Zai, G; Diniz, B J; Reis, V N S; Hounie, A G; Conceição do Rosário, M; Mariani, D; Requena, G L; Puga, R; Souza-Duran, F L; Shavitt, R G; Pauls, D L; Miguel, E C; Fernandez, T V
Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein–protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10−8 per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular
Cittaro, Davide; Lampis, Valentina; Luchetti, Alessandra; Coccurello, Roberto; Guffanti, Alessandro; Felsani, Armando; Moles, Anna; Stupka, Elia; D’ Amato, Francesca R.; Battaglia, Marco
Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice’s respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders. PMID:27121911
Cittaro, Davide; Lampis, Valentina; Luchetti, Alessandra; Coccurello, Roberto; Guffanti, Alessandro; Felsani, Armando; Moles, Anna; Stupka, Elia; D' Amato, Francesca R; Battaglia, Marco
Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice's respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders.
Childhood maltreatment, which markedly increases the risk of psychopathology such as depression, PTSD, and reduced cognitive abilities, is associated with structural and functional brain differences. Our earlier studies elucidated potential discernible effects on the brain morphology of childhood maltreatment on the gray matter volume or cortical thickness. Further, our preliminary studies revealed a significantly reduced gray matter volume (GMV) in the left primary visual cortex (Brodmann area 17) in the reactive attachment disorder (RAD) group compared to the typically developed group. These visual cortex GMV abnormalities may also be associated with such visual stimulus-induced emotion regulation impairments of RAD, leading to an increase in the risk of future psychopathology. Brain regions that process and convey the adverse sensory input of the abuse might be modified specifically by such experiences, particularly in subjects exposed to a single type of maltreatment. Thus, exposure to multiple types of maltreatment is more commonly associated with morphological alterations in corticolimbic regions.
Moey, Ching; Hinze, Susan J; Brueton, Louise; Morton, Jenny; McMullan, Dominic J; Kamien, Benjamin; Barnett, Christopher P; Brunetti-Pierri, Nicola; Nicholl, Jillian; Gecz, Jozef; Shoubridge, Cheryl
Copy number variations are a common cause of intellectual disability (ID). Determining the contribution of copy number variants (CNVs), particularly gains, to disease remains challenging. Here, we report four males with ID with sub-microscopic duplications at Xp11.2 and review the few cases with overlapping duplications reported to date. We established the extent of the duplicated regions in each case encompassing a minimum of three known disease genes TSPYL2, KDM5C and IQSEC2 with one case also duplicating the known disease gene HUWE1. Patients with a duplication encompassing TSPYL2, KDM5C and IQSEC2 without gains of nearby SMC1A and HUWE1 genes have not been reported thus far. All cases presented with ID and significant deficits of speech development. Some patients also manifested behavioral disturbances such as hyperactivity and attention-deficit/hyperactivity disorder. Lymphoblastic cell lines from patients show markedly elevated levels of TSPYL2, KDM5C and SMC1A, transcripts consistent with the extent of their CNVs. The duplicated region in our patients contains several genes known to escape X-inactivation, including KDM5C, IQSEC2 and SMC1A. In silico analysis of expression data in selected gene expression omnibus series indicates that dosage of these genes, especially IQSEC2, is similar in males and females despite the fact they escape from X-inactivation in females. Taken together, the data suggest that gains in Xp11.22 including IQSEC2 cause ID and are associated with hyperactivity and attention-deficit/hyperactivity disorder, and are likely to be dosage-sensitive in males. PMID:26059843
Sharpe, Kimberly; Di Pietro, Nina; Jacob, Karen J; Illes, Judy
Parents and primary caregivers of children with Cerebral Palsy (CP) and Autism Spectrum Disorder (ASD) are faced with difficult treatment choices and management options for their children. The potential of stem cell technologies as an interventional strategy for CP and ASD has gained attention in the last decade. Information about these interventions varies in quality, resulting in a complex landscape for parent decision making for a child's care. Further complicating this landscape are clinics that advertise these interventions as a legitimate treatment for a fee. In this study, we surveyed individuals who considered taking their child with ASD or CP abroad for stem cell interventions on their use of different sources of stem cell related health information and their level of trust in these sources. Participants reported that while the Internet was their most frequent source of information, it was not well-trusted. Rather, information sources trusted most were researchers and the science journals in which they publish, other parents of children with CP and ASD, and healthcare providers. These findings highlight a dichotomy between information-seeking preferences and information-trusted sources. We discuss the challenges of health science communication and present innovative opportunities to increase communication with trusted and reliable sources as part of an integrated multi-pronged approach.
Whitaker, Ashley M; Bell, Terece S; Houskamp, Beth M; O'Callaghan, Erin T
Intellectual giftedness is associated with strong strategic verbal memory while attention-deficit hyperactivity disorder (ADHD) is associated with strategic verbal memory deficits; however, no previous research has explored how this contradiction manifests in gifted populations with diagnoses of ADHD. The purpose of this study was to explore strategic verbal memory processes among intellectually gifted youth with and without ADHD to provide clarification regarding this specific aspect of neuropsychological functioning within this population. One hundred twenty-five youth completed neuropsychological evaluations including the Wechsler Intelligence Scale for Children-Fourth Edition and California Verbal Learning Test-Children's Version (CVLT-C). Results revealed significant differences between groups, with intellectually gifted youth with ADHD achieving lower T scores on CVLT-C Trials 1 through 5 compared with intellectually gifted youth without ADHD, and intellectually gifted youth with ADHD achieving higher T scores than youth of average intellectual abilities with ADHD. Additionally, repeated-measures analysis of variance revealed a main effect improvement among gifted youth with ADHD in short-delay recall when provided with organizational cues. Findings revealed new evidence about the role of twice exceptionality (specifically intellectual giftedness and ADHD) in strategic verbal memory and have important implications for parents, educators, psychologists and neuropsychologists, and other mental health professionals working with this population.
Wirgenes, K V; Sønderby, I E; Haukvik, U K; Mattingsdal, M; Tesli, M; Athanasiu, L; Sundet, K; Røssberg, J I; Dale, A M; Brown, A A; Agartz, I; Melle, I; Djurovic, S; Andreassen, O A
TCF4 is involved in neurodevelopment, and intergenic and intronic variants in or close to the TCF4 gene have been associated with susceptibility to schizophrenia. However, the functional role of TCF4 at the level of gene expression and relationship to severity of core psychotic phenotypes are not known. TCF4 mRNA expression level in peripheral blood was determined in a large sample of patients with psychosis spectrum disorders (n = 596) and healthy controls (n = 385). The previously identified TCF4 risk variants (rs12966547 (G), rs9960767 (C), rs4309482 (A), rs2958182 (T) and rs17512836 (C)) were tested for association with characteristic psychosis phenotypes, including neurocognitive traits, psychotic symptoms and structural magnetic resonance imaging brain morphometric measures, using a linear regression model. Further, we explored the association of additional 59 single nucleotide polymorphisms (SNPs) covering the TCF4 gene to these phenotypes. The rs12966547 and rs4309482 risk variants were associated with poorer verbal fluency in the total sample. There were significant associations of other TCF4 SNPs with negative symptoms, verbal learning, executive functioning and age at onset in psychotic patients and brain abnormalities in total sample. The TCF4 mRNA expression level was significantly increased in psychosis patients compared with controls and positively correlated with positive- and negative-symptom levels. The increase in TCF4 mRNA expression level in psychosis patients and the association of TCF4 SNPs with core psychotic phenotypes across clinical, cognitive and brain morphological domains support that common TCF4 variants are involved in psychosis pathology, probably related to abnormal neurodevelopment.
Isles, Anthony R.; Ingason, Andrés; Lowther, Chelsea; Gawlick, Micha; Stöber, Gerald; Potter, Harry; Georgieva, Lyudmila; Pizzo, Lucilla; Ozaki, Norio; Kushima, Itaru; Ikeda, Masashi; Iwata, Nakao; Levinson, Douglas F.; Gejman, Pablo V.; Shi, Jianxin; Sanders, Alan R.; Duan, Jubao; Sisodiya, Sanjay; Costain, Gregory; Degenhardt, Franziska; Giegling, Ina; Rujescu, Dan; Hreidarsson, Stefan J.; Saemundsen, Evald; Ahn, Joo Wook; Ogilvie, Caroline; Stefansson, Hreinn; Stefansson, Kari; O’Donovan, Michael C.; Owen, Michael J.; Bassett, Anne; Kirov, George
Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally
Pulido, José; Indave-Ruiz, B Iciar; Colell-Ortega, Esther; Ruiz-García, Mónica; Bartroli, Montserrat; Barrio, Gregorio
Based on the review of scientific papers and institutional reports on the subject and analysis of some secondary data, we assess the alcohol-related harm in Spain between 1990 and 2011. In 2011 they could be attributable to alcohol, 10% of the total mortality of the population aged 15-64, and about 30% of deaths due to traffic accidents. Among the population aged 15-64 years at least 0.8% had alcohol use disorders, an additional 5% could have harmful alcohol consumption that would need clinical evaluation, and about 20% had had some acute alcohol intoxication (AAI) in the last year. The AAI accounted for approximately 0.5-1.1 % of hospital emergency visits. Social costs of alcohol could represent 1% of gross domestic product. The prevalence of alcohol-related harm was significantly higher in men than women, with a male/female ratio greater than three for alcohol-related mortality and serious injuries, and this situation has hardly changed in the last 20 years. Alcohol-related harm has followed a downward trend, except for AAI. In 1990-2011 the standardized mortality rates related to alcohol decreased by half. Large gaps in knowledge and uncertainties on alcohol-related harm in Spanish population, clearly justify the institutional support for the research in this field and the implementation of a comprehensive monitoring system.
Bozzi, Yuri; Casarosa, Simona; Caleo, Matteo
Epilepsy is characterized by spontaneous recurrent seizures and comprises a diverse group of syndromes with different etiologies. Epileptogenesis refers to the process whereby the brain becomes epileptic and can be related to several factors, such as acquired structural brain lesions, inborn brain malformations, alterations in neuronal signaling, and defects in maturation and plasticity of neuronal networks. In this review, we will focus on alterations of brain development that lead to an hyperexcitability phenotype in adulthood, providing examples from both animal and human studies. Malformations of cortical development (including focal cortical dysplasia, lissencephaly, heterotopia, and polymicrogyria) are frequently epileptogenic and result from defects in cell proliferation in the germinal zone and/or impaired neuronal migration and differentiation. Delayed or reduced arrival of inhibitory interneurons into the cortical plate is another possible cause of epileptogenesis. GABAergic neurons are generated during early development in the ganglionic eminences, and failure to pursue migration toward the cortex alters the excitatory/inhibitory balance resulting in aberrant network hyperexcitability. More subtle defects in the developmental assembly of excitatory and inhibitory synapses are also involved in epilepsy. For example, mutations in the presynaptic proteins synapsins and SNAP-25 cause derangements of synaptic transmission and plasticity which underlie appearance of an epileptic phenotype. Finally, there is evidence that defects in synapse elimination and remodeling during early “critical periods” can trigger hyperexcitability later in life. Further clarification of the developmental pathways to epilepsy has important implications for disease prevention and therapy. PMID:22457654
Camacho, Ricardo; McCauley, Brandon; Szczech Moser, Christy
Over 70 years ago Dr. Karel Bobath and his wife Bertha Bobath began to craft the therapeutic intervention now known as neurodevelopmental treatment (NDT). This edition of Reviews, Tools, and Resources will highlight a historical review of research studies that have been completed, current websites, books, and blogs focusing on NDT.
Corrao, G.; Bagnardi, V.; Vittadini, G.; Favilli, S.
STUDY OBJECTIVE—To investigate the utility of capture-recapture methods to estimate prevalence of subjects with alcohol related disorders using multiple incomplete lists. DESIGN—This was a cross sectional study of alcohol related disorders in a large community. SETTING—During 1997 identified cases with known alcohol related disorders were independently flagged by four sources (self help volunteering groups; psychiatric ambulatory; public alcohology service; hospital discharges). PATIENTS—381 records were flagged, corresponding to 349 individual cases from a target population resident in a northern Italy area. MAIN RESULTS—The two sample capture-recapture estimates were clearly biased because of dependencies among sources. Estimates based on log-linear models showed prevalent counts ranged from 2297 (95% confidence intervals: 1524, 3794) to 2523 (95% confidence intervals: 1623, 4627) after adjustment for dependence among sources only or also for heterogeneity in catchability among age categories (< 50 and ⩾ 50 years), respectively. CONCLUSIONS—The study suggests that capture-recapture is an appropriate approach for estimating prevalence of subjects with alcohol related problems who seek or need treatment and assistance when different lists of alcoholics can be obtained from different types of agencies involved with problematic use of alcohol. Critical factors are the complexity in case definition and the analysis of heterogeneity among people. Accurate estimates are needed to plan and evaluate public health interventions. Keywords: alcohol related problems; capture-recapture; log-linear models PMID:10890872
... 49 Transportation 5 2014-10-01 2014-10-01 false Other alcohol-related conduct. 382.505 Section 382... SUBSTANCES AND ALCOHOL USE AND TESTING Consequences for Drivers Engaging in Substance Use-Related Conduct § 382.505 Other alcohol-related conduct. (a) No driver tested under the provisions of subpart C of...
... 49 Transportation 7 2013-10-01 2013-10-01 false Other alcohol-related conduct. 655.35 Section 655... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PREVENTION OF ALCOHOL MISUSE AND PROHIBITED DRUG USE IN TRANSIT OPERATIONS Prohibited Alcohol Use § 655.35 Other alcohol-related conduct. (a) No employer shall permit...
... 49 Transportation 7 2014-10-01 2014-10-01 false Other alcohol-related conduct. 655.35 Section 655... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PREVENTION OF ALCOHOL MISUSE AND PROHIBITED DRUG USE IN TRANSIT OPERATIONS Prohibited Alcohol Use § 655.35 Other alcohol-related conduct. (a) No employer shall permit...
... 49 Transportation 5 2011-10-01 2011-10-01 false Other alcohol-related conduct. 382.505 Section 382... SUBSTANCES AND ALCOHOL USE AND TESTING Consequences for Drivers Engaging in Substance Use-Related Conduct § 382.505 Other alcohol-related conduct. (a) No driver tested under the provisions of subpart C of...
... 49 Transportation 3 2010-10-01 2010-10-01 false Other alcohol-related conduct. 199.237 Section 199... MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PIPELINE SAFETY DRUG AND ALCOHOL TESTING Alcohol Misuse Prevention Program § 199.237 Other alcohol-related conduct. (a) No operator...
... 49 Transportation 5 2010-10-01 2010-10-01 false Other alcohol-related conduct. 382.505 Section 382... SUBSTANCES AND ALCOHOL USE AND TESTING Consequences for Drivers Engaging in Substance Use-Related Conduct § 382.505 Other alcohol-related conduct. (a) No driver tested under the provisions of subpart C of...
... 49 Transportation 7 2011-10-01 2011-10-01 false Other alcohol-related conduct. 655.35 Section 655... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PREVENTION OF ALCOHOL MISUSE AND PROHIBITED DRUG USE IN TRANSIT OPERATIONS Prohibited Alcohol Use § 655.35 Other alcohol-related conduct. (a) No employer shall permit...
... 49 Transportation 5 2012-10-01 2012-10-01 false Other alcohol-related conduct. 382.505 Section 382... SUBSTANCES AND ALCOHOL USE AND TESTING Consequences for Drivers Engaging in Substance Use-Related Conduct § 382.505 Other alcohol-related conduct. (a) No driver tested under the provisions of subpart C of...
... 49 Transportation 7 2010-10-01 2010-10-01 false Other alcohol-related conduct. 655.35 Section 655... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PREVENTION OF ALCOHOL MISUSE AND PROHIBITED DRUG USE IN TRANSIT OPERATIONS Prohibited Alcohol Use § 655.35 Other alcohol-related conduct. (a) No employer shall permit...
... 49 Transportation 3 2011-10-01 2011-10-01 false Other alcohol-related conduct. 199.237 Section 199... MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PIPELINE SAFETY DRUG AND ALCOHOL TESTING Alcohol Misuse Prevention Program § 199.237 Other alcohol-related conduct. (a) No operator...
... 49 Transportation 3 2013-10-01 2013-10-01 false Other alcohol-related conduct. 199.237 Section 199... MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PIPELINE SAFETY DRUG AND ALCOHOL TESTING Alcohol Misuse Prevention Program § 199.237 Other alcohol-related conduct. (a) No operator...
... 49 Transportation 5 2013-10-01 2013-10-01 false Other alcohol-related conduct. 382.505 Section 382... SUBSTANCES AND ALCOHOL USE AND TESTING Consequences for Drivers Engaging in Substance Use-Related Conduct § 382.505 Other alcohol-related conduct. (a) No driver tested under the provisions of subpart C of...
... 49 Transportation 3 2014-10-01 2014-10-01 false Other alcohol-related conduct. 199.237 Section 199... MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PIPELINE SAFETY DRUG AND ALCOHOL TESTING Alcohol Misuse Prevention Program § 199.237 Other alcohol-related conduct. (a) No operator...
... 49 Transportation 7 2012-10-01 2012-10-01 false Other alcohol-related conduct. 655.35 Section 655... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PREVENTION OF ALCOHOL MISUSE AND PROHIBITED DRUG USE IN TRANSIT OPERATIONS Prohibited Alcohol Use § 655.35 Other alcohol-related conduct. (a) No employer shall permit...
... 49 Transportation 3 2012-10-01 2012-10-01 false Other alcohol-related conduct. 199.237 Section 199... MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PIPELINE SAFETY DRUG AND ALCOHOL TESTING Alcohol Misuse Prevention Program § 199.237 Other alcohol-related conduct. (a) No operator...
Mother/offspring co-administration of the traditional herbal remedy yokukansan during the nursing period influences grooming and cerebellar serotonin levels in a rat model of neurodevelopmental disorders.
Muneoka, Katsumasa; Kuwagata, Makiko; Ogawa, Tetsuo; Shioda, Seiji
Neurodevelopmental impairment in the serotonergic system may be involved in autism spectrum disorder. Yokukansan is a traditional herbal remedy for restlessness and agitation in children, and mother-infant co-administration (MICA) to both the child and the nursing mother is one of the recommended treatment approaches. Recent studies have revealed the neuropharmacological properties of Yokukansan (YKS), including its 5-HT1A (serotonin) receptor agonistic effects. We investigated the influence of YKS treatment on behavior in a novel environment and on brain monoamine metabolism during the nursing period in an animal model of neurodevelopmental disorders, prenatally BrdU (5-bromo-2'-deoxyuridine)-treated rats (BrdU-rats). YKS treatment did not influence locomotor activity in BrdU-rats but reduced grooming in open-field tests. YKS treatment without MICA disrupted the correlation between locomotor behaviors and rearing and altered levels of serotonin and its metabolite in the cerebellum. These effects were not observed in the group receiving YKS treatment with MICA. These data indicate a direct pharmacological effect of YKS on the development of grooming behavior and profound effects on cerebellar serotonin metabolism, which is thought to be influenced by nursing conditions.
Shrader-Frechette, Kristin; ChoGlueck, Christopher
Neurodevelopmental disorders such as autism affect one-eighth of all U.S. newborns. Yet scientists, accessing the same data and using Bradford-Hill guidelines, draw different conclusions about the causes of these disorders. They disagree about the pesticide-harm hypothesis, that typical United States prenatal pesticide exposure can cause neurodevelopmental damage. This article aims to discover whether apparent scientific disagreement about this hypothesis might be partly attributable to questionable interpretations of the Bradford-Hill causal guidelines. Key scientists, who claim to employ Bradford-Hill causal guidelines, yet fail to accept the pesticide-harm hypothesis, fall into errors of trimming the guidelines, requiring statistically-significant data, and ignoring semi-experimental evidence. However, the main scientists who accept the hypothesis appear to commit none of these errors. Although settling disagreement over the pesticide-harm hypothesis requires extensive analysis, this article suggests that at least some conflicts may arise because of questionable interpretations of the guidelines.
Voas, Robert B.; Fell, James C.
Alcohol-related health policy research is responsible for guiding the implementation of laws and public health policies that have reduced alcohol-related highway injuries and deaths, as well as other alcohol-related problems over the last 40 years. This research, which tests theories about potential policy changes and responds to specific problems, has examined a vast array of prevention programs. This article briefly identifies 10 program categories and highlights four programs to illustrate the scope and complexity of the individual health policy areas within the categories. PMID:23579933
Ferns, Terry; Cork, Alison
Internationally, violence in the emergency department (ED) is of a constant concern to emergency practitioners. Frequently, both original research papers and anecdotal reports emphasise the phenomenon of alcohol related aggression in the ED. In this first paper, we highlight the literatures discussion of alcohol related violence in the emergency department and the potential psychological effects of alcohol intoxication. In the second we offer personal and organisational strategies clinical nursing staff may consider appropriate to minimise the risk of assault when caring for service users projecting alcohol related aggression.
Orchowski, Lindsay M; Mastroleo, Nadine R; Borsari, Brian
The prevalence of alcohol-related regretted sex in college students warrants a better understanding of the characteristics of students who report such experiences. Therefore, the present study examined correlates of regretted sexual experiences involving alcohol use among 2 specific high-risk college student samples: students mandated to alcohol intervention (n = 522) and volunteer 1st-year students transitioning to college (n = 481). Results indicated that alcohol-related regretted sex occurred at similar rates in mandated and volunteer students, with approximately 25% of the students reporting at least 1 occurrence in the past month. Women were more likely to report alcohol-related regretted sex compared with men. The belief that alcohol use would result in "liquid courage" was associated with alcohol-related regretted sex among college students, even after accounting for greater alcohol use and problem alcohol use behaviors. These findings have significant implications for intervention efforts and future research.
Orchowski, Lindsay M.; Mastroleo, Nadine R.; Borsari, Brian
The prevalence of alcohol-related regretted sex in college students warrants a better understanding of the characteristics of students who report such experiences. Therefore, the present study examined correlates of regretted sexual experiences involving alcohol use among two specific high-risk college student samples: Students mandated to alcohol intervention (N = 522) and volunteer first-year students transitioning to college (N = 481). Results indicated that alcohol-related regretted sex occurred in similar rates in mandated and volunteer students, with approximately 25% of the students reporting at least one occurrence in the past month. Women were more likely to report alcohol-related regretted sex compared to men. The belief that alcohol use would result in “liquid courage” was associated with alcohol-related regretted sex among college students, even after accounting for greater alcohol use and problem alcohol use behaviors. These findings have significant implications for intervention efforts and future research. PMID:22448762
Arterberry, Brooke J; Smith, Ashley E; Martens, Matthew P; Cadigan, Jennifer M; Murphy, James G
The present study examined the unique contributions of protective behavioral strategies and social norms in predicting alcohol-related outcomes. Participants were 363 students from a large public university in the Midwest who reported at least one binge-drinking episode (5+/4+ drinks for men/women in one sitting) in the past 30 days. Data were collected 1/2010-3/2011. We used SEM to test models where protective behavioral strategies (PBS) and social norms were predictors of both alcohol use and alcohol-related problems, after controlling for the effects of gender. Both PBS and descriptive norms had relationships with alcohol use. PBS also had a relationship with alcohol-related problems. Overall, the findings suggest that PBS and social norms have unique associations with distinct alcohol-related outcomes.
REDUCING ALCOHOL-RELATED SEXUAL ASSAULT IN THE MARINE CORPS 5a.&CONTRACT&NUMBER! N/A 5b.&GRANT&NUMBER! N/A 5c.&PROGRAM&ELEMENT&NUMBER! N/A 6...reduce alcohol-related sexual assault in the Marine Corps. It advocates more emphasis and training on the interplay between alcohol and sexual ...assault, as well as male and female-specific training on the issue. 15.&SUBJECT&TERMS! Sexual Assault, Alcohol, Incapacitation, Marine Corps
Cork, Alison; Ferns, Terry
Violence in the emergency department (ED) is a global problem. In our first paper, we highlighted the potential psychological effects of alcohol intoxication, the literatures discussion of alcohol related violence in the emergency department and the importance of developing positive nurse/service user relationships. In this second paper, we discuss personal and organisational strategies clinical nursing staff may consider appropriate to minimise the risk of assault when caring for service users projecting alcohol related aggression.
Tripp, Jessica C.; McDevitt-Murphy, Meghan E.; Avery, Megan L.; Bracken, Katherine L.
Objective Posttraumatic stress disorder (PTSD), alcohol use, and alcohol-related consequences have been linked to emotion dysregulation. Sex differences exist in both emotion regulation dimensions and alcohol use patterns. This investigation examined facets of emotion dysregulation as potential mediators of the relationship between PTSD symptoms and alcohol-related consequences and whether differences may exist across sexes. Methods Participants included 240 college students with a trauma history who reported using alcohol within the past three months and completed measures of PTSD symptoms, emotion dysregulation, alcohol consumption, alcohol-related consequences, and negative affect. The six facets of emotion dysregulation were examined as mediators of the relationship between PTSD symptoms and alcohol-related consequences in the full sample and by sex. Results There were differences in sexes on several variables, with women reporting higher PTSD scores and Lack of Emotional Awareness. Men reported significantly higher drinks per week in a typical week and a heavy week. There were significant associations between the variables for the full sample, with PTSD showing associations with five facets of emotion dysregulation subscales: Impulse Control Difficulties when Upset, Difficulties Engaging in Goal-Directed Behavior, Nonacceptance of Emotional Responses, Lack of Emotional Clarity, and Limited Access to Emotion Regulation Strategies. Alcohol-related consequences were associated with four aspects of emotion dysregulation: Impulse Control Difficulties when Upset, Difficulties Engaging in Goal-Direct Behavior, Nonacceptance of Emotional Reponses, and Limited Access to Emotion Regulation Strategies. Two aspects of emotion regulation, Impulse Control Difficulties and Difficulties Engaging in Goal Directed Behavior, mediated the relationship between PTSD symptoms and alcohol-related consequences in the full sample, even after adjusting for the effects of negative affect
Pettersson, Erik; Anckarsäter, Henrik; Gillberg, Christopher; Lichtenstein, Paul
Background: Although neurodevelopmental disorders are demarcated as discrete entities in the Diagnostic Statistical Manual of mental disorders, empirical evidence indicates that there is a high degree of overlap among them. The first aim of this investigation was to explore if a single general factor could account for the large degree of observed…
Tang, Yi-lang; Xiang, Xiao-jun; Wang, Xu-yi; Cubells, Joseph F; Babor, Thomas F; Hao, Wei
In China, alcohol consumption is increasing faster than anywhere else in the world. A steady increase in alcohol production has also been observed in the country, together with a rise in alcohol-related harm. Despite these trends, China's policies on the sale and consumption of alcoholic beverages are weak compared with those of other countries in Asia. Weakest of all are its policies on taxation, drink driving laws, alcohol sale to minors and marketing licenses. The authors of this descriptive paper draw attention to the urgent need for public health professionals and government officials in China to prioritize population surveillance, research and interventions designed to reduce alcohol use disorders. They describe China's current alcohol policies and recent trends in alcohol-related harm and highlight the need for health officials to conduct a thorough policy review from a public health perspective, using as a model the World Health Organization's global strategy to reduce the harmful use of alcohol.
Acharya, U Rajendra; S, Vidya; Bhat, Shreya; Adeli, Hojjat; Adeli, Amir
Alcoholism is a severe disorder that affects the functionality of neurons in the central nervous system (CNS) and alters the behavior of the affected person. Electroencephalogram (EEG) signals can be used as a diagnostic tool in the evaluation of subjects with alcoholism. The neurophysiological interpretation of EEG signals in persons with alcoholism (PWA) is based on observation and interpretation of the frequency and power in their EEGs compared to EEG signals from persons without alcoholism. This paper presents a review of the known features of EEGs obtained from PWA and proposes that the impact of alcoholism on the brain can be determined by computer-aided analysis of EEGs through extracting the minute variations in the EEG signals that can differentiate the EEGs of PWA from those of nonaffected persons. The authors advance the idea of automated computer-aided diagnosis (CAD) of alcoholism by employing the EEG signals. This is achieved through judicious combination of signal processing techniques such as wavelet, nonlinear dynamics, and chaos theory and pattern recognition and classification techniques. A CAD system is cost-effective and efficient and can be used as a decision support system by physicians in the diagnosis and treatment of alcoholism especially those who do not specialize in alcoholism or neurophysiology. It can also be of great value to rehabilitation centers to assess PWA over time and to monitor the impact of treatment aimed at minimizing or reversing the effects of the disease on the brain. A CAD system can be used to determine the extent of alcoholism-related changes in EEG signals (low, medium, high) and the effectiveness of therapeutic plans.
Gurvich, Eugenia M.; Kenna, George A.; Leggio, Lorenzo
With a better understanding of the biologic basis of alcohol dependence and the considerable financial burden of alcohol abuse and dependence, the number of alcohol-related clinical pharmacotherapy trials has been on the rise. Subsequently, the potential to find efficacious treatments is more promising. Unfortunately, alcohol-related trials face a number of challenges, as a result of the difficulties that arise from traditional and outdated methods to collect data and ensure medication adherence. Novel technology-based assessments, such as ecological momentary assessment, interactive voice response, transdermal sensor and medication-event monitoring system provide a prospective solution—albeit not without possible concerns—to the difficulties faced in alcohol-related clinical trials. Clinical trials are meant to define the efficacy of the treatment and to determine an effective and safe dosage. However, due to lack of adherence a drug could inappropriately or mistakenly be judged as ineffective for treating a specific disorder. The described technologies may be important tools to prevent false negatives in validating drug efficacy, to provide consistency in clinical trials and to improve available data regarding the study of pharmacotherapies for alcohol dependence. PMID:23955872
Savova, V; Vinogradova, S; Pruss, D; Gimelbrant, A A; Weiss, L A
Over 3000 human genes can be expressed from a single allele in one cell, and from the other allele-or both-in neighboring cells. Little is known about the consequences of this epigenetic phenomenon, monoallelic expression (MAE). We hypothesized that MAE increases expression variability, with a potential impact on human disease. Here, we use a chromatin signature to infer MAE for genes in lymphoblastoid cell lines and human fetal brain tissue. We confirm that across clones MAE status correlates with expression level, and that in human tissue data sets, MAE genes show increased expression variability. We then compare mono- and biallelic genes at three distinct scales. In the human population, we observe that genes with polymorphisms influencing expression variance are more likely to be MAE (P<1.1 × 10(-6)). At the trans-species level, we find gene expression differences and directional selection between humans and chimpanzees more common among MAE genes (P<0.05). Extending to human disease, we show that MAE genes are under-represented in neurodevelopmental copy number variants (CNVs) (P<2.2 × 10(-10)), suggesting that pathogenic variants acting via expression level are less likely to involve MAE genes. Using neuropsychiatric single-nucleotide polymorphism (SNP) and single-nucleotide variant (SNV) data, we see that genes with pathogenic expression-altering or loss-of-function variants are less likely MAE (P<7.5 × 10(-11)) and genes with only missense or gain-of-function variants are more likely MAE (P<1.4 × 10(-6)). Together, our results suggest that MAE genes tolerate a greater range of expression level than biallelic expression (BAE) genes, and this information may be useful in prediction of pathogenicity.Molecular Psychiatry advance online publication, 7 March 2017; doi:10.1038/mp.2017.13.
Lionel, Anath C.; Tammimies, Kristiina; Vaags, Andrea K.; Rosenfeld, Jill A.; Ahn, Joo Wook; Merico, Daniele; Noor, Abdul; Runke, Cassandra K.; Pillalamarri, Vamsee K.; Carter, Melissa T.; Gazzellone, Matthew J.; Thiruvahindrapuram, Bhooma; Fagerberg, Christina; Laulund, Lone W.; Pellecchia, Giovanna; Lamoureux, Sylvia; Deshpande, Charu; Clayton-Smith, Jill; White, Ann C.; Leather, Susan; Trounce, John; Melanie Bedford, H.; Hatchwell, Eli; Eis, Peggy S.; Yuen, Ryan K.C.; Walker, Susan; Uddin, Mohammed; Geraghty, Michael T.; Nikkel, Sarah M.; Tomiak, Eva M.; Fernandez, Bridget A.; Soreni, Noam; Crosbie, Jennifer; Arnold, Paul D.; Schachar, Russell J.; Roberts, Wendy; Paterson, Andrew D.; So, Joyce; Szatmari, Peter; Chrysler, Christina; Woodbury-Smith, Marc; Brian Lowry, R.; Zwaigenbaum, Lonnie; Mandyam, Divya; Wei, John; MacDonald, Jeffrey R.; Howe, Jennifer L.; Nalpathamkalam, Thomas; Wang, Zhuozhi; Tolson, Daniel; Cobb, David S.; Wilks, Timothy M.; Sorensen, Mark J.; Bader, Patricia I.; An, Yu; Wu, Bai-Lin; Musumeci, Sebastiano Antonino; Romano, Corrado; Postorivo, Diana; Nardone, Anna M.; Monica, Matteo Della; Scarano, Gioacchino; Zoccante, Leonardo; Novara, Francesca; Zuffardi, Orsetta; Ciccone, Roberto; Antona, Vincenzo; Carella, Massimo; Zelante, Leopoldo; Cavalli, Pietro; Poggiani, Carlo; Cavallari, Ugo; Argiropoulos, Bob; Chernos, Judy; Brasch-Andersen, Charlotte; Speevak, Marsha; Fichera, Marco; Ogilvie, Caroline Mackie; Shen, Yiping; Hodge, Jennelle C.; Talkowski, Michael E.; Stavropoulos, Dimitri J.; Marshall, Christian R.; Scherer, Stephen W.
Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3′ terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3′-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3′ end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment. PMID:24381304
Klein, Hugh; Shiffman, Kenneth S
This study, based on a stratified (by decade of production) random sample of 1,221 animated cartoons and 4,201 characters appearing in those cartoons, seeks to determine the prevalence of alcohol-related content; how, if at all, the prevalence changed between 1930 and 1996 (the years spanned by this research); and the types of messages that animated cartoons convey about beverage alcohol and drinking in terms of the characteristics that are associated with alcohol use, the contexts in which alcohol is used in cartoons, and the reasons why cartoon characters purportedly consume alcohol. Approximately 1 cartoon in 11 was found to contain alcohol-related content, indicating that the average child or adolescent viewer is exposed to approximately 24 alcohol-related messages each week just from the cartoons that he/she watches. Data indicated that the prevalence of alcohol-related content declined significantly over the years. Quite often, alcohol consumption was shown to result in no effects whatsoever for the drinker, and alcohol use often occurred when characters were alone. Overall, mixed, ambivalent messages were provided about drinking and the types of characters that did/not consume alcoholic beverages.
Brown, James D.
Since the first publication on fetal alcohol syndrome appeared in the scientific literature over 30 years ago, there has been a great deal of research interest in the topic. This paper reviews findings within the past 10 years related to causes, frequency, and diagnosis of alcohol-related disabilities, before turning to the impact these…
Klein, Hugh; Shiffman, Kenneth S.
This study, based on a stratified (by decade of production) random sample of 1,221 animated cartoons and 4,201 characters appearing in those cartoons, seeks to determine the prevalence of alcohol-related content; how, if at all, the prevalence changed between 1930 and 1996 (the years spanned by this research); and the types of messages that animated cartoons convey about beverage alcohol and drinking in terms of the characteristics that are associated with alcohol use, the contexts in which alcohol is used in cartoons, and the reasons why cartoon characters purportedly consume alcohol. Approximately 1 cartoon in 11 was found to contain alcohol-related content, indicating that the average child or adolescent viewer is exposed to approximately 24 alcohol-related messages each week just from the cartoons that he/she watches. Data indicated that the prevalence of alcohol-related content declined significantly over the years. Quite often, alcohol consumption was shown to result in no effects whatsoever for the drinker, and alcohol use often occurred when characters were alone. Overall, mixed, ambivalent messages were provided about drinking and the types of characters that did/not consume alcoholic beverages. PMID:24350176
Hoffman, Eric W.; Pinkleton, Bruce E.; Weintraub Austin, Erica; Reyes-Velázquez, Wanda
Objective: Alcohol marketers have increasingly moved their advertising efforts into digital and social media venues. As a result, the purpose of this study is to investigate associations between students' use of social media, their exposure to alcohol marketing messages through social media, and their alcohol-related beliefs and behaviors.…
Background Sexual offences are a global public health concern. Recent changes in the law in England and Wales have dramatically altered the legal landscape of sexual offences, but sexual assaults where the victim is voluntarily intoxicated by alcohol continue to have low conviction rates. Worldwide, students are high consumers of alcohol. This research aimed to compare male and female students in relation to their knowledge and attitudes about alcohol and sexual activity and to identify factors associated with being the victim of alcohol-related non-consensual sex. Methods 1,110 students completed an online questionnaire. Drinking levels were measured using the Alcohol Use Disorder Identification Test. Non-consensual sexual experiences were measured using the Sexual Experience Survey. Univariate and multivariate analyses were undertaken using chi square and backwards stepwise logistic regression respectively. Results A third of respondents had experienced alcohol-related non-consensual sex. Male and female students differed in the importance they gave to cues in deciding if a person wished to have sex with them and their understanding of the law of consent. 82.2% of women who had experienced alcohol-related non-consensual sex were hazardous drinkers compared to 62.9% who drank at lower levels (P < 0.001). Differences existed between men and women, and between those who had and had not experienced alcohol-related non-consensual sex, in relation to assessments of culpability in scenarios depicting alcohol-related intercourse. A third of respondents believed that a significant proportion of rapes were false allegations; significantly more men than women responded in this way. Conclusions Alcohol-related coerced sexual activity is a significant occurrence among students; attitudinal and knowledge differences between males and females may explain this. Educational messages that focus upon what is deemed acceptable sexual behaviour, the law and rape myths are needed but
Stern, Francine Martin; Gorga, Delia
Use of neurodevelopmental treatment, also known as the Bobath method, is discussed, including its history, philosophy, goals, and treatment emphasis with infants and children with movement disorders. Examples of children before and after therapeutic intervention illustrate use of the technique, and controversies in measuring therapy efficacy are…
Kurth, Lisa; Haussmann, Robert
Objective: To investigate a potential relationship between coincidental increases in perinatal Pitocin usage and subsequent childhood ADHD onset in an attempt to isolate a specific risk factor as an early biomarker of this neurodevelopmental disorder. Method: Maternal labor/delivery and corresponding childbirth records of 172 regionally diverse,…
Sanders, James L.; Breen, Rebecca E. Hudson; Netelenbos, Nicole
Background: Diagnostic criteria have recently been introduced in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), for neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). The purpose of this study is to assess the classification of this condition using the Canadian fetal alcohol spectrum disorder (FASD) multidisciplinary diagnostic guidelines as the standard of comparison. First, classification of ND-PAE was compared with Canadian FASD diagnoses of fetal alcohol syndrome (FAS), partial FAS and alcohol-related neurodevelopmental disorder. Second, classification of ND-PAE was compared with FAS and pFAS only, a criterion for which includes facial features highly predictive of prenatal alcohol exposure and effects. Methods: Eighty-two patients underwent multidisciplinary clinical evaluations using the Canadian FASD diagnostic guidelines between 2011 and 2015. Two clinicians independently reviewed patient files for evidence of diagnostic criteria for ND-PAE when applying an impairment cut-off level of 2 or more standard deviations below the mean, or clinically significant impairment in the absence of standardized norm-referenced measures. Results: Good interrater reliability was established between clinicians (κ = 0.79). Classifications of ND-PAE and Canadian FASD diagnoses, including alcohol-related neurodevelopmental disorder, were moderately correlated (Cramer V  = 0.44, p < 0.01). However, ND-PAE possessed low sensitivity in FASD identification. Further, there was no correlation between ND-PAE and FAS/pFAS classifications (Cramer V  = 0.05, p > 0.05). Interpretation: Although there is considerable overlap between both sets of criteria, ND-PAE was less likely to identify patients with FASD. Although the neurobehavioral domains assessed by ND-PAE are supported in research, its diagnostic structure restricts the identification of FASD at the impairment threshold of 2 or more standard deviations. A
Youngstrom, Eric; LaKind, Judy S.; Kenworthy, Lauren; Lipkin, Paul H.; Goodman, Michael; Squibb, Katherine; Mattison, Donald R.; Anthony, Bruno J.; Anthony, Laura Gutermuth
With research suggesting increasing incidence of pediatric neurodevelopmental disorders, questions regarding etiology continue to be raised. Neurodevelopmental function tests have been used in epidemiology studies to evaluate relationships between environmental chemical exposures and neurodevelopmental deficits. Limitations of currently used tests and difficulties with their interpretation have been described, but a comprehensive critical examination of tests commonly used in studies of environmental chemicals and pediatric neurodevelopmental disorders has not been conducted. We provide here a listing and critical evaluation of commonly used neurodevelopmental tests in studies exploring effects from chemical exposures and recommend measures that are not often used, but should be considered. We also discuss important considerations in selecting appropriate tests and provide a case study by reviewing the literature on polychlorinated biphenyls. PMID:20195443
Simons, Jeffrey S; Christopher, Michael S; McLaury, Ann E
This study examined relations between personal strivings and alcohol use among college students. Personal strivings are ongoing goals that individuals are characteristically trying to achieve through their behavior. Participants generated lists of personal strivings following standard instructions and then completed an assessment of alcohol use and related problems. Participants returned to complete a follow-up assessment of drinking behavior after 30 days. Personal strivings were coded into content categories by trained raters using a coding manual. Four content categories were examined for this study: achievement, affiliation, health, and self-presentation. A series of t tests revealed that participants endorsing achievement strivings reported less alcohol-related problems and marginally fewer instances of binge drinking during the 30-day follow-up period. In contrast, participants endorsing self-presentation strivings reported more alcohol-related problems during the follow-up period.
Tourism and fatal single motor vehicle accidents, an index of alcohol-related motor accidents, are examined in a cross-sectional analysis of the 50 states of the Union and the District of Columbia. A multiple regression model is employed in which average mileage driven, percent of metropolitan residents, and number of licensed drivers are statistically controlled. Tourism is found to be positively associated with the single motor vehicle fatality rate. Further research and policy implications are discussed.
Jonsson et al.'s excellent review of the literature on quality of life (QoL) and childhood mental and behavioural disorders (Jonsson et al., ) highlights the need for studies that utilise child self-reported QoL, in contrast to parent or proxy QoL measures, and further challenges the field to develop QoL measures that 'put the child's own views and priorities first'.
McPeake, Joanne; Forrest, Ewan; Quasim, Tara; Kinsella, John; O'Neill, Anna
Objective To examine the impact of critical care on future alcohol-related behaviour. Further, it aimed to explore patterns of recovery for patients with and without alcohol use disorders beyond the hospital environment. Design In-depth, semistructured interviews with participants (patients) 3–7 months post intensive care discharge. Setting The setting for this study was a 20-bedded mixed intensive care unit (ICU), in a large teaching hospital in Scotland. On admission, patients were allocated to one of the three alcohol groups: low risk, harmful/hazardous and alcohol dependency. Participants 21 participants who received mechanical ventilation for greater than 3 days were interviewed between March 2013 and June 2014. Interventions None. Measurements and main results Four themes which impacted on recovery from ICU were identified in this patient group: psychological resilience, support for activities of daily living, social support and cohesion and the impact of alcohol use disorders on recovery. Participants also discussed the importance of personalised goal setting and appropriate and timely rehabilitation for alcohol-related behaviours during the critical care recovery period. Conclusions There is a significant interplay between alcohol misuse and recovery from critical illness. This study has demonstrated that at present, there is a haphazard approach to rehabilitation for patients after ICU. A more targeted rehabilitation pathway for patients leaving critical care, with specific emphasis on alcohol misuse if appropriate, requires to be generated. PMID:27048633
Madison, Jon M.; Zhou, Fen; Nigam, Aparna; Hussain, Ali; Barker, Douglas D.; Nehme, Ralda; van der Ven, Karlijn; Hsu, Jenny; Wolf, Pavlina; Fleishman, Morgan; O’Dushlaine, Colm; Rose, Sam; Chambert, Kimberly; Lau, Frank H.; Ahfeldt, Tim; Rueckert, Erroll H.; Sheridan, Steven D.; Fass, Daniel M.; Nemesh, James; Mullen, Thomas E.; Daheron, Laurence; McCarroll, Steve; Sklar, Pamela; Perlis, Roy H.; Haggarty, Stephen J.
Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD we applied a family-based paradigm to derive and characterize a set of 12 induced pluripotent stem cell (iPSC) lines from a quartet consisting of two BD-affected brothers and their two unaffected parents. Initially, no significant phenotypic differences were observed between iPSCs derived from the different family members. However, upon directed neural differentiation we observed that CXCR4 (CXC chemokine receptor-4) expressing central nervous system (CNS) neural progenitor cells (NPCs) from both BD patients compared to their unaffected parents exhibited multiple phenotypic differences at the level of neurogenesis and expression of genes critical for neuroplasticity, including WNT pathway components and ion channel subunits. Treatment of the CXCR4+ NPCs with a pharmacological inhibitor of glycogen synthase kinase 3 (GSK3), a known regulator of WNT signaling, was found to rescue a progenitor proliferation deficit in the BD-patient NPCs. Taken together, these studies provide new cellular tools for dissecting the pathophysiology of BD and evidence for dysregulation of key pathways involved in neurodevelopment and neuroplasticity. Future generation of additional iPSCs following a family-based paradigm for modeling complex neuropsychiatric disorders in conjunction with in-depth phenotyping holds promise for providing insights into the pathophysiological substrates of BD and is likely to inform the development of targeted therapeutics for its treatment and ideally prevention. PMID:25733313
Deutsch, Stephen I; Burket, Jessica A; Benson, Andrew D; Urbano, Maria R
Array comparative genomic hybridization (array CGH) has led to the identification of microdeletions of the proximal region of chromosome 15q between breakpoints (BP) 3 or BP4 and BP5 encompassing CHRNA7, the gene encoding the α7-nicotinic acetylcholine receptor (α7nAChR) subunit. Phenotypic manifestations of persons with these microdeletions are variable and some heterozygous carriers are seemingly unaffected, consistent with their variable expressivity and incomplete penetrance. Nonetheless, the 15q13.3 deletion syndrome is associated with several neuropsychiatric disorders, including idiopathic generalized epilepsy, intellectual disability, autism spectrum disorders (ASDs) and schizophrenia. Haploinsufficient expression of CHRNA7 in this syndrome has highlighted important roles the α7nAChR plays in the developing brain and normal processes of attention, cognition, memory and behavior throughout life. Importantly, the existence of the 15q13.3 deletion syndrome contributes to an emerging literature supporting clinical trials therapeutically targeting the α7nAChR in disorders such as ASDs and schizophrenia, including the larger population of patients with no evidence of haploinsufficient expression of CHRNA7. Translational clinical trials will be facilitated by the existence of positive allosteric modulators (PAMs) of the α7nAChR that act at sites on the receptor distinct from the orthosteric site that binds acetylcholine and choline, the receptor's endogenous ligands. PAMs lack intrinsic efficacy by themselves, but act where and when the endogenous ligands are released in response to relevant social and cognitive provocations to increase the likelihood they will result in α7nAChR ion channel activation.
Angkaw, Abigail C; Haller, Moira; Pittman, James O E; Nunnink, Sarah E; Norman, Sonya B; Lemmer, Jennifer A; McLay, Robert N; Baker, Dewleen G
Veterans returning from Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) have been found to be at increased risk for post-traumatic stress disorder (PTSD) and alcohol use disorders, leading to negative mental health-related quality of life (MHRQoL). The current study examined the unique impact of alcohol consumption levels versus alcohol-related consequences on the relationship between PTSD symptoms and MHRQoL in a sample of OEF/OIF combat veterans (N = 205, median age 29, 95% men). Mediation analyses indicated that the effect of PTSD symptoms on MHRQoL was explained only by alcohol-related consequences and not by alcohol consumption. Findings highlight the importance of including alcohol-related consequences in clinical assessment and intervention programs for OEF/OIF veterans. Additionally, this study enhances knowledge regarding the underlying mechanisms of functional impairment related to PTSD and alcohol use disorders.
Bedoyan, Jirair Krikor; Schaibley, Valerie M; Peng, Weiping; Bai, Yongsheng; Mondal, Kajari; Shetty, Amol C; Durham, Mark; Micucci, Joseph A; Dhiraaj, Arti; Skidmore, Jennifer M; Kaplan, Julie B; Skinner, Cindy; Schwartz, Charles E; Antonellis, Anthony; Zwick, Michael E; Cavalcoli, James D; Li, Jun Z
Background and aim Martin–Probst syndrome (MPS) is a rare X-linked disorder characterised by deafness, cognitive impairment, short stature and distinct craniofacial dysmorphisms, among other features. The authors sought to identify the causative mutation for MPS. Methods and results Massively parallel sequencing in two affected, related male subjects with MPS identified a RAB40AL (also called RLGP) missense mutation (chrX:102,079,078-102,079,079AC→GA p.D59G; hg18). RAB40AL encodes a small Ras-like GTPase protein with one suppressor of cytokine signalling box. The p.D59G variant is located in a highly conserved region of the GTPase domain between β-2 and β-3 strands. Using RT-PCR, the authors show that RAB40AL is expressed in human fetal and adult brain and kidney, and adult lung, heart, liver and skeletal muscle. RAB40AL appears to be a primate innovation, with no orthologues found in mouse, Xenopus or zebrafish. Western analysis and fluorescence microscopy of GFP-tagged RAB40AL constructs from transiently transfected COS7 cells show that the D59G missense change renders RAB40AL unstable and disrupts its cytoplasmic localisation. Conclusions This is the first study to show that mutation of RAB40AL is associated with a human disorder. Identification of RAB40AL as the gene mutated in MPS allows for further investigations into the molecular mechanism(s) of RAB40AL and its roles in diverse processes such as cognition, hearing and skeletal development. PMID:22581972
Neurodevelopmental Effects of Environmental Exposures
Sherry G. Selevan, Pauline Mendola, Deborah C. Rice (US EPA, Washington,
The nervous system starts development early in gestation and continues to develop through adolescence. Thus, critical windows of vuln...
Aylward, Glen P
Long-term follow-up of infants born prematurely is necessary to determine neurodevelopmental outcomes, particularly with the expansion of interest from major disabilities to high prevalence/low severity dysfunctions. Models of pathogenesis include changes due to developmental disruptions and to injury, the magnitude and type of change influenced by the infant's age, and central nervous system recovery and reorganization. Alterations in neurogenesis, migration, myelination, cell death, and synaptogenesis occur even in the absence of insult. Despite increased knowledge regarding these processes, the functional significance of brain abnormalities is unclear. Because of methodologic problems in follow-up studies, it is difficult to characterize outcome definitively. Nonetheless, an acceptable degree of agreement across studies is found with regard to specific neurodevelopmental outcomes: motor/neurologic function, visuomotor integrative skills, IQ, academic achievement, language, executive function, and attention-deficit hyperactivity disorder/behavioral issues. In general, children born prematurely have more problems in these areas than do their normal birth weight counterparts. Suggestions for improved analyses and clarification of outcomes include use of cluster analysis, structural equation modeling, growth curve analysis, developmental epidemiologic approaches, and better control of background variables using risk indexes and factor scores. Better assessment techniques measuring functions documented to be at higher risk of problems are discussed.
Winter, Christine; Djodari-Irani, Anais; Sohr, Reinhard; Morgenstern, Rudolf; Feldon, Joram; Juckel, Georg; Meyer, Urs
Maternal infection during pregnancy enhances the offspring's risk for severe neuropsychiatric disorders in later life, including schizophrenia. Recent attempts to model this association in animals provided further experimental evidence for a causal relationship between in-utero immune challenge and the postnatal emergence of a wide spectrum of behavioural, pharmacological and neuroanatomical dysfunctions implicated in schizophrenia. However, it still remains unknown whether the prenatal infection-induced changes in brain and behavioural functions may be associated with multiple changes at the neurochemical level. Here, we tested this hypothesis in a recently established mouse model of viral-like infection. Pregnant dams on gestation day 9 were exposed to viral mimetic polyriboinosinic-polyribocytidilic acid (PolyI:C, 5 mg/kg i.v.) or vehicle treatment, and basal neurotransmitter levels were then compared in the adult brains of animals born to PolyI:C- or vehicle-treated mothers by high-performance liquid chromatography on post-mortem tissue. We found that prenatal immune activation significantly increased the levels of dopamine and its major metabolites in the lateral globus pallidus and prefrontal cortex, whilst at the same time it decreased serotonin and its metabolite in the hippocampus, nucleus accumbens and lateral globus pallidus. In addition, a specific reduction of the inhibitory amino acid taurine in the hippocampus was noted in prenatally PolyI:C-exposed offspring relative to controls, whereas central glutamate and gamma-aminobutyric acid (GABA) content was largely unaffected by prenatal immune activation. Our results thus confirm that maternal immunological stimulation during early/middle pregnancy is sufficient to induce long-term changes in multiple neurotransmitter levels in the brains of adult offspring. This further supports the possibility that infection-mediated interference with early fetal brain development may predispose the developing organism
Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders.
Ayhan, Y; Abazyan, B; Nomura, J; Kim, R; Ladenheim, B; Krasnova, I N; Sawa, A; Margolis, R L; Cadet, J L; Mori, S; Vogel, M W; Ross, C A; Pletnikov, M V
Strong genetic evidence implicates mutations and polymorphisms in the gene Disrupted-In-Schizophrenia-1 (DISC1) as risk factors for both schizophrenia and mood disorders. Recent studies have shown that DISC1 has important functions in both brain development and adult brain function. We have described earlier a transgenic mouse model of inducible expression of mutant human DISC1 (hDISC1) that acts in a dominant-negative manner to induce the marked neurobehavioral abnormalities. To gain insight into the roles of DISC1 at various stages of neurodevelopment, we examined the effects of mutant hDISC1 expressed during (1) only prenatal period, (2) only postnatal period, or (3) both periods. All periods of expression similarly led to decreased levels of cortical dopamine (DA) and fewer parvalbumin-positive neurons in the cortex. Combined prenatal and postnatal expression produced increased aggression and enhanced response to psychostimulants in male mice along with increased linear density of dendritic spines on neurons of the dentate gyrus of the hippocampus, and lower levels of endogenous DISC1 and LIS1. Prenatal expression only resulted in smaller brain volume, whereas selective postnatal expression gave rise to decreased social behavior in male mice and depression-like responses in female mice as well as enlarged lateral ventricles and decreased DA content in the hippocampus of female mice, and decreased level of endogenous DISC1. Our data show that mutant hDISC1 exerts differential effects on neurobehavioral phenotypes, depending on the stage of development at which the protein is expressed. The multiple and diverse abnormalities detected in mutant DISC1 mice are reminiscent of findings in major mental diseases.
Sutherland, Greg T; Sheedy, Donna; Kril, Jillian J
The New South Wales Tissue Resource Centre at the University of Sydney, Australia, is one of the few human brain banks dedicated to the study of the effects of chronic alcoholism. The bank was affiliated in 1994 as a member of the National Network of Brain Banks and also focuses on schizophrenia and healthy control tissue. Alcohol abuse is a major problem worldwide, manifesting in such conditions as fetal alcohol syndrome, adolescent binge drinking, alcohol dependency, and alcoholic neurodegeneration. The latter is also referred to as alcohol-related brain damage (ARBD). The study of postmortem brain tissue is ideally suited to determining the effects of long-term alcohol abuse, but it also makes an important contribution to understanding pathogenesis across the spectrum of alcohol misuse disorders and potentially other neurodegenerative diseases. Tissue from the bank has contributed to 330 peer-reviewed journal articles including 120 related to alcohol research. Using the results of these articles, this review chronicles advances in alcohol-related brain research since 2003, the so-called genomic age. In particular, it concentrates on transcriptomic approaches to the pathogenesis of ARBD and builds on earlier reviews of structural changes (Harper et al. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:951) and proteomics (Matsumoto et al. Expert Rev Proteomics 2007;4:539).
Beck, Anne; Heinz, Adrienne J; Heinz, Andreas
Alcohol-related violence, a longstanding, serious, and pervasive social problem, has provided researchers from diverse disciplines with a model to study individual differences in aggressive and violent behavior. Of course, not all alcohol consumers will become aggressive after drinking and similarly, not all individuals with alcohol use disorders will exhibit such untoward behavior. Rather, the relationship is best conceptualized as complex and indirect and is influenced by a constellation of social, cognitive, and biological factors that differ greatly from one person to the next. Animal experiments and human studies have elucidated how these mechanisms and processes explain (i.e., mediate) the relation between acute and chronic alcohol consumption and aggressive behavior. Further, the rich body of literature on alcohol-related aggression has allowed for identification of several potential high-yield targets for clinical intervention, e.g., cognitive training for executive dysfunction; psychopharmacology targeting affect and threat perception, which may also generalize to other psychiatric conditions characterized by aggressive behavior. Here we aim to integrate pertinent findings, derived from different methodological approaches and theoretical models, which explain heterogeneity in aggressive responses to alcohol. A translational platform is provided, highlighting common factors linking alcohol and aggression that warrant further, interdisciplinary study in order to reduce the devastating social impact of this phenomenon.
Tang, Yi-lang; Xiang, Xiao-jun; Wang, Xu-yi; Cubells, Joseph F; Babor, Thomas F
Abstract In China, alcohol consumption is increasing faster than anywhere else in the world. A steady increase in alcohol production has also been observed in the country, together with a rise in alcohol-related harm. Despite these trends, China’s policies on the sale and consumption of alcoholic beverages are weak compared with those of other countries in Asia. Weakest of all are its policies on taxation, drink driving laws, alcohol sale to minors and marketing licenses. The authors of this descriptive paper draw attention to the urgent need for public health professionals and government officials in China to prioritize population surveillance, research and interventions designed to reduce alcohol use disorders. They describe China’s current alcohol policies and recent trends in alcohol-related harm and highlight the need for health officials to conduct a thorough policy review from a public health perspective, using as a model the World Health Organization’s global strategy to reduce the harmful use of alcohol. PMID:23599550
Westgate, Erin C; Neighbors, Clayton; Heppner, Hannes; Jahn, Susanna; Lindgren, Kristen P
Objective: This study investigated whether self-reports of alcohol-related postings on Facebook by oneself or one’s Facebook friends were related to common motives for drinking and were uniquely predictive of self-reported alcohol outcomes (alcohol consumption, problems, and cravings). Method: Pacific Northwest undergraduates completed a survey of alcohol outcomes, drinking motives, and alcoholrelated Facebook postings. Participants completed the survey online as part of a larger study on alcohol use and cognitive associations. Participants were randomly selected through the university registrar’s office and consisted of 1,106 undergraduates (449 men, 654 women, 2 transgender, 1 declined to answer) between the ages of 18 and 25 years (M = 20.40, SD = 1.60) at a large university in the Pacific Northwest. Seven participants were excluded from analyses because of missing or suspect data. Results: Alcohol-related postings on Facebook were significantly correlated with social, enhancement, conformity, and coping motives for drinking (all ps < .001). After drinking motives were controlled for, self–alcohol-related postings independently and positively predicted the number of drinks per week, alcohol-related problems, risk of alcohol use disorders, and alcohol cravings (all ps < .001). In contrast, friends’ alcohol-related postings only predicted the risk of alcohol use disorders (p < .05) and marginally predicted alcohol-related problems (p = .07). Conclusions: Posting alcohol-related content on social media platforms such as Facebook is associated with common motivations for drinking and is, in itself, a strong predictive indicator of drinking outcomes independent of drinking motives. Moreover, self-related posting activity appears to be more predictive than Facebook friends’ activity. These findings suggest that social media platforms may be a useful target for future preventative and intervention efforts. PMID:24766750
Shim, Kyu-Won; Park, Eun-Kyung; Kim, Ju-Seong; Kim, Yong-Oock
Craniosynostosis is the premature fusion of calvarial sutures, resulting in deformed craniofacial appearance. Hence, for a long time, it has been considered an aesthetic disorder. Fused sutures restrict growth adjacent to the suture, but compensatory skull growth occurs to accommodate the growing brain. The primary goal for the management of this craniofacial deformity has been to release the constricted skull and reform the distorted shape of the skull vault. However, the intellectual and behavioral prognosis of affected children has also been taken into consideration since the beginning of the modern era of surgical management of craniosynostosis. A growing body of literature indicates that extensive surgery, such as the whole-vault cranioplasty approach, would result in better outcomes. In addition, the age at treatment is becoming a major concern for optimal outcome in terms of cosmetic results as well as neurodevelopment. This review will discuss major concerns regarding neurodevelopmental issues and related factors. PMID:27226855
Valle, Rubén; Sánchez, Elard; Perales, Alberto
In order to evaluate the frequency of depressive symptomatology (DS) and alcohol-related problems (ARP) during the academic training of medical students from Universidad Nacional Mayor de San Marcos, a cross-sectional study was conducted among students from first to sixth year of career. The Zung Self-Rating depression scale was used to evaluate DS and the CAGE questionnaire to evaluate ARP. 23.3% of participants had DS, and 7.3% had ARP. We found that the frequency of DS and ARP was higher among students in the first years of career. We recommend it is necessary to take action in the prevention and detection of these disorders from the first years of training of medical students.
MELLION, MICHELLE L.; NGUYEN, VANANH; TONG, MING; GILCHRIST, JAMES; DE LA MONTE, SUZANNE
Introduction The aim of this work was to determine the effect of chronic alcohol exposure on peripheral nerves in a nutritionally balanced rat model of alcoholism. Methods Three different strains of adult male rats were pair-fed for 8 weeks with isocaloric liquid diets containing 0% or 37% ethanol. Nerve conduction studies (NCS) were performed. Peripheral nerve and muscle were examined histologically with morphometrics. Results Ethanol exposure significantly slowed velocity in tibial and fibular nerves, but not in the plantar nerve in all 3 strains. Studies of the sciatic nerve revealed decreased fiber diameters and increased regenerative sprouts in peripheral nerves. There was muscle denervation of ethanol-exposed rats in all 3 strains. Conclusions Chronic ethanol exposure caused a polyneuropathy characterized by axonal degeneration despite adequate nutrition. These results suggest that ethanol exposure has direct neurotoxic effects on peripheral nerves. This model may be useful in understanding the underlying mechanism(s) of alcohol-related peripheral neuropathy. PMID:23761140
Heinz, Adrienne J; Beck, Anne; Meyer-Lindenberg, Andreas; Sterzer, Philipp; Heinz, Andreas
Alcohol-related violence is a serious and common social problem. Moreover, violent behaviour is much more common in alcohol-dependent individuals. Animal experiments and human studies have provided insights into the acute effect of alcohol on aggressive behaviour and into common factors underlying acute and chronic alcohol intake and aggression. These studies have shown that environmental factors, such as early-life stress, interact with genetic variations in serotonin-related genes that affect serotonergic and GABAergic neurotransmission. This leads to increased amygdala activity and impaired prefrontal function that, together, predispose to both increased alcohol intake and impulsive aggression. In addition, acute and chronic alcohol intake can further impair executive control and thereby facilitate aggressive behaviour.
Io, Aro; Yoshimoto, Hisashi
Japan passed the national law "Basic Act on Measures against Alcohol-related Health Harm" on December 2013. This law is expected to prevent inappropriate drinking that leads to alcohol-related problems such as physical and mental disorder, drunk driving, suicide, domestic violence, child abuse, and poor work performance. The physician's responsibilities under this law are described as follows: i) to provide high quality and appropriate medical care concerning alcohol-related health harm; ii) to reduce or eliminate the consumption of alcohol, thus preventing the progression of alcohol-related health harm; and iii) to coordinate these efforts amongst medical institutions. Based on this law, we believe that Japanese physicians will have essential roles in achieving the goals of this law and that we can fulfill our responsibilities by observing the following aspects: a) changing our message to the patients from "drink sensibly and moderately" to "low-risk drinking; but any drinking has a risk of harm and low-risk drinking is not risk-free"; b) encouraging the spread and use of Screening, Brief Intervention, and Referral to Treatment (SBIRT); and c) establishing community healthcare systems for alcohol-related problems, including dementia in the elderly and during alcohol emergencies.
Sukhwal, Mahima; Suman, L N
The aim of the present study was to examine spirituality, religiosity, and alcohol-related beliefs among college students. The sample consisted of 236 college students - 120 girls and 116 boys. The age range of the sample was between 18 and 21 years. The tools used in the study were Personal Information Data Sheet, Scale for Assessment of Attitudes toward Drinking and Alcoholism (SAADA), Alcohol Expectancy Questionnaire - Adult Form (AEQ), Beliefs and Values Scale (BVS), and The Religious Background and Behavior Questionnaire (RBBQ). The data were analyzed using t-test and Pearson's product moment correlation. Higher spirituality, religiosity, and both the components of religiosity - God Consciousness and Formal Practices, were all associated with less acceptance of drinking and alcoholism. Positive affect and higher spirituality were both associated with religiosity as well as its components. A positive correlation was found among religiosity and both its components. The results revealed gender differences in that the God Consciousness component of religiosity was found to be higher in girls, but not boys, who did not have exposure to alcohol through prior use or alcohol use in family. The implications for primary prevention for college students are discussed.
Godlaski, Aaron J; Giancola, Peter R
The purpose of this investigation was to examine (a) whether irritability mediates the relation between executive functioning (EF) and alcohol-related aggression and (b) whether the alcohol-aggression relation is better explained by the interactive effects of EF and irritability above and beyond the effects of either variable alone. EF was measured using seven well-established neuropsychological tests. Irritability was assessed with the Caprara Irritability Scale. Participants were 313 male and female social drinkers between 21 and 35 years of age. Following the consumption of an alcohol or a placebo beverage, participants were tested on a laboratory aggression task in which electric shocks were given to and received from a fictitious opponent under the guise of a competitive reaction-time task. Aggression was operationalized as the shock intensities administered to the fictitious opponent. Results indicated that irritability successfully mediated the relation between EF and intoxicated aggression for men only. Despite the fact that irritability and EF both independently moderated the alcohol-aggression relation in previous studies, no significant interaction for their combined effect was detected here. The findings are discussed, in part, within a cognitive neoassociationistic framework for aggressive behavior.
Sachdeva, Ankur; Chandra, Mina; Choudhary, Mona; Dayal, Prabhoo; Anand, Kuljeet Singh
Context Alcohol consumption has escalated rapidly in many countries over the past decade. Evidence suggests a correlation between alcohol use and cognitive decline. We have systematically reviewed the concept and controversies, epidemiology, nosology, neuropathology and neurobiology, neuropsychology and management updates of alcohol-related dementia (ARD) in this paper. Evidence Acquisition We retrieved papers for this review by searching the PubMed database for terms “alcohol and dementia”, “alcohol and cognitive impairment”, and “alcohol and wernicke-korsakoff” mentioned in the title of the published papers. A total of 131 studies showed up. Appropriate studies were shortlisted and included (n = 72). Cross-references if relevant were considered from the selected studies. Eligible articles were fully read by the authors and the results were compiled. Results The prolonged and excessive use of alcohol may lead to structural and functional brain damage, leading to ARD. The cognitive deficits are most frequently observed in domains of visuospatial functions, memory and executive tasks, with a potential of partial recovery if abstinence is maintained. However, there are doubts regarding the etiopathogenesis, nosological status, prevalence and diagnostic criteria for ARD, due to difficulty in assessment and various confounding factors. Conclusions With growing cohort of young and middle-aged people, there is a probable risk of upsurge of ARD. Presently, there are dilemmas over the diagnosis of independent ARD. Thus, there is a need to develop evidence-based guidelines for diagnosis and management of ARD through further systematic studies. PMID:27818965
Chailangkarn, Thanathom; Trujillo, Cleber A.; Freitas, Beatriz C.; Hrvoj-Mihic, Branka; Herai, Roberto H.; Yu, Diana X.; Brown, Timothy T.; Marchetto, Maria C. N.; Bardy, Cedric; McHenry, Lauren; Stefanacci, Lisa; Järvinen, Anna; Searcy, Yvonne M.; DeWitt, Michelle; Wong, Wenny; Lai, Philip; Ard, M. Colin; Hanson, Kari L.; Romero, Sarah; Jacobs, Bob; Dale, Anders M.; Dai, Li; Korenberg, Julie R.; Gage, Fred H.; Bellugi, Ursula; Halgren, Eric; Semendeferi, Katerina; Muotri, Alysson R.
Summary Williams syndrome (WS) is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with WS lack precisely the same set of genes, with breakpoints in chromosome band 7q11.231–5. The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioral pathologies in humans, remains largely unexplored. Here, we investigate neural progenitor cells (NPCs) and cortical neurons derived from WS and typically developing (TD) induced pluripotent stem cells (iPSCs). WS NPCs have an increased doubling time and apoptosis compared to TD NPCs. Using an atypical WS subject6, 7, we narrowed this cellular phenotype to a single gene candidate, FZD9. At the neuronal stage, WS-derived layers V/VI cortical neurons were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in WS neurons were validated after Golgi staining of postmortem layers V/VI cortical neurons. This human iPSC model8 fills in the current knowledge gap in WS cellular biology and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain. PMID:27509850
Chailangkarn, Thanathom; Trujillo, Cleber A; Freitas, Beatriz C; Hrvoj-Mihic, Branka; Herai, Roberto H; Yu, Diana X; Brown, Timothy T; Marchetto, Maria C; Bardy, Cedric; McHenry, Lauren; Stefanacci, Lisa; Järvinen, Anna; Searcy, Yvonne M; DeWitt, Michelle; Wong, Wenny; Lai, Philip; Ard, M Colin; Hanson, Kari L; Romero, Sarah; Jacobs, Bob; Dale, Anders M; Dai, Li; Korenberg, Julie R; Gage, Fred H; Bellugi, Ursula; Halgren, Eric; Semendeferi, Katerina; Muotri, Alysson R
Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.
Bakare, Muideen O; Bello-Mojeed, Mashudat A; Munir, Kerim M; Ogun, Oluwayemi C; Eaton, Julian
Late diagnosis and interventions characterize childhood neurodevelopmental disorders in Sub-Saharan Africa. This has negatively impacted on the prognosis of the children with neurodevelopmental disorders. This study examined the prevalence and pattern of neurodevelopmental delays among children under the age of 3 years attending immunization clinics in Lagos State, Nigeria and also affords opportunity of early follow-up and interventions, which had been documented to improve prognosis. The study involved two stage assessments; which consisted of first phase screening of the children for neurodevelopmental delays in immunization clinics at primary healthcare centers Lagos State, Nigeria and second phase which consists of definitive clinical evaluation and follow-up interventions for children screened positive for neurodevelopmental delays. Twenty seven (0.9%) of a total of 3,011 children under the age of 3 years were screened positive for neurodevelopmental delays and subsequently undergoing clinical evaluation and follow-up interventions. Preliminary working diagnoses among these children include cerebral palsy, autism spectrum disorder trait, nutritional deficiency, Down syndrome and Non-specific neurodevelopmental delay with co-morbid seizure disorder accounting for 33.3%, 14.8%, 18.5%, 7.4% and 25.9% respectively. This is a preliminary report that would be followed up with information on medium and long term intervention phase.
Zlatic, Stephanie; Comstra, Heather Skye; Gokhale, Avanti; Petris, Michael J; Faundez, Victor
ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging from intellectual disability to neurodegeneration. Severe ATP7A loss-of-function alleles trigger Menkes disease, a copper deficiency condition where systemic and neurodegenerative phenotypes dominate clinical outcomes. The pathogenesis of these manifestations has been attributed to the hypoactivity of a limited number of copper-dependent enzymes, a hypothesis that we refer as the oligoenzymatic pathogenic hypothesis. This hypothesis, which has dominated the field for 25 years, only explains some systemic Menkes phenotypes. However, we argue that this hypothesis does not fully account for the Menkes neurodegeneration or neurodevelopmental phenotypes. Here, we propose revisions of the oligoenzymatic hypothesis that could illuminate the pathogenesis of Menkes neurodegeneration and neurodevelopmental defects through unsuspected overlap with other neurological conditions including Parkinson's, intellectual disability, and schizophrenia.
Zlatic, Stephanie; Comstra, Heather Skye; Gokhale, Avanti; Petris, Michael J.; Faundez, Victor
ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging from intellectual disability to neurodegeneration. Severe ATP7A loss-of function alleles trigger Menkes disease, a copper deficiency condition where systemic and neurodegenerative phenotypes dominate clinical outcomes. The pathogenesis of these manifestations has been attributed to hypoactivity of a limited number of copper-dependent enzymes, a hypothesis that we refer as the oligoenzymatic pathogenic hypothesis. This hypothesis, which has dominated the field for 25 years, only explains some systemic Menkes phenotypes. However, we argue that this hypothesis does not fully account for the Menkes neurodegeneration or neurodevelopmental phenotypes. Here, we propose revisions of the oligoenzymatic hypothesis that could illuminate the pathogenesis of Menkes neurodegeneration and neurodevelopmental defects through unsuspected overlap with other neurological conditions including Parkinson’s, intellectual disability, and schizophrenia. PMID:25583185
Mellion, Michelle L.; Silbermann, Elizabeth; Gilchrist, James M.; Machan, Jason T.; Leggio, Lorenzo; de la Monte, Suzanne
Background Alcohol-related peripheral neuropathy (ALN) is generally characterized as an axonal large-fiber polyneuropathy caused by thiamine deficiency. We hypothesized, based on clinical observations, that ALN is associated with a small-fiber polyneuropathy that can be diagnosed with skin biopsy in heavy alcohol drinking subjects with normal thiamine status. Methods Eighteen individuals (9 heavy alcohol drinking subjects and 9 healthy control subjects) were assessed for the potential utility of skin biopsies in detecting ALN-associated small nerve fiber degeneration. Heavy drinking was defined as greater than 4 drinks/d and 5 drinks/d in women and men, respectively, as determined by the Timeline Follow-Back and lifetime drinking history. All subjects underwent neurological examination, nerve conduction studies, and skin biopsies to quantify end nerve fiber densities (ENFD). Other causes of neuropathy were excluded and thiamine status was assessed. Results Average ENFD were significantly decreased at the calf in the alcohol group as compared with control group (p < 0.0001). Histological sections demonstrated striking attrition and architectural simplification of intraepidermal nerve fibers in the heavy alcohol drinking subjects. There were no significant intergroup differences with respect to clinical assessments of neuropathy or thiamine status. Conclusions ALN is associated with a small-fiber neuropathy that can be detected with skin biopsy in heavy alcohol drinking individuals with normal thiamine status. Skin biopsy is a useful, minimally invasive biomarker that could extend studies to understand the effect of alcohol on the peripheral nerves and to evaluate potential therapeutic agents in larger clinical trials. PMID:24961481
Silm, Siiri; Ahas, Rein
We studied alcohol consumption and its consequences as a seasonal phenomenon in Estonia and analysed the social and environmental factors that may cause its seasonal rhythm. There are two important questions when researching the seasonality of human activities: (1) whether it is caused by natural or social factors, and (2) whether the impact of the factors is direct or indirect. Often the seasonality of social phenomena is caused by social factors, but the triggering mechanisms are related to environmental factors like temperature, precipitation, and radiation via the circannual calendar. The indicators of alcohol consumption in the current paper are grouped as: (1) pre-consumption phenomena, i.e. production, tax and excise, sales (beer, wine and vodka are analysed separately), and (2) post-consumption phenomena, i.e. alcohol-related crime and traffic accidents and the number of people detained in lockups and admitted to alcohol treatment clinics. In addition, seasonal variability in the amount of alcohol advertising has been studied, and a survey has been carried out among 87 students of Tartu University. The analysis shows that different phenomena related to alcohol have a clear seasonal rhythm in Estonia. The peak period of phenomena related to beer is in the summer, from June to August and the low point is during the first months of the year. Beer consumption correlates well with air temperature. The consumption of vodka increases sharply at the end of the year and in June; the production of vodka does not have a significant correlation with negative temperatures. The consumption of wine increases during summer and in December. The consequences of alcohol consumption, expressed as the rate of traffic accidents or the frequency of medical treatment, also show seasonal variability. Seasonal variability of alcohol consumption in Estonia is influenced by natural factors (temperature, humidity, etc.) and by social factors (celebrations, vacations, etc.). However
Buckner, Julia D; Terlecki, Meredith A
Social anxiety disorder more than quadruples the risk of developing an alcohol use disorder, yet it is inconsistently linked to drinking frequency. Inconsistent findings may be at least partially due to lack of attention to drinking context - it may be that socially anxious individuals are especially vulnerable to drinking more often in specific contexts that increase their risk for alcohol-related problems. For instance, socially anxious persons may drink more often while alone, before social situations for "liquid courage" and/or after social situations to manage negative thoughts about their performance. Among current (past-month) drinkers (N=776), social anxiety was significantly, positively related to solitary drinking frequency and was negatively related to social drinking frequency. Social anxiety was indirectly (via solitary drinking frequency) related to greater past-month drinking frequency and more drinking-related problems. Social anxiety was also indirectly (via social drinking frequency) negatively related to past-month drinking frequency and drinking-related problems. Findings suggest that socially anxious persons may be vulnerable to more frequent drinking in particular contexts (in this case alone) and that this context-specific drinking may play an important role in drinking problems among these high-risk individuals.
Chang, Koyin; Wu, Chin-Chih; Ying, Yung-Hsiang
Multiple alcohol control policies have been enacted since the early 1980s to keep drunk drivers off the roads and to prevent more alcohol-related traffic fatalities. In this paper, we analyze nine traffic policies to determine the extent to which each policy contributes to effective alcohol-related fatality prevention. Compared with the existing literature, this paper addresses a more comprehensive set of traffic policies. In addition, we used a panel GLS model that holds regional effects and state-specific time effects constant to analyze their impact on alcohol-related fatalities with two distinct rates: alcohol-related traffic deaths per capita and alcohol-related traffic deaths per total traffic deaths. While per capita alcohol-related traffic deaths is used more often in other studies, alcohol-related traffic deaths per total traffic deaths better reflects the impact of policies on deterring drunk driving. In addition, regional analyses were conducted to determine the policies that are more effective in certain regions. The findings of this study suggest that zero tolerance laws and increased beer taxes are the most effective policies in reducing alcohol-related fatalities in all regions.
Doumas, Diana M.
This study examined drinking motives as predictors of alcohol-related consequences among student athletes and nonathletes. Results indicated that the highest level of alcohol-related consequences was reported by student athletes with high levels of both coping and conformity motives. (Contains 2 tables and 2 figures.)
Isaak, Matthew I.; Perkins, David R.; Labatut, Tiffany R.
Objective: This study investigated the psychometric properties of the Disregulated Alcohol-Related Behaviors Inventory (DARBI), a measure of harmful alcohol-related behavior, and the relationship between protective behavior use and scores on the DARBI and several other measures. Participants: Participants were 281 undergraduate volunteers (60%…
Taylor, Dexter M.; Johnson, Mark B.; Voas, Robert B.; Turrisi, Robert
Restricting alcohol consumption on campus is a measure often used by college administrators to prevent alcohol abuse and-alcohol-related problems. The effect of dry campus policies on alcohol consumption and alcohol-related problems, however, remains poorly understood. This report will compare characteristics of two dry campuses with descriptions…
Schertz, Mitchell; Zuk, Luba; Green, Dido
Congenital muscular torticollis is a common condition, but long-term neurodevelopmental follow-up is lacking. This study reports on neurodevelopmental outcome of 68 children, aged 7 to 9 years, with a history of congenital muscular torticollis, excluding children with torticollis due to other conditions. Thirty-eight children were examined for presence of neurodevelopmental disorders. Telephone interview data were available for an additional 30 children. Of those examined, 22/38 (57.9%) had or were at risk for a developmental disorder (attention-deficit hyperactivity disorder (ADHD), developmental coordination disorder, language impairment, autistic spectrum disorder) on at least 1 of the assessments administered, 23/38 (60.5%) had received developmental treatment during childhood. One child, based on a telephone interview, had a history of developmental treatment. Therefore, 30/68 (44.1%) children of the total sample demonstrated a developmental delay/disorder, currently (22/68) or previously (8/68). Our findings suggest congenital muscular torticollis to be a significant risk factor for later neurodevelopmental conditions with disorders presenting at different stages of development.
Forsyth, Alasdair J M; Davidson, Neil
This paper investigates the relationship between community off-sales premises and alcohol-related detritus (litter/remains) in residential neighbourhoods. This was accomplished by photographing all brand-identifiable alcohol product detritus (glass, packaging, etc.) where they lay and mapping these against the presence of off-sales outlets (licensed convenience stores) in the community. It was hypothesised that alcohol-related detritus would be greatest near to such alcohol outlets. However, although there was some evidence of a "broken bottles effect", accumulations of alcohol-related detritus near some off-sales premises, it is concluded that local area deprivation is a better predictor of such alcohol-related incivility than is outlet provision. The implications of these findings are discussed in relation to current social responsibility policy developments which are designed to make the alcohol industry liable for alcohol-related incivilities.
Romano, Eduardo O; Tippetts, A Scott; Voas, Robert B
This paper investigates the role of race/ethnicity, language skills (a proxy for acculturation among Hispanics in Arizona, California, New Mexico, and Texas), income, and education level on alcohol-related fatal motor vehicle crashes. Using the Fatality Analysis Reporting System (FARS), we confirmed previous state-based studies showing that high income and education levels have a protective influence on alcohol-related fatal motor vehicle crashes. We also confirmed that language proficiency/acculturation tends to increase the vulnerability of Hispanic women to alcohol-related fatalities. Differences in alcohol-related fatality rates across Hispanic subgroups are observed. Future reductions in alcohol-related traffic fatalities may require prevention policies that take into account existent variations in acculturation, income, and education among racial/ethnic groups and subgroups.
Chachamovich, Eduardo; Ding, Yang; Turecki, Gustavo
Suicide is one of the major causes of deaths worldwide. Several studies have showed that alcohol use disorders (AUD) are associated with suicide ideation, suicide attempts, and suicide completion. The majority of the theoretical conceptualization and the bulk of evidence on suicidal behavior and AUD are based on investigations of nonfatal cases because data on nonfatal suicidal behaviors are more readily available. This study aims to explore demographic, clinical, and behavioral dimensions in a large sample of alcohol-related suicides compared to an age-gender matched sample of non-AUD suicides to identify specific factors associated with AUD suicides. We conducted a psychological autopsy study with 158 pairs of AUD and non-AUD suicides. Findings showed that AUD suicides have lower educational level, more biological children and were more likely to be heavy smokers (OR=3.32). Cases were more likely to have family history of alcohol (OR=1.73) and drug abuse (OR=3.61). Subjects had similar prevalences of depressive disorders, anxiety disorders or psychotic disorders. AUD suicides were more likely to meet criteria for current cocaine abuse/dependence (OR=6.64). With respect to personality disorders, AUD suicides presented higher prevalence of Antisocial Personality Disorder (OR=4.68), and were less likely to meet criteria for Avoidant (OR=0.26) and Obsessive-Compulsive Personality Disorders (OR=0.35). Impulsivity scores were higher in AUD suicides (p=0.18), as well as aggression scores (p<0.001). Results form the conditional logistic regression models showed that cocaine abuse/dependence (OR=4.20) and Antisocial Personality Disorder (OR=6.24) were associated with AUD suicide. After controlling for impulsive-aggressive behaviors, levels of aggression were the only psychopathological feature statistically different between AUD and non-AUD suicides (OR=1.28). In conclusion, higher levels of aggressive behaviors are a specific characteristic of AUD suicides. Apart from
Williams, Janet F; Smith, Vincent C
Prenatal exposure to alcohol can damage the developing fetus and is the leading preventable cause of birth defects and intellectual and neurodevelopmental disabilities. In 1973, fetal alcohol syndrome was first described as a specific cluster of birth defects resulting from alcohol exposure in utero. Subsequently, research unequivocally revealed that prenatal alcohol exposure causes a broad range of adverse developmental effects. Fetal alcohol spectrum disorder (FASD) is the general term that encompasses the range of adverse effects associated with prenatal alcohol exposure. The diagnostic criteria for fetal alcohol syndrome are specific, and comprehensive efforts are ongoing to establish definitive criteria for diagnosing the other FASDs. A large and growing body of research has led to evidence-based FASD education of professionals and the public, broader prevention initiatives, and recommended treatment approaches based on the following premises:▪ Alcohol-related birth defects and developmental disabilities are completely preventable when pregnant women abstain from alcohol use.▪ Neurocognitive and behavioral problems resulting from prenatal alcohol exposure are lifelong.▪ Early recognition, diagnosis, and therapy for any condition along the FASD continuum can result in improved outcomes.▪ During pregnancy:◦no amount of alcohol intake should be considered safe;◦there is no safe trimester to drink alcohol;◦all forms of alcohol, such as beer, wine, and liquor, pose similar risk; and◦binge drinking poses dose-related risk to the developing fetus.
Oscar-Berman, Marlene; Bowirrat, Abdalla
Alcoholism is a complex, multifactorial disorder involving problematic ethanol ingestion; it results from the interplay between genetic and environmental factors. Personality, likewise, is formed from a combination of inherited and acquired influences. Because selected dimensions of emotional temperament are associated with distinct neurochemical substrates contributing to specific personality phenotypes, certain aspects of abnormal emotional traits in alcoholics may be inherited. Emotions involve complex subjective experiences engaging multiple brain regions, most notably the cortex, limbic system, and cerebellum. Results of in vivo magnetic resonance imaging and post-mortem neuropathological studies of alcoholics indicate that the greatest cortical loss occurs in the frontal lobes, with concurrent thinning of the corpus callosum. Additional damage has been documented for the amygdala and hippocampus, as well as in the white matter of the cerebellum. All of the critical areas of alcoholism-related brain damage are important for normal emotional functioning. When changes occur in these brain regions, either as a consequence of chronic ethanol abuse or from a genetic anomaly affecting temperament and/or a vulnerability to alcoholism, corresponding changes in emotional functions are to be expected. In alcoholics, such changes have been observed in their perception and evaluation of emotional facial expressions, interpretation of emotional intonations in vocal utterances, and appreciation of the meaning of emotional materials. PMID:18568071
Marczinski, Cecile A; Hertzenberg, Heather; Goddard, Perilou; Maloney, Sarah F; Stamates, Amy L; O'Connor, Kathleen
The purpose of this study was to determine if a brief 10-item alcohol-related Facebook® activity (ARFA) questionnaire would predict alcohol use patterns in college students (N = 146). During a single laboratory session, participants first privately logged on to their Facebook® profiles while they completed the ARFA measure, which queries past 30 day postings related to alcohol use and intoxication. Participants were then asked to complete five additional questionnaires: three measures of alcohol use (the Alcohol Use Disorders Identification Test [AUDIT], the Timeline Follow-Back [TLFB], and the Personal Drinking Habits Questionnaire [PDHQ]), the Barratt Impulsiveness Scale (BIS-11), and the Marlowe-Crowne Social Desirability Scale (MC-SDS). Regression analyses revealed that total ARFA scores were significant predictors of recent drinking behaviors, as assessed by the AUDIT, TLFB, and PDHQ measures. Moreover, impulsivity (BIS-11) and social desirability (MC-SDS) did not predict recent drinking behaviors when ARFA total scores were included in the regressions. The findings suggest that social media activity measured via the ARFA scale may be useful as a research tool for identifying risky alcohol use.
Marczinski, Cecile A.; Hertzenberg, Heather; Goddard, Perilou; Maloney, Sarah F.; Stamates, Amy L.; O’Connor, Kathleen
The purpose of this study was to determine if a brief 10-item alcohol-related Facebook® activity (ARFA) questionnaire would predict alcohol use patterns in college students (N = 146). During a single laboratory session, participants first privately logged on to their Facebook® profiles while they completed the ARFA measure, which queries past 30 day postings related to alcohol use and intoxication. Participants were then asked to complete five additional questionnaires: three measures of alcohol use (the Alcohol Use Disorders Identification Test [AUDIT], the Timeline Follow-Back [TLFB], and the Personal Drinking Habits Questionnaire [PDHQ]), the Barratt Impulsiveness Scale (BIS-11), and the Marlowe-Crowne Social Desirability Scale (MC-SDS). Regression analyses revealed that total ARFA scores were significant predictors of recent drinking behaviors, as assessed by the AUDIT, TLFB, and PDHQ measures. Moreover, impulsivity (BIS-11) and social desirability (MC-SDS) did not predict recent drinking behaviors when ARFA total scores were included in the regressions. The findings suggest that social media activity measured via the ARFA scale may be useful as a research tool for identifying risky alcohol use. PMID:28138317
Younge, Noelle; Goldstein, Ricki F; Bann, Carla M; Hintz, Susan R; Patel, Ravi M; Smith, P Brian; Bell, Edward F; Rysavy, Matthew A; Duncan, Andrea F; Vohr, Betty R; Das, Abhik; Goldberg, Ronald N; Higgins, Rosemary D; Cotten, C Michael
Background Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes. Methods We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs (2000-2003 [epoch 1], 2004-2007 [epoch 2], and 2008-2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death. Results Data on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% (217 of 1391) in epoch 1 to 20% (276 of 1348) in epoch 3 (P=0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly (15% [207 of 1391] in epoch 1 and 16% [211 of 1348] in epoch 3, P=0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment (as compared with death) and the rate of survival without neurodevelopmental impairment (as compared with death) increased over time
Miller, A R
Prenatal alcohol exposure is a risk factor for neurologically based cognitive and adaptive disability. Diagnostic nomenclature for prenatally exposed children with cognitive and adaptive disability who lack features for foetal alcohol syndrome (FAS) or partial FAS includes the terms alcohol-related neurodevelopmental disorder (ARND) and foetal alcohol spectrum disorder(s) (FASD). Although these terms are now widely used, this paper argues that both are problematic. ARND is flawed by unjustifiably turning a risk factor into a causal factor and shrouding the result in terminological ambiguity, while FASD is not appropriate as a clinical label, and its use as a proxy for ARND deflects critical attention from the causal inferencing that is integral to diagnosing children with an alcohol-related teratogenic condition. Existing nomenclature is at odds with logical and evidence-based diagnosing and also has implications for interpretation of epidemiological data. Diagnostic nomenclature that is not tightly linked to causal inference is preferable at the present stage of this field's development.
Richardson, E.A.; Hill, S.E.; Mitchell, R.; Pearce, J.; Shortt, N.K.
Alcohol consumption may be influenced by the local alcohol retailing environment. This study is the first to examine neighbourhood alcohol outlet availability (on- and off-sales outlets) and alcohol-related health outcomes in Scotland. Alcohol-related hospitalisations and deaths were significantly higher in neighbourhoods with higher outlet densities, and off-sales outlets were more important than on-sales outlets. The relationships held for most age groups, including those under the legal minimum drinking age, although were not significant for the youngest legal drinkers (18–25 years). Alcohol-related deaths and hospitalisations were higher in more income-deprived neighbourhoods, and the gradient in deaths (but not hospitalisations) was marginally larger in neighbourhoods with higher off-sales outlet densities. Efforts to reduce alcohol-related harm should consider the potentially important role of the alcohol retail environment. PMID:25840352
Meyer, Urs; Feldon, Joram
Human epidemiological studies have provided compelling evidence that the risk of developing schizophrenia is significantly enhanced following prenatal and/or perinatal exposure to various environmental insults, including maternal exposure to stress, infection and/or immune activation, nutritional deficiencies and obstetric complications. Based on these associations, a great deal of interest has been centered upon the establishment of neurodevelopmental animal models which are based on prenatal and/or perinatal exposure to such environmental stimuli. In the present review, we describe this relatively novel class of epidemiology-based animal models in relation to the etiology, neurobiology and psychopharmacology of schizophrenia. Thereby, we discuss the general design and practical implementation of these models, and we provide an integrative summary of experimental findings derived from diverse epidemiology-based models, including models of maternal exposure to psychological stress, glucocorticoid treatment, viral infection, immune activating agents, protein deprivation, vitamin D deficiency, as well as models of obstetric complications in the form of birth by Caesarian section and perinatal/postnatal hypoxia. We highlight that the long-term consequences of prenatal exposure to these environmental challenges in animals successfully capture a broad spectrum of structural and functional brain abnormalities implicated in schizophrenia, some of which can be normalized by acute and/or chronic antipsychotic drug treatment. We thus conclude that epidemiology-driven neurodevelopmental models of schizophrenia are characterized by a high level of face, construct and predictive validity, including intrinsic etiological significance to the disorder. They also fulfill the expectation of the neurodevelopmental theory, such that the effects of prenatal environmental insults often only emerge after puberty. Epidemiologically based animal models not only provide indispensable
Monem, Ramey G; Fillmore, Mark T
Studies of visual attention find that drinkers spend more time attending to images of alcohol-related stimuli compared to neutral images. It is believed that this attentional bias contributes to the maintenance of alcohol use. However, no research has examined the possibility that this bias of visual attention might actually impede the functioning of other modalities, such as the processing of accompanying auditory stimuli. This study aimed to determine if alcohol-related images engender greater sensory dominance than neutral images, such that processing accompanying information from another modality (audition) would be impeded. Drinkers who had an attentional bias to alcohol-related images performed a multisensory perception task that measured how alcohol-related versus neutral visual images affected their ability to detect and respond to simultaneously presented auditory signals. In accord with the hypothesis, compared with neutral images, the presentation of alcohol-related images impaired the ability to detect and respond to auditory signals. Increased dominance of the visual modality was demonstrated by more bimodal targets being misclassified as visual-only targets in the alcohol target condition compared with that of the neutral. Findings suggest that increased processing of alcohol-related stimuli may impede an individual's ability to encode and interpret information obtained from other sensory modalities.
Walvoort, Serge JW; van der Heijden, Paul T; Kessels, Roy PC; Egger, Jos IM
Aim Impaired illness insight may hamper treatment outcome in patients with alcohol-related cognitive deficits. In this study, a short questionnaire for the assessment of illness insight (eg, the Q8) was investigated in patients with Korsakoff’s syndrome (KS) and in alcohol use disorder (AUD) patients with mild neurocognitive deficits. Methods First, reliability coefficients were computed and internal structure was investigated. Then, comparisons were made between patients with KS and patients with AUD. Furthermore, correlations with the Dysexecutive Questionnaire (DEX) were investigated. Finally, Q8 total scores were correlated with neuropsychological tests for processing speed, memory, and executive function. Results Internal consistency of the Q8 was acceptable (ie, Cronbach’s α =0.73). The Q8 items represent one factor, and scores differ significantly between AUD and KS patients. The Q8 total score, related to the DEX discrepancy score and scores on neuropsychological tests as was hypothesized, indicates that a higher degree of illness insight is associated with a higher level of cognitive functioning. Conclusion The Q8 is a short, valid, and easy-to-administer questionnaire to reliably assess illness insight in patients with moderate-to-severe alcohol-related cognitive dysfunction. PMID:27445476
Msall, Michael E.
Approximately 400,000 preschool children have a major neurodevelopmental disorder impacting on mobility, cognitive-adaptive, or communicative skills. As many as 1 in 3 children live at psychosocial disadvantage because of poverty, parental mental illness or substance misuse, or low parental educational (i.e. less than high school). In the past…
Rogers, Elizabeth E; Hintz, Susan R
Infants born at extreme preterm gestation are at risk for both death and disability. Although rates of survival have improved for this population, and some evidence suggests a trend toward decreased neuromotor impairment over the past decades, a significant improvement in overall early neurodevelopmental outcome has not yet been realized. This review will examine the rates and types of neurodevelopmental impairment seen after extremely preterm birth, including neurosensory, motor, cognitive, and behavioral outcomes. We focus on early outcomes in the first 18-36 months of life, as the majority of large neonatal studies examining neurodevelopmental outcomes stop at this age. However, this early age is clearly just a first glimpse into lifetime outcomes; the neurodevelopmental effects of extreme prematurity may last through school age, adolescence, and beyond. Importantly, prematurity appears to be an independent risk factor for adverse development, but this population demonstrates considerable variability in the types and severity of impairments. Understanding both the nature and prevalence of neurodevelopmental impairment among extremely preterm infants is important because it can lead to targeted interventions that in turn may lead to improved outcomes.
Iwamoto, Derek; Takamatsu, Stephanie; Castellanos, Jeanett
Binge drinking (five drinks or more in a 2-h sitting for men or four or more drinks in a 2-h sitting for women) and alcohol-related problems are a growing problem among Asian American young adults. The current study examines the sociocultural (i.e., generational status and ethnic identity) determinants of binge drinking and alcohol-related problems across U.S.-born, young-adult, Asian American ethnic groups. Data were collected from 1,575 Asian American undergraduates from a public university in Southern California. Chinese Americans consisted of the largest Asian ethnicity in the study, followed by Vietnamese, Filipino, Korean, South Asian, Japanese, Multi-Asian, and "other Asian American." Participants completed a web-based assessment of binge drinking, alcohol-related problems, ethnic identity, descriptive norms (i.e., perceived peer drinking norms), and demographic information. An analysis of variance was used to determine potential gender and ethnic differences in binge drinking and alcohol-related problems. Negative binomial regression was selected to examine the relationship between the predictors and outcomes in our model. There were no gender differences between Asian American men and women in regards to binge drinking; however, men reported more alcohol-related problems. Japanese Americans reported the highest number of binge-drinking episodes and alcohol-related problems, followed by Filipino and Multi-Asian Americans (e.g., Chinese and Korean). Living off-campus; higher scores in descriptive norms; Greek status; and belonging to the ethnic groups Japanese, Filipino, Multi-Asian, Korean, and South Asian increased the risk of engaging in binge drinking. Quantity of alcohol consumed, Greek status, gender, Filipino, South Asian, other Asian, and lower ethnic identity scores were related to alcohol-related problems. Using one of the largest samples collected to date on sociocultural determinants and drinking among U.S.-born Asian American young adults, the
Tajnia, Armin; Lichtenstein, Paul; Lundström, Sebastian; Anckarsäter, Henrik; Nilsson, Thomas; Råstam, Maria
Background. Over the last few decades, an increasing number of studies have suggested a connection between neurodevelopmental problems (NDPs) and body mass index (BMI). Attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) both seem to carry an increased risk for developing extreme BMI. However, the results are inconsistent, and there have been only a few studies of the general population of children. Aims. We had three aims with the present study: (1) to define the prevalence of extreme (low or high) BMI in the group of children with ADHD and/or ASDs compared to the group of children without these NDPs; (2) to analyze whether extreme BMI is associated with the subdomains within the diagnostic categories of ADHD or ASD; and (3) to investigate the contribution of genetic and environmental factors to BMI in boys and girls at ages 9 and 12. Method. Parents of 9- or 12-year-old twins (n = 12,496) were interviewed using the Autism—Tics, ADHD and other Comorbidities (A-TAC) inventory as part of the Child and Adolescent Twin Study in Sweden (CATSS). Univariate and multivariate generalized estimated equation models were used to analyze associations between extremes in BMI and NDPs. Results. ADHD screen-positive cases followed BMI distributions similar to those of children without ADHD or ASD. Significant association was found between ADHD and BMI only among 12-year-old girls, where the inattention subdomain of ADHD was significantly associated with the high extreme BMI. ASD scores were associated with both the low and the high extremes of BMI. Compared to children without ADHD or ASD, the prevalence of ASD screen-positive cases was three times greater in the high extreme BMI group and double as much in the low extreme BMI group. Stereotyped and repetitive behaviors were significantly associated with high extreme BMIs. Conclusion. Children with ASD, with or without coexisting ADHD, are more prone to have low or high extreme BMIs than children
Paley, Blair; O'Connor, Mary J
Exposure to alcohol in utero is considered to be the leading cause of developmental disabilities of known etiology. The most severe consequence of such exposure, fetal alcohol syndrome (FAS), is characterized by a distinct constellation of characteristic facial anomalies, growth retardation, and central nervous system (CNS) dysfunction. Some individuals with prenatal alcohol exposure (PAE) do not meet the full criteria for FAS, but instead are diagnosed with partial FAS, alcohol related neurodevelopmental disorder (ARND), or alcohol related birth defects (ARBD). The entire continuum of effects from PAE is increasingly being referred to under the umbrella term of fetal alcohol spectrum disorders (FASDs). An extensive body of research has documented major cognitive, behavioral, adaptive, social, and emotional impairments among individuals with FASDs. Although FAS was identified in the U.S. over 35 years ago, the development, evaluation, and dissemination of evidence-based interventions for individuals with FASDs have lagged behind significantly. Encouragingly, however, in recent years there has been a marked increase in efforts to design and test interventions to remediate the impairments associated with prenatal alcohol exposure. This article will review treatment needs and considerations for individuals with FASDs and their families, current empirically tested treatment approaches, case management issues, and suggestions for future directions in research on the treatment of FASDs.
Crews, Fulton T
Human studies have found alcoholics to have a smaller brain size than moderate drinkers; however, these studies are complicated by many uncontrollable factors, including timing and amount of alcohol use. Animal experiments, which can control many factors, have established that alcohol can cause damage to brain cells (i.e., neurons), which results in their loss of structure or function (i.e., neurodegeneration) in multiple brain regions, similar to the damage found in human alcoholics. In addition, animal studies indicate that inhibition of the creation of neurons (i.e., neurogenesis) and other brain-cell genesis contributes to alcoholic neurodegeneration. Animal studies also suggest that neurodegeneration changes cognition, contributing to alcohol use disorders. Risk factors such as adolescent age and genetic predisposition toward alcohol consumption worsen neurodegeneration. Mild impairment of executive functions similar to that found in humans occurs in animals following binge alcohol treatment. Thus, animal studies suggest that heavy alcohol use contributes to neurodegeneration and the progressive loss of control over drinking. Despite the negative consequences of heavy drinking, there is hope of recovery with abstinence, which in animal models can result in neural stem-cell proliferation and the formation of new neurons and other brain cells, indicative of brain growth.
Cservenka, Anita; Gillespie, Alicia J; Michael, Paul G; Nagel, Bonnie J
Objective: A family history of alcoholism is a significant risk factor for the development of alcohol use disorders (AUDs). Because common structural abnormalities are present in reward and affective brain regions in alcoholics and those with familial alcoholism, the current study examined the relationship between familial loading of AUDs and volumes of the amygdala and nucleus accumbens (NAcc) in largely alcohol-naive adolescents, ages 12–16 years (N = 140). Method: The amygdala and NAcc were delineated on each participant’s T1-weighted anatomical scan, using FMRIB Software Library’s FMRIB Integrated Registration & Segmentation Tool, and visually inspected for accuracy and volume outliers. In the 140 participants with accurate segmentation (75 male/65 female), subcortical volumes were represented as a ratio to intracranial volume (ICV). A family history density (FHD) score was calculated for each adolescent based on the presence of AUDs in first- and second-degree relatives (range: 0.03–1.50; higher scores represent a greater prevalence of familial AUDs). Multiple regressions, with age and sex controlled for, examined the association between FHD and left and right amygdala and NAcc volume/ICV. Results: There was a significant positive relationship between FHD and left NAcc volume/ICV (ΔR2 = .04, p = .02). Post hoc regressions indicated that this effect was only significant in females (ΔR2 = .11, p = .006). Conclusions: This finding suggests that the degree of familial alcoholism, genetic or otherwise, is associated with alterations in reward-related brain structure. Further work will be necessary to examine whether FHD is related to future alcohol-related problems and reward-related behaviors. PMID:25486393
Pabst, Alexander; Kraus, Ludwig; Piontek, Daniela; Mueller, Stefanie; Demmel, Ralf
This study investigates pathways from alcohol outcome expectancies to alcohol-related problems (ARPs), considering alcohol volume and episodic heavy drinking (EHD) as potential mediators. It is further examined whether these pathways vary by age. The population-based sample comprised 6,823 individuals aged 18 to 64 years reporting alcohol use in the past year. Direct and indirect effects of five alcohol expectancies (social assertiveness, tension reduction, sexual enhancement, cognitive impairment, aggression) and alcohol use (average daily intake, EHD) on a latent measure of ARPs (six items of the Alcohol Use Disorders Identification Test) were investigated. A multiple-group structural equation model with three age groups (18 to 24, 25 to 44, 45 to 64 years) was examined. In individuals aged 18 to 24 years, social assertiveness expectancies were positively associated with average intake and EHD, which in turn were associated with more ARPs. In addition, expectancies related to cognitive impairment and aggression were directly linked to more ARPs without mediation in this age group. In individuals aged 25 years and older, tension reduction expectancies were associated with more ARPs through increased average intake. In contrast, high scores on cognitive impairment were associated with lower average intake and in turn with fewer ARPs. Challenging expectancies of sociability in young and expectancies of relaxation in mid adulthood might help decrease high-risk drinking and subsequently ARPs. Considering negative alcohol expectancies may help to identify younger individuals at high risk for ARPs, even if they have not previously exhibited repeated excessive drinking. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
Gaher, Raluca M.; Simons, Jeffrey S.; Hahn, Nicole L; Hofman, Jamie Hansen; Hofman, Jamie Hansen; Buchkoski, Jerome
Posttraumatic stress disorder (PTSD) represents a debilitating psychiatric condition that is affecting the lives of many returning veterans. PTSD and alcohol use and dependence are highly comorbid. The purpose of this study was to understand the functional mechanisms between PTSD and alcohol use and problems. Specifically, the role of negative urgency and emotional intelligence were investigated as vulnerability and resiliency factors, respectively. This study utilized experience sampling to test associations between PTSD symptoms and alcohol use and related problems in a sample of 90 OIF/OEF veterans. Participants completed eight brief questionnaires daily for two weeks on palmtop computers. Elevations in PTSD symptoms during the day were associated with subsequent increases in alcohol use and associated problems that night. PTSD symptoms were associated with greater problems above and beyond the effect of drinking level at both the within- and between- person level. Emotional intelligence was associated with lower negative urgency, fewer PTSD symptoms, and less alcohol use and associated problems. The effects of emotional intelligence were primarily indirect via negative urgency and the effects of negative urgency on alcohol use and problems were indirect via its positive association with PTSD symptoms. Hypothesized cross-level effects of emotional intelligence and negative urgency were not supported. The findings suggest a functional association between PTSD symptoms and alcohol consumption. The association between PTSD symptoms and alcohol consumption is consistent with a self-medication model. However, the significant associations between PTSD symptoms and alcohol problems, after controlling for use level, suggest a broader role of dysregulation. PMID:25134021
Mackenbach, Johan P.; Kulhánová, Ivana; Bopp, Matthias; Borrell, Carme; Deboosere, Patrick; Kovács, Katalin; Looman, Caspar W. N.; Leinsalu, Mall; Mäkelä, Pia; Martikainen, Pekka; Menvielle, Gwenn; Rodríguez-Sanz, Maica; Rychtaříková, Jitka; de Gelder, Rianne
Background Socioeconomic inequalities in alcohol-related mortality have been documented in several European countries, but it is unknown whether the magnitude of these inequalities differs between countries and whether these inequalities increase or decrease over time. Methods and Findings We collected and harmonized data on mortality from four alcohol-related causes (alcoholic psychosis, dependence, and abuse; alcoholic cardiomyopathy; alcoholic liver cirrhosis; and accidental poisoning by alcohol) by age, sex, education level, and occupational class in 20 European populations from 17 different countries, both for a recent period and for previous points in time, using data from mortality registers. Mortality was age-standardized using the European Standard Population, and measures for both relative and absolute inequality between low and high socioeconomic groups (as measured by educational level and occupational class) were calculated. Rates of alcohol-related mortality are higher in lower educational and occupational groups in all countries. Both relative and absolute inequalities are largest in Eastern Europe, and Finland and Denmark also have very large absolute inequalities in alcohol-related mortality. For example, for educational inequality among Finnish men, the relative index of inequality is 3.6 (95% CI 3.3–4.0) and the slope index of inequality is 112.5 (95% CI 106.2–118.8) deaths per 100,000 person-years. Over time, the relative inequality in alcohol-related mortality has increased in many countries, but the main change is a strong rise of absolute inequality in several countries in Eastern Europe (Hungary, Lithuania, Estonia) and Northern Europe (Finland, Denmark) because of a rapid rise in alcohol-related mortality in lower socioeconomic groups. In some of these countries, alcohol-related causes now account for 10% or more of the socioeconomic inequality in total mortality. Because our study relies on routinely collected underlying causes of
London, Leslie; Beseler, Cheryl; Bouchard, Maryse F.; Bellinger, David C.; Colosio, Claudio; Grandjean, Philippe; Harari, Raul; Kootbodien, Tahira; Kromhout, Hans; Little, Francesca; Meijster, Tim; Moretto, Angelo; Rohlman, Diane S.; Stallones, Lorann
The association between pesticide exposure and neurobehavioral and neurodevelopmental effects is an area of increasing concern. This symposium brought together participants to explore the neurotoxic effects of pesticides across the lifespan. Endpoints examined included neurobehavioral, affective and neurodevelopmental outcomes amongst occupational (both adolescent and adult workers) and non-occupational populations (children). The symposium discussion highlighted many challenges for researchers concerned with the prevention of neurotoxic illness due to pesticides and generated a number of directions for further research and policy interventions for the protection of human health, highlighting the importance of examining potential long-term effects across the lifespan arising from early adolescent, childhood or pre-natal exposure. PMID:22269431
Houben, Katrijn; Nederkoorn, Chantal; Wiers, Reinout W; Jansen, Anita
According to dual-process models, excessive alcohol use emerges when response inhibition ability is insufficient to inhibit automatic impulses to drink alcohol. This study examined whether strengthening response inhibition for alcohol-related cues decreases alcohol intake. Fifty-two heavy drinking students were randomly assigned to one of two conditions: In the beer/no-go condition, participants performed a go/no-go task that consistently paired alcohol-related stimuli with a stopping response, to increase response inhibition for alcohol-related stimuli. In the beer/go condition, in contrast, participants were always required to respond to alcohol-related stimuli during the go/no-go task. Before and after the go/no-go manipulation, we measured weekly alcohol intake and implicit attitudes toward alcohol. In addition, we measured alcohol consumption during a taste test immediately after the go/no-go manipulation. Following the manipulation, participants in the beer/no-go condition demonstrated significantly increased negative implicit attitudes toward alcohol, and a significant reduction in weekly alcohol intake, while participants in the beer/go condition showed a non-significant increase in implicit positive attitudes toward alcohol and a significant increase in weekly alcohol intake. This study demonstrates that repeatedly stopping prepotent responses toward alcohol-related stimuli can be an effective strategy to reduce excessive alcohol use.
McMurran, Mary; Riemsma, Rob; Manning, Nathan; Misso, Kate; Kleijnen, Jos
Treatment programmes specifically for women offenders are under-developed. A systematic review of studies that could inform interventions for alcohol-related offending by women is reported. Three questions were addressed: 1) What is the most up to date knowledge of 'what works' with females who commit alcohol-related offences? 2) What are the identifiable risk-needs factors for non-alcohol dependent women who commit offences involving alcohol misuse? 3) Are there differences between male and female alcohol-related offending? Four studies addressed the effectiveness of psychosocial interventions; three addressed identifiable risk-needs; and 19 addressed differences between male and female offenders' alcohol-related offending. Heterogeneity of these studies precluded meta-analyses, and so a narrative synthesis method was used. There is insufficient evidence to answer the question of what treatment works with women who commit alcohol-related offences. Drunk-driving is most widely studied, and women offenders appear to have more psychosocial problems than men. Alcohol increases the likelihood of violence for both men and women, and, while the mechanisms whereby alcohol increases the likelihood of violence are likely the same in men and women, the effect may be moderated by gender-associated issues. Again, women offenders appear to have more psychosocial problems than men. Implications for developing interventions are discussed.
Kachadourian, Lorig K; Homish, Gregory G; Quigley, Brian M; Leonard, Kenneth E
The direct and interactive effects of alcohol expectancies for aggression, dispositional hostility, and heavy alcohol consumption on alcohol-related physical aggression were examined across the first four years of marriage in a sample of 634 newlywed couples. For husbands, alcohol aggression expectancies predicted increases in alcohol-related aggression; across husbands and wives, however, aggression expectancies were not found to interact with hostility or alcohol consumption to predict physical aggression. Consistent with previous research, hostility and alcohol consumption interacted with each other to predict alcohol-related aggression. Specifically, for both husbands and wives high in dispositional hostility, heavy alcohol consumption was positively associated with the occurrence of alcohol-related aggression; for those low in dispositional hostility, however, there was no association between alcohol consumption and alcohol-related aggression. Findings are contrasted with previous longitudinal research on alcohol aggression expectancies and physical aggression in married couples. The article discusses the extent to which findings may vary depending on whether expectancies are assessed in relation to alcohol's effect on one's own behavior versus alcohol's effect on others' behavior.
Samaco, Rodney C; Fryer, John D; Ren, Jun; Fyffe, Sharyl; Chao, Hsiao-Tuan; Sun, Yaling; Greer, John J; Zoghbi, Huda Y; Neul, Jeffrey L
Rett Syndrome, an X-linked dominant neurodevelopmental disorder characterized by regression of language and hand use, is primarily caused by mutations in methyl-CpG-binding protein 2 (MECP2). Loss of function mutations in MECP2 are also found in other neurodevelopmental disorders such as autism, Angelman-like syndrome and non-specific mental retardation. Furthermore, duplication of the MECP2 genomic region results in mental retardation with speech and social problems. The common features of human neurodevelopmental disorders caused by the loss or increase of MeCP2 function suggest that even modest alterations of MeCP2 protein levels result in neurodevelopmental problems. To determine whether a small reduction in MeCP2 level has phenotypic consequences, we characterized a conditional mouse allele of Mecp2 that expresses 50% of the wild-type level of MeCP2. Upon careful behavioral analysis, mice that harbor this allele display a spectrum of abnormalities such as learning and motor deficits, decreased anxiety, altered social behavior and nest building, decreased pain recognition and disrupted breathing patterns. These results indicate that precise control of MeCP2 is critical for normal behavior and predict that human neurodevelopmental disorders will result from a subtle reduction in MeCP2 expression.
Johansson, Edvard; Böckerman, Petri; Prättälä, Ritva; Uutela, Antti
This paper explores the connection between alcohol-related mortality, drinking behavior, and macroeconomic conditions in Finland using both aggregate and microlevel data from recent decades. The aggregate data reveal that an improvement in economic conditions produces a decrease in alcohol-related mortality. Microlevel data show that alcohol consumption increases during economic expansion while the probability of being a drinker remains unchanged. This demonstrates that alcohol-related mortality and self-reported alcohol consumption may be delinked in the short-run business cycle context. One explanation for this paradox is that most harmful forms of drinking are not captured in survey-based data used to study the effect of macroeconomic conditions on alcohol consumption. Our evidence does not overwhelmingly support the conclusions reported for the United States that temporary economic downturns are good for health.
Park, Hee Sun; Lee, Dong Wook
Two studies are reported using the theory of planned behavior (TPB) to predict and explain joining and not joining alcohol-related social gatherings among Korean undergraduates in various engineering majors. Specifically, considering that the attitudinal component of TPB is behavioral-outcome-based, the current study investigated whether the outcomes of engaging in a behavior and of not engaging in a behavior would similarly predict intentions to engage in a behavior and intentions to not engage in a behavior. The current study also examined whether intentions to engage and intentions to not engage would be significantly related to self-reported behavior a week later. Participants in Study 1 reported TPB components (attitudes toward behavior, subjective norms, perceived behavioral control, and behavioral intentions) concerning joining alcohol-related social gatherings. Participants in Study 2 reported TPB components concerning not joining alcohol-related social gatherings. Additionally, a week later, the participants in both studies reported their participation in alcohol-related social gatherings from the past week. Generally, the results showed that the TPB components were significantly associated with undergraduates' intentions to join and intentions to not join. Specifically, conversation-related attitudes and senior-junior relationship-related attitudes were significantly related to intentions to join, and only group-related attitudes were significantly related to intentions to not join. Intentions to join and intentions to not join were not significantly related to self-reported behavior of joining alcohol-related social gatherings a week later. The findings from the current research provide some evidence that joining or not joining alcohol-related social gatherings may not be mere behavioral opposites, predictable by the presence or absence of the same behavioral outcomes. These two aspects of the behavior may require assessment of different behavioral
Wolke, Dieter; And Others
The study examined pre-, peri-, and neonatal factors in 271 British infants (weighing less than 1500 grams at birth), 188 of whom survived to 2 years. The study represented an attempt to define those factors which predict normal neurodevelopmental outcome in very low birth weight (VLBW) infants. Surviving infants were seen at 3, 6, 9, 12, and 24…
Gmel, Gerhard; Kuendig, Hervé; Gaume, Jacques; Daeppen, Jean-Bernard
Alcohol-related injuries are responsible for a large share of the global mortality and morbidity burden. Scant information existed, however, for Switzerland. Based on 3653 injured patients and 3519 patients attending the emergency department of the Lausanne University Hospital for other reasons, alcohol attributable fractions with regard to the alcohol consumption in the 6 hours before the injury were estimated. Among men 17% of all injures were alcohol attributable, and 12% among women. Relative risks increased in dose-response relationship with alcohol intake. Leisure time related injuries were most likely to be alcohol attributable. Most of the alcohol-related injuries occurred at already small ethanol quantities ingested.
Miller, Carlin J; Hynd, George W
Developmental Gerstmann's syndrome is a neurodevelopmental disorder infrequently described in the literature. The limited literature might result from controversy surrounding developmental Gerstmann's syndrome as a "true syndrome." Developmental Gerstmann's syndrome requires a tetrad of symptoms: left-right confusion, finger agnosia, dyscalculia, and dysgraphia, with constructional dyspraxia often included as a fifth symptom. The etiology of developmental Gerstmann's syndrome is unknown, but several hypotheses have been proposed, and none have been conclusively confirmed. Based on the paucity of recent research on developmental Gerstmann's syndrome, individuals who meet the criteria for the disorder could be given other diagnoses. A clustering of neuropsychologic features across other seemingly related disorders suggests that the conceptualization of the tetrad of symptoms traditionally associated with developmental Gerstmann's syndrome more appropriately reflects soft signs that are commonly associated with a number of other neurodevelopmental disorders. Thus, although developmental Gerstmann's syndrome is of historical interest to neurodevelopmental specialists, there appears to be no basis for considering this disorder as a unique syndrome.
Ghibellini, Giulia; Brancati, Francesco; Castori, Marco
In the last decade, increasing attention has been devoted to the extra-articular and extra-cutaneous manifestations of joint hypermobility syndrome, also termed Ehlers-Danlos syndrome, hypermobility type (i.e., JHS/EDS-HT). Despite the fact that the current diagnostic criteria for both disorders remain focused on joint hypermobility, musculoskeletal pain and skin changes, medical practice and research have started investigating a wide spectrum of visceral, neurological and developmental complications, which represent major burdens for affected individuals. In particular, children with generalized joint hypermobility often present with various neurodevelopmental issues and can be referred for neurological consultation. It is common that investigations in these patients yield negative or inconsistent results, eventually leading to the exclusion of any structural neurological or muscle disorder. In the context of specialized clinics for connective tissue disorders, a clear relationship between generalized joint hypermobility and a characteristic neurodevelopmental profile affecting coordination is emerging. The clinical features of these patients tend to overlap with those of developmental coordination disorder and can be associated with learning and other disabilities. Physical and psychological consequences of these additional difficulties add to the chief manifestations of the pre-existing connective tissue disorder, affecting the well-being and development of children and their families. In this review, particular attention is devoted to the nature of the link between joint hypermobility, coordination difficulties and neurodevelopmental issues in children. Presumed pathogenesis and management issues are explored in order to attract more attention on this association and nurture future clinical research.
Hughes, Clarissa; Julian, Roberta; Richman, Matthew; Mason, Ron; Long, Gillian
This paper outlines early findings from the Tasmanian-based Social Norms Analysis Project (SNAP). The Social Norms model is presented as a theoretically informed, evidence-based model for reducing alcohol-related harm in youthful populations by utilising the complex and often positive contributions peer groups make to adolescent health and…
Wattenmaker McGann, Amanda
Previous literature provides an overview of the multiple relationships between alcohol use, protective behavioral strategies (PBS), alcohol-related negative consequences, depression, and sleep problems among college students, as well as differences by individual level characteristics, such as age, gender, and race/ethnicity. The purpose of this…
Voas, Robert B.; Torres, Pedro; Romano, Eduardo; Lacey, John H.
Objective: The purpose of this study was to determine whether the relative risk of being involved in an alcohol-related crash has changed over the decade from 1996 to 2007, a period during which there has been little evidence of a reduction in the percentage of all fatal crashes involving alcohol. Method: We compared blood-alcohol information for the 2006 and 2007 crash cases (N = 6,863, 22.8% of them women) drawn from the U.S. Fatality Analysis Reporting System (FARS) with control blood-alcohol data from participants in the 2007 U.S. National Roadside Survey (N = 6,823). Risk estimates were computed and compared with those previously obtained from the 1996 FARS and roadside survey data. Results: Although the adult relative risk of being involved in a fatal alcohol-related crash apparently did not change from 1996 to 2007, the risk for involvement in an alcohol-related crash for underage women has increased to the point where it has become the same as that for underage men. Further, the risk that sober underage men will become involved in a fatal crash has doubled over the 1996–2007 period. Conclusions: Compared with estimates obtained from a decade earlier, young women in this study are at an increased risk of involvement in alcohol-related crashes. Similarly, underage sober drivers in this study are more at risk of involvement in a crash than they were a decade earlier. PMID:22456239
Diulio, Andrea R; Cero, Ian; Witte, Tracy K; Correia, Christopher J
The present study investigated the role specific types of alcohol-related problems and life satisfaction play in predicting motivation to change alcohol use. Participants were 548 college students mandated to complete a brief intervention following an alcohol-related policy violation. Using hierarchical multiple regression, we tested for the presence of interaction and quadratic effects on baseline data collected prior to the intervention. A significant interaction indicated that the relationship between a respondent's personal consequences and his/her motivation to change differs depending upon the level of concurrent social consequences. Additionally quadratic effects for abuse/dependence symptoms and life satisfaction were found. The quadratic probes suggest that abuse/dependence symptoms and poor life satisfaction are both positively associated with motivation to change for a majority of the sample; however, the nature of these relationships changes for participants with more extreme scores. Results support the utility of using a multidimensional measure of alcohol related problems and assessing non-linear relationships when assessing predictors of motivation to change. The results also suggest that the best strategies for increasing motivation may vary depending on the types of alcohol-related problems and level of life satisfaction the student is experiencing and highlight potential directions for future research.
... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Consequences for employees engaging in alcohol-related conduct. 120.221 Section 120.221 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION... Medicine, Attn: Drug Abatement Division (AAM-800), 800 Independence Avenue, SW., Washington, DC 20591....
... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Consequences for employees engaging in alcohol-related conduct. 120.221 Section 120.221 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION..., Office of Aerospace Medicine, Attn: Drug Abatement Division (AAM-800), 800 Independence Avenue,...
... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Consequences for employees engaging in alcohol-related conduct. 120.221 Section 120.221 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION..., Office of Aerospace Medicine, Attn: Drug Abatement Division (AAM-800), 800 Independence Avenue,...
... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Consequences for employees engaging in alcohol-related conduct. 120.221 Section 120.221 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION..., Office of Aerospace Medicine, Attn: Drug Abatement Division (AAM-800), 800 Independence Avenue,...
Cavanagh, Lucia; Obasi, Ezemenari M.
The present study applied the Go/No-Go Association Test (GNAT; Nosek & Banaji, 2001) to measure alcohol-related implicit cognitions. Additionally, it assessed the role of implicit cognitions as a potential moderator in the relationship between explicit predictors of alcohol use and hazardous drinking behavior. University undergraduate students (N = 214) completed self-report questionnaires assessing reasons for drinking and reported alcohol use. Participants also completed two GNATs assessing implicit-alcohol-related cognitions associated with attitude (good-bad) and perceived safety (safe-dangerous). As expected, participants held implicit appraisals of alcohol as ‘‘bad’’ and ‘‘dangerous’’ in the context of nonalcoholic drinks, and as ‘‘good’’ and ‘‘safe’’ in the context of licit and illicit drugs. Implicit alcohol-related cognitions moderated the relationship between drinking to cope with negative affect and hazardous drinking and drinking due to cues or craving and hazardous drinking. These findings highlight the multidimensional nature of implicit cognitions and the role of negative implicit alcohol-related associations in moderating relationships between explicit processes and subsequent alcohol use behaviors. PMID:26989352
Alberta Dept. of Education, Edmonton. Special Education Branch.
This guide provides a review of the characteristics of children with fetal alcohol syndrome (FAS) or possible prenatal alcohol-related effects (PPAE) and describes specific intervention strategies. Section 1 offers a general review of the diagnostic procedures, the prevalence of FAS and the physical, educational, and behavioral characteristics of…
Lee, Christine M.; Maggs, Jennifer L.; Neighbors, Clayton; Patrick, Megan E.
While recent attention suggests that positive and negative alcohol-related expectancies are important determinants of alcohol use, less is known about what types of consequences young people report actually experiencing when drinking alcohol. The present study (N = 742, 54% women) examined positive (Fun/Social, Relaxation/Coping, Positive Image)…
Mounteney, J.; Haugland, S.; Skutle, A.
This study focuses on a vulnerable group of pupils often missed by mainstream school surveys. It explores alcohol use and alcohol-related problems for a sample of truants of secondary school age, comparing behaviours with a school-based sample from the same geographical area. Analyses are based on a survey among truants (n = 107) and a school…
Shook, Janice; Hiestand, Brian C.
Objective: In 2003, after several post-college football game riots, multiple strategies including strict enforcement of open container laws were instituted by the authors' city and university. The authors compared alcohol-related visits to the on-campus emergency department (ED) associated with home football games in 2002 and 2006, hypothesizing…
The present paper addressed the problem of the origin of alcohol-related social norms in the Saami minority in northern Norway. Based on data from studies of comparable ethnic minorities in Greenland, North America and Australia it could be expected that alcohol use- and abuse would be more prevalent in the Saami than in the Norwegian populations of northern Norway. No data to support this hypothesis exist. On the contrary, available data suggest that drinking problems in this group are similar to those of the majority in the area. The present paper developed the hypothesis that Saami alcohol-related social norms originated in the Laestadian religious revival. The paper investigated the impact of the Laestadian culture in the formation of alcohol-related social norms. It was concluded that the Laestadian sobriety norm, and the norm of abstinence from the use of adiafora, have influenced alcohol-related behaviour in the Saami group in such a way that this group does not conform to the drinking behaviour found in comparable minorities.
Juth, Vanessa; Smyth, Joshua M.; Thompson, Kevin; Nodes, Jennifer
Research on alcohol consumption among college students is often limited by self-reported outcomes and a narrow focus of predictor factors. This study examined both traditional risk factors for alcohol use as well as broader factors (e.g., weather, seasons) in predicting objective negative outcomes of alcohol use--alcohol-related legal infractions…
Mikhailovich, Katja; George, Amanda; Rickwood, Debra; Parker, Rhian
Studies documenting the harm associated with excessive drinking amongst university students are numerous. Fewer studies have explored the experience of non-drinkers in the university setting. In 2008, 826 students aged 18-29 years responded to an online survey aiming to investigate alcohol use and alcohol related harm at an Australian university.…
Roberts, Sarah C. M.; Bond, Jason; Korcha, Rachael; Greenfield, Thomas K.
This study explores whether associations between consuming alcohol in bars and alcohol-related harms are consistent across countries and whether country-level characteristics modify associations. We hypothesized that genderedness of bar drinking modifies associations, such that odds of harms associated with bar drinking increase more rapidly in…
Howard, Donna E.; Griffin, Melinda A.; Boekeloo, Bradley O.
This study examined the psychosocial correlates of alcohol-related sexual assault. Undergraduate students (N = 551) were recruited to complete a web-based survey. The outcome was a composite of 2 items: "experienced an unwanted sexual advance" or "was the victim of sexual assault or date rape" as a result of another's alcohol use. The predictors…
Rice, Kenneth G.; Van Arsdale, Amy C.
This study investigated the association between perfectionism (categorized by adaptive perfectionistic, maladaptive perfectionistic, or nonperfectionistic groups), perceived stress, drinking alcohol to cope, and alcohol-related problems in a large sample of college students (N = 354). Maladaptive perfectionists reported significantly higher levels…
Turner, James; Bauerle, Jennifer; Keller, Adrienne
Objective: Determine rate of college student alcohol-related vehicular traffic fatalities in Virginia during 2007. Participants: Undergraduates at colleges and universities in Virginia. Methods: Institutions with membership in the American College Health Association were invited to participate in a survey. Data collected from institutional reports…
Caldeira, Valerie; Woodin, Erica M.
Alcohol-related partnAer aggression is a pervasive social problem throughout various life stages, including the transition to parenthood. Previous research shows that alcohol use is associated with partner aggression perpetration for both men and women; however, not all individuals who consume alcohol act aggressively. In this study, the…
Pedrelli, Paola; Collado, Anahi; Shapero, Benjamin G.; Brill, Charlotte; MacPherson, Laura
Objectives: Comprehensive models elucidating the intricate associations of depressive symptoms, coping motives, alcohol use, alcohol-related problems (ARPs), and gender among young adults have been scarcely examined. This study investigated relationships among these variables and the effect of gender on these pathways. Methods: College students (N…
Leahy, Matthew M.; Jouriles, Ernest N.; Walters, Scott T.
This project examined the reliability and validity of a newly developed measure of college students' receptiveness to alcohol related information and advice. Participants were 116 college students who reported having consumed alcohol at some point in their lifetime. Participants completed a measure of receptiveness to alcohol-related…
Lindgren, Kristen P; Mullins, Peter M; Neighbors, Clayton; Blayney, Jessica A
Curiosity, composed of two factors: exploration and absorption, has been previously associated with life satisfaction, life meaningfulness, and enhanced positive affect. It also shares some overlap with sensation seeking, which has been linked to alcohol use and other addictive behaviors. The present research explored the association between curiosity and college women's problematic drinking in the context of sensation seeking. Participants (79 women) completed questionnaires measuring curiosity, sensation seeking, alcohol consumption, and consequences related to alcohol consumption. A zero-inflated negative binomial model indicated that curiosity and sensation seeking accounted for unique variance in alcohol-related problems after controlling for drinking. The curiosity factors had opposing relationships to alcohol-related problems: higher scores on absorption were associated with more alcohol-related problems whereas higher scores on exploration were associated with fewer alcohol-related problems. Should findings be replicated, the curiosity factors may represent additional prevention and intervention targets. Future directions for research about curiosity and drinking and for the inclusion of positive psychology constructs in addictive behaviors research are discussed.
Gilbertson, Troy A.
This randomized experiment examines the effects of contextual information on undergraduate college student's levels of alcohol-related incident guardianship at college parties. The research is conceptualized using routine activities theory and the theory of planned behavior. The experiment examines attitudinal variations about heavy drinking…
Ahmed, Rimsha; Hustad, John T. P.; LaSalle, Linda; Borsari, Brian
Objective: The purpose of this study is to investigate whether pregaming (ie, drinking prior to a social event) is a risk factor for hospitalization. Participants: Participants (N = 516) were undergraduate students with an alcohol-related sanction. Methods: Participants completed a survey about alcohol use, as well as behaviors and experiences,…
Zhang, RuiJie; Li, Xia; Jiang, YongShuai; Liu, GuiYou; Li, ChuanXing; Zhang, Fan; Xiao, Yun; Gong, BinSheng
High-throughout single nucleotide polymorphism detection technology and the existing knowledge provide strong support for mining the disease-related haplotypes and genes. In this study, first, we apply four kinds of haplotype identification methods (Confidence Intervals, Four Gamete Tests, Solid Spine of LD and fusing method of haplotype block) into high-throughout SNP genotype data to identify blocks, then use cluster analysis to verify the effectiveness of the four methods, and select the alcoholism-related SNP haplotypes through risk analysis. Second, we establish a mapping from haplotypes to alcoholism-related genes. Third, we inquire NCBI SNP and gene databases to locate the blocks and identify the candidate genes. In the end, we make gene function annotation by KEGG, Biocarta, and GO database. We find 159 haplotype blocks, which relate to the alcoholism most possibly on chromosome 1 approximately 22, including 227 haplotypes, of which 102 SNP haplotypes may increase the risk of alcoholism. We get 121 alcoholism-related genes and verify their reliability by the functional annotation of biology. In a word, we not only can handle the SNP data easily, but also can locate the disease-related genes precisely by combining our novel strategies of mining alcoholism-related haplotypes and genes with existing knowledge framework.
Guo, Lan; Deng, Jianxiong; He, Yuan; Deng, Xueqing; Huang, Jinghui; Huang, Guoliang; Gao, Xue; Zhang, Wei-Hong; Lu, Ciyong
Abstract Alcohol misuse among adolescents is a common issue worldwide and is an emerging problem in China. This study aimed to investigate the prevalence of alcohol drinking and alcohol-related problems among Chinese adolescents and to explore their risk factors and connections. A cross-sectional study using an anonymous questionnaire was conducted among junior and senior high school students between 2010 and 2012. Data on self-reported alcohol use, alcohol-related problems, school factors, family factors, and psychosocial factors were collected. Descriptive analyses were made of the proportions of sociodemographics, family, school, and psychosocial factors. Multilevel logistic regression models were conducted to analyze the risk factors for alcohol drinking and alcohol-related problems. Of the 105,752 students who ranged in age from 9 to 21 years, the prevalence of current drinking among students was 7.3%, and 13.2% students reported having alcohol-related problems. Male students were 1.78 (95% confidence interval [CI] = 1.69–1.87) times more likely to be involved in current drinking and 1.86 (95% CI = 1.79–1.93) times more likely to have alcohol-related problems. Higher grade level students were at a higher risk of current drinking (adjusted odds ratio [AOR] = 1.09, 95% CI = 1.05–1.13) and having alcohol-related problems (AOR = 1.43, 95% CI = 1.42–1.58). Older students were more likely to report current drinking (AOR = 1.06, 95% CI = 1.04–1.17) and having alcohol-related problems (AOR = 1.83, 95% CI = 1.82–1.85). Having poor classmate relations (AOR = 1.28, 95% CI = 1.03–1.37), having poor relationships with teachers (AOR = 1.08, 95% CI = 1.00–1.16), and below average academic achievement (AOR = 1.50, 95% CI = 1.41–1.59) were positively associated with current drinking. Moreover, students with suicidal ideation were at a higher risk of current drinking (AOR = 1.70, 95% CI = 1.61–1.81) and having alcohol-related problems (AOR = 2.08, 95% CI = 1
Miyake, Kunio; Hirasawa, Takae; Koide, Tsuyoshi; Kubota, Takeo
Autism was previously thought to be caused by environmental factors. However, genetic factors are now considered to be more contributory to the pathogenesis of autism, based on the recent findings of mutations in the genes which encode synaptic molecules associated with the communication between neurons. Epigenetic is a mechanism that controls gene expression without changing DNA sequence but by changing chromosomal histone modifications and its abnormality is associated with several neurodevelopmental diseases. Since epigenetic modifications are known to be affected by environmental factors such as nutrition, drugs and mental stress, autistic diseases are not only caused by congenital genetic defects, but may also be caused by environmental factors via epigenetic mechanism. In this chapter, we introduce autistic diseases caused by epigenetic failures and discuss epigenetic changes by environmental factors and discuss new treatments for neurodevelopmental diseases based on the recent epigenetic findings.
Perez-Garcia, Carlos G
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(-/-) HER4(heart) 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.
Velez-Ruiz, Naymee J; Meador, Kimford J
Many studies investigating cognitive outcomes in children of women with epilepsy report an increased risk of mental impairment. Verbal scores on neuropsychometric measures may be selectively more involved. While a variety of factors contribute to the cognitive problems of children of women with epilepsy, antiepileptic drugs (AEDs) appear to play a major role. The mechanisms by which AEDs affect neurodevelopmental outcomes remain poorly defined. Animal models suggest that AED-induced apoptosis, altered neurotransmitter environment, and impaired synaptogenesis are some of the mechanisms responsible for cognitive and behavioral teratogenesis. AEDs that are known to induce apoptosis, such as valproate, appear to affect children's neurodevelopment in a more severe fashion. Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains, and these appear to persist at least until the age of 6. Some studies have shown neurodevelopmental deficiencies associated with the use of phenobarbital and possibly phenytoin. So far, most of the investigations available suggest that fetal exposures to lamotrigine or levetiracetam are safer with regard to cognition when compared with other AEDs. Studies on carbamazepine show contradictory results, but most information available suggests that major poor cognitive outcomes should not be attributed to this medication. Overall, children exposed to polytherapy prenatally appear to have worse cognitive and behavioral outcomes compared with children exposed to monotherapy, and with the unexposed. There is an increase risk of neurodevelopmental deficits when polytherapy involves the use of valproate versus other agents.
Collett, Brent R.; Speltz, Matthew L.; Cloonan, Yona Keich; Leroux, Brian G.; Kelly, Judith P.; Werler, Martha M.
Objective To determine whether preadolescent children with hemifacial microsomia (HFM) have higher risk of neurodevelopmental delays than unaffected control individuals. Design Case-control follow-up study of neurodevelopment in children with and without HFM. Setting Case individuals were originally recruited from 26 craniofacial centers across the United States and Canada, and controls were recruited through community pediatricians. Participants One hundred thirty-six children with HFM (cases) and 568 unaffected children (controls). Main Exposure History of HFM. Main Outcome Measures The Peabody Picture Vocabulary Test–Third Edition, the Beery-Buktenica Developmental Test of Visual Motor Integration–Fifth Edition, and the Academic Competence scales from the Child Behavior Checklist and the Teacher Report Form. Results Children with HFM scored lower than controls on all measures (effect size = −0.27 to −0.45; P < .001 to P = .008). Compared with controls, cases were 2 to 3 times as likely to score in the at-risk range. Relative to controls, outcomes were worse for male cases and those whose mothers were 25 years or younger at the time of their birth. Cases with HFM plus other malformations had poorer outcomes, as did cases with hearing, vision, or speech impairments. Conclusions This is the first study, to our knowledge, to show that children with HFM have poorer neurodevelopmental outcomes than unaffected children, but further study using more detailed assessments is indicated. Clinically, the findings suggest that early neurodevelopmental screening is warranted for all children with HFM. PMID:21300653
Bickle Graz, M; Cevey-Macherel, M; Forcada-Guex, M; Truttmann, A; Ha-Vinh Leuchter, R; Sizonenko, S; Huppi, P S; Borradori Tolsa, C
Preterm children born before 32 weeks of gestation represent 1% of the annual births in Switzerland, and are the most at risk of neurodevelopmental disabilities. A neurological surveillance is thus implemented in the neonatal units, and multidisciplinary neurodevelopmental follow-up is offered to all our preterm patients. The follow-up clinics of the University hospitals in Lausanne and Geneva follow the Swiss guidelines for follow-up. An extended history and neurological examination is taken at each appointment, and a standardized test of development is performed. These examinations, which take place between the ages of 3 months and 9 years old, allow the early identification and treatment of developmental disorders frequent in this population, such as motor, cognitive or behavioral disorders, as well as the monitoring of the quality of neonatal care.
Janecka, M; Mill, J; Basson, M A; Goriely, A; Spiers, H; Reichenberg, A; Schalkwyk, L; Fernandes, C
Multiple epidemiological studies suggest a relationship between advanced paternal age (APA) at conception and adverse neurodevelopmental outcomes in offspring, particularly with regard to increased risk for autism and schizophrenia. Conclusive evidence about how age-related changes in paternal gametes, or age-independent behavioral traits affect neural development is still lacking. Recent evidence suggests that the origins of APA effects are likely to be multidimensional, involving both inherited predisposition and de novo events. Here we provide a review of the epidemiological and molecular findings to date. Focusing on the latter, we present the evidence for genetic and epigenetic mechanisms underpinning the association between late fatherhood and disorder in offspring. We also discuss the limitations of the APA literature. We propose that different hypotheses relating to the origins of the APA effects are not mutually exclusive. Instead, multiple mechanisms likely contribute, reflecting the etiological complexity of neurodevelopmental disorders. PMID:28140401
Lamis, Dorian A.; Malone, Patrick S.
The relationship among alcohol-related problems, perceived burdensomeness, thwarted belongingness, and suicide proneness in undergraduate college students (N = 996) was examined. As hypothesized, alcohol-related problems, perceived burdensomeness, and thwarted belongingness were all significantly and positively correlated with suicide proneness.…
Plant, Martin, Ed.
Alcohol consumption has risen dramatically in many countries since the Second World War. Accompanying this rise has been a rise in alcohol-related problems, including liver cirrhosis mortality, alcohol dependence, and alcohol-related crimes and accidents. Alcohol misuse presents huge health, social, and legal problems throughout most of Europe and…
Oksenberg, N; Haliburton, G D E; Eckalbar, W L; Oren, I; Nishizaki, S; Murphy, K; Pollard, K S; Birnbaum, R Y; Ahituv, N
The autism susceptibility candidate 2 gene (AUTS2) has been associated with multiple neurological diseases including autism spectrum disorders (ASDs). Previous studies showed that AUTS2 has an important neurodevelopmental function and is a suspected master regulator of genes implicated in ASD-related pathways. However, the regulatory role and targets of Auts2 are not well known. Here, by using ChIP-seq (chromatin immunoprecipitation followed by deep sequencing) and RNA-seq on mouse embryonic day 16.5 forebrains, we elucidated the gene regulatory networks of Auts2. We find that the majority of promoters bound by Auts2 belong to genes highly expressed in the developing forebrain, suggesting that Auts2 is involved in transcriptional activation. Auts2 non-promoter-bound regions significantly overlap developing brain-associated enhancer marks and are located near genes involved in neurodevelopment. Auts2-marked sequences are enriched for binding site motifs of neurodevelopmental transcription factors, including Pitx3 and TCF3. In addition, we characterized two functional brain enhancers marked by Auts2 near NRXN1 and ATP2B2, both ASD-implicated genes. Our results implicate Auts2 as an active regulator of important neurodevelopmental genes and pathways and identify novel genomic regions that could be associated with ASD and other neurodevelopmental diseases.
Brennan, Iain R
This study identifies the individual, situational, and alcohol-related factors associated with reporting violent victimization to the police. Factors positively associated with reporting included older age and incident severity (the assailant's use of a weapon, incurring injury that required attendance at an emergency department). Factors negatively associated with reporting included higher educational qualifications, assault in the nighttime economy (NTE), and drinking more than two alcoholic drinks immediately prior to victimization. It is possible that drinkers engage in "moratorium" on reporting violence in the NTE. Recognizing and reducing the acceptability of violence in the NTE may help reduce incidence of alcohol-related violence. Organizations that use police records of violence to inform practice and policy should account for uneven distributions in reporting behavior when analyzing trends in violence.
Boloursaz, Samine; Nekooei, Sirous; Seilanian Toosi, Farrokh; Rezaei-Dalouei, Hossein; Davachi, Behrooz; Kazemi, Sahar
Objectives. The aim of this article is to represent the first reported case with cooccurrence of two rare alcohol related complications. Case Report. We report a 38-year-old man with chronic alcoholism who presented with both cranial and peripheral nerve palsy. On MRI examination characteristic findings of Marchiafava-Bignami disease were recognized. Discussion. Marchiafava-Bignami disease (MBD) is a rare complication of long-term, heavy alcohol abuse that has characteristic MRI findings. Acute alcohol related polyneuropathy (AARP) is another rare and not-well-understood complication of chronic alcohol abuse. We could not find any previous report of the cooccurrence of these two complications in the literature. PMID:27668107
Negrete, J C
There is agreement that physicians can play a major role in the prevention of alcohol problems among their patients and that medical schools should prepare physicians for this role by teaching three major subject areas: knowledge, attitudes and clinical skills. Despite this agreement and the acknowledged high prevalence of alcohol problems in clinical populations, medical school coverage of these problems is not proportional to their importance. Barriers to adequate coverage of alcohol problems are traditional attitudes, confusion as to whether such problems are "medical" and lack of adequate faculty role models. These problems could be remedied by encouragement and training of interested faculty members, establishment of substance abuse centres in university medical schools, integration of alcohol-related material with relevant topics in all departments and inclusion of alcohol-related questions on medical qualifying exams. PMID:2224672
Brown, Stephen L; Coyne, Sarah M; Barlow, Alexandra; Qualter, Pamela
In adults, alcohol-related stimuli prime aggressive responding without ingestion or belief of ingestion. This represents either experiential or socially-and culturally-mediated learning. Using a laboratory-based competitive aggression paradigm, we replicated adult findings in 103 11-14 year old adolescents below the legal UK drinking age. Using a two-independent group design, priming with alcohol-related imagery led participants to deliver louder noise punishments in a competition task than priming with beverage-related images. This effect was stronger in participants scoring low on an internalization measure. Priming effects in relatively alcohol-naïve participants could constitute evidence of socio-cultural transmission of scripts linking alcohol use and aggression. The enhanced effect in lower internalization scorers suggests that alcohol priming might undermine behavioral inhibition processes in otherwise stable adolescents.
Weafer, Jessica; Fillmore, Mark T.
The acute impairing effects of alcohol on inhibitory control are well-established, and these disinhibiting effects are thought to play a role in its abuse potential. Alcohol impairment of inhibitory control is typically assessed in the context of arbitrary cues, yet drinking environments are comprised of an array of alcohol-related cues that are thought to influence drinking behavior. Recent evidence suggests that alcohol-related stimuli reduce behavioral control in sober drinkers, suggesting that alcohol impairment of inhibitory control might be potentiated in the context of alcohol cues. The current study tested this hypothesis by examining performance on the attentional-bias behavioral activation (ABBA) task that measures the degree to which alcohol-related stimuli can reduce inhibition of inappropriate responses in a between-subjects design. Social drinkers (N=40) performed the task in a sober condition, and then again following placebo (0.0 g/kg) and a moderate dose of alcohol (0.65 g/kg) in counter-balanced order. Inhibitory failures were greater following alcohol images compared to neutral images in sober drinkers, replicating previous findings with the ABBA task. Moreover, alcohol-related cues exacerbated alcohol impairment of inhibitory control as evidenced by more pronounced alcohol-induced disinhibition following alcohol cues compared to neutral cues. Finally, regression analyses showed that greater alcohol-induced disinhibition following alcohol cues predicted greater self-reported alcohol consumption. These findings have important implications regarding factors contributing to binge or ‘loss of control’ drinking. That is, the additive effect of disrupted control mechanisms via both alcohol-cues and the pharmacological effects of the drug could compromise an individual’s control over ongoing alcohol consumption. PMID:25134023
Chang, Jeffrey S; Hsiao, Jenn-Ren; Chen, Che-Hong
The occurrence of more than 200 diseases, including cancer, can be attributed to alcohol drinking. The global cancer deaths attributed to alcohol-consumption rose from 243,000 in 1990 to 337,400 in 2010. In 2010, cancer deaths due to alcohol consumption accounted for 4.2% of all cancer deaths. Strong epidemiological evidence has established the causal role of alcohol in the development of various cancers, including esophageal cancer, head and neck cancer, liver cancer, breast cancer, and colorectal cancer. The evidence for the association between alcohol and other cancers is inconclusive. Because of the high prevalence of ALDH2*2 allele among East Asian populations, East Asians may be more susceptible to the carcinogenic effect of alcohol, with most evidence coming from studies of esophageal cancer and head and neck cancer, while data for other cancers are more limited. The high prevalence of ALDH2*2 allele in East Asian populations may have important public health implications and may be utilized to reduce the occurrence of alcohol-related cancers among East Asians, including: 1) Identification of individuals at high risk of developing alcohol-related cancers by screening for ALDH2 polymorphism; 2) Incorporation of ALDH2 polymorphism screening into behavioral intervention program for promoting alcohol abstinence or reducing alcohol consumption; 3) Using ALDH2 polymorphism as a prognostic indicator for alcohol-related cancers; 4) Targeting ALDH2 for chemoprevention; and 5) Setting guidelines for alcohol consumption among ALDH2 deficient individuals. Future studies should evaluate whether these strategies are effective for preventing the occurrence of alcohol-related cancers.
Palmer, Barton W.; Jeste, Dilip V.
A review of literature on the neurodevelopmental origins of schizophemia is presented, with particular attention to neurodevelopmental processes in late-onset schizophemia. Definitions of the term “neurodevelopmental” as used in schizophernia literature are first provided. Next, evidence for the developmental origins of the neuropathology in schizophemia is reviewed. This evidence includes studies of the associations between schizophemia and neurodevelopmental brain aberrations, minor physical anomalies, obstetric complications, prenatal viral exposure, childhood neuromotor abnormalities, and pandysmaturation. A brief discussion of the predominant theories about the neurodevelopmental origins of schizophemia is then provided. The concept and nature of “late-onset schizophenia ”is next defined and discussed. Finally, the neurodevelopmental literature is discussed in relation to the phenomenon of late-onset schizophemia. Based on this review, we conclude that there exists a strong likelihood that late-onset schizophrenia involves neurodevelopmental processes. PMID:21584112
Monk, Rebecca L; Heim, Derek
This study aimed to contrast student and not student outcome expectancies, and explore the diversity of alcohol-related cognitions within a wider student sample. Participants (n=549) were college students (higher education-typically aged 15-18 years), university students (further education-typically aged 18-22 years) and business people (white collar professionals <50 years) who completed questionnaires in their place of work or education. Overall positive expectancies were higher in the college students than in the business or university samples. However, not all expectancy subcategories followed this pattern. Participant groups of similar age were therefore alike in some aspects of their alcohol-related cognitions but different in others. Similarly, participant groups whom are divergent in age appeared to be alike in some of their alcohol-related cognitions, such as tension reduction expectancies. Research often homogenises students as a specific sub-set of the population, this paper hi-lights that this may be an over-simplification. Furthermore, the largely exclusive focus on student groups within research in this area may also be an oversight, given the diversity of the findings demonstrated between these groups.
Parrish, K M; Higuchi, S; Muramatsu, T; Stinson, F S; Harford, T C
In Japan, per capita alcohol consumption increased sharply during the post World War II period followed by an increase in cirrhosis mortality. The prevalence of alcoholic cirrhosis among hospitalized patients also increased, from 11% in 1969 to 18% in 1985. Despite an increase in the percentage of drinkers among young women, over 80% of women in Japan are still abstainers or light drinkers. Thus, female cirrhosis mortality rates can be used as a proxy measure of non-alcohol-related cirrhosis mortality rates to estimate alcohol-related cirrhosis deaths among Japanese men. Employing this method, we conclude that two-thirds of cirrhosis deaths among men between 24 and 85 years of age and half of all cirrhosis deaths were attributable to alcohol. Two factors are probably responsible for the differences in proportional morbidity and proportional mortality of alcohol-related cirrhosis: differences in survival rates between alcoholic and non-alcoholic cirrhosis patients and detection bias toward post-hepatic cirrhosis. The synergistic effect of alcohol on viral hepatitis may in part explain excess cirrhosis deaths among Japanese men.
Bekman, Nicole M; Anderson, Kristen G; Trim, Ryan S; Metrik, Jane; Diulio, Andrea R; Myers, Mark G; Brown, Sandra A
Alcohol-related cognitions, particularly expectancies for drinking and nondrinking and motives for nondrinking, are involved in the initiation, maintenance, and cessation of alcohol use and are hypothesized to play key roles in adolescent decision making. This study explored (a) the relationships between alcohol use expectancies, nondrinking expectancies, and nondrinking motives; (b) the roles of these cognitions across hypothesized developmental stages of adolescent alcohol use; and (c) the relationships between these cognitions and recent or intended future changes in drinking behavior in a cross-sectional sample. Surveys assessing alcohol use behaviors and attitudes were administered to 1,648 high school students. Heavier drinkers reported more positive alcohol use expectancies and fewer nondrinking motives than did lighter drinkers or nondrinkers; however, nondrinking expectancies only differed between nondrinkers and rare drinkers and all subsequent drinking classes. Alcohol use expectancies, nondrinking expectancies, and nondrinking motives differentiated students who recently initiated alcohol from those who had not, while nondrinking expectancies and nondrinking motives differentiated binge-drinking students who had made recent efforts to reduce/stop their drinking from those who had not. Intentions to initiate or reduce drinking in the coming month were also associated with these alcohol-related cognitions. Drinking and nondrinking expectancies and motives for not drinking may play critical roles in decisions to alter alcohol-use behavior during adolescence. Future exploration of temporal relationships between changes in alcohol-related cognitions and behavioral decision making will be useful in the refinement of effective prevention and intervention strategies.
Lasimbang, Helen Benedict; Shoesmith, Wendy; Mohd Daud, Mohd Nazri Bin; Kaur, Nirmal; Jin, Margaret Chin Pau; Singh, Jaswant; John, Wilfred; Salumbi, Edna; Amir, Lidwina
Alcohol is the number three contributor to the burden of disease worldwide so must remain a priority health promotion issue internationally. Malaysia is a Muslim country and alcohol-related harm was not seen as a priority until recently, because it only affects a minority of the population. Sabah has more than 30 different ethnic groups, and alcohol has a traditional role in the cultural practices of many of these groups. In 2009, the Intervention Group for Alcohol Misuse (IGAM) was formed, under the umbrella of Mercy Malaysia by a group of healthcare workers, academics, members of the Clergy and people who were previously alcohol-dependent concerned about the harmful effects of excessive alcohol consumption. IGAM in collaboration with other bodies have organized public seminars, visited villages and schools, encouraged the formation of a support group and trained healthcare professionals in health promotion intervention. The focus later changed to empowering communities to find solutions to alcohol-related harm in their community in a way which is sensitive to their culture. A standard tool-kit was developed using WHO materials as a guide. Village committees were formed and adapted the toolkit according to their needs. This strategy has been shown to be effective, in that 90% of the 20 committees formed are actively and successfully involved in health promotion to reduce alcohol-related harm in their communities.
Sha, L; MacIntyre, L; Machell, J A; Kelly, M P; Porteous, D J; Brandon, N J; Muir, W J; Blackwood, D H; Watson, D G; Clapcote, S J; Pickard, B S
The basic helix-loop-helix PAS (Per, Arnt, Sim) domain transcription factor gene NPAS3 is a replicated genetic risk factor for psychiatric disorders. A knockout (KO) mouse model exhibits behavioral and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 etiopathology, we combined immunofluorescent, transcriptomic and metabonomic approaches. Intense Npas3 immunoreactivity was observed in the hippocampal subgranular zone-the site of adult neurogenesis--but was restricted to maturing, rather than proliferating, neuronal precursor cells. Microarray analysis of a HEK293 cell line over-expressing NPAS3 showed that transcriptional targets varied according to circadian rhythm context and C-terminal deletion. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was just one of many NPAS3 target genes also regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental function. The parallel repression of multiple glycolysis genes by NPAS3 reveals a second role in the regulation of glucose metabolism. Comparison of wild-type and Npas3 KO metabolite composition using high-resolution mass spectrometry confirmed these transcriptional findings. KO brain tissue contained significantly altered levels of NAD(+), glycolysis metabolites (such as dihydroxyacetone phosphate and fructose-1,6-bisphosphate), pentose phosphate pathway components and Kreb's cycle intermediates (succinate and α-ketoglutarate). The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of mental illness etiology, and may provide a mechanism for innate and medication-induced susceptibility to diabetes commonly reported in psychiatric patients.
Walker, Suellen M
Nociceptive pathways are functional following birth. In addition to physiological and behavioral responses, neurophysiological measures and neuroimaging evaluate nociceptive pathway function and quantify responses to noxious stimuli in preterm and term neonates. Intensive care and surgery can expose neonates to painful stimuli when the developing nervous system is sensitive to changing input, resulting in persistent impacts into later childhood. Early pain experience has been correlated with increased sensitivity to subsequent painful stimuli, impaired neurodevelopmental outcomes, and structural changes in brain development. Parallel preclinical studies have elucidated underlying mechanisms and evaluate preventive strategies to inform future clinical trials.
Peterson, Roselyn; Russo, Joan; Darnell, Doyanne; Wang, Jin; Ingraham, Leah; Zatzick, Douglas
Objective Approximately 30 million Americans present to acute care medical settings annually after incurring traumatic injuries. Posttraumatic stress disorder and depressive symptoms are endemic among injury survivors. Our paper is a replication and extension of a previous report documenting a pattern of multiple traumatic life events across patients admitted to Level I trauma centers for an alcohol-related injury. Method This study is a secondary analysis of a nationwide 20-site randomized trial of an alcohol brief intervention with 660 traumatically injured inpatients. Pre-injury trauma history was assessed using the National Comorbidity Survey trauma history screen at the 6 month time point. Results Most common traumatic events experienced by our population of alcohol positive trauma survivors were having had someone close unexpectedly die, followed by having seen someone badly beaten or injured. Of particular note, there is high reported prevalence of rape/sexual assault, and childhood abuse and neglect among physically injured trauma survivors. Additional trauma histories are increasingly common among alcohol-positive patients admitted for a traumatic injury. Conclusions Due to the high rate of experienced multiple traumatic events among acutely injured inpatients, the trauma history screen could be productively integrated into screening and brief intervention procedures developed for acute care settings. PMID:26745689
James, Eric J; Gu, Jenny; Ramirez-Vizcarrondo, Carolina M; Hasan, Mashfiq; Truszkowski, Torrey L S; Tan, Yuqi; Oupravanh, Phouangmaly M; Khakhalin, Arseny S; Aizenman, Carlos D
Autism spectrum disorder (ASD) is increasingly thought to result from low-level deficits in synaptic development and neural circuit formation that cascade into more complex cognitive symptoms. However, the link between synaptic dysfunction and behavior is not well understood. By comparing the effects of abnormal circuit formation and behavioral outcomes across different species, it should be possible to pinpoint the conserved fundamental processes that result in disease. Here we use a novel model for neurodevelopmental disorders in which we expose Xenopus laevis tadpoles to valproic acid (VPA) during a critical time point in brain development at which neurogenesis and neural circuit formation required for sensory processing are occurring. VPA is a commonly prescribed antiepileptic drug with known teratogenic effects. In utero exposure to VPA in humans or rodents results in a higher incidence of ASD or ASD-like behavior later in life. We find that tadpoles exposed to VPA have abnormal sensorimotor and schooling behavior that is accompanied by hyperconnected neural networks in the optic tectum, increased excitatory and inhibitory synaptic drive, elevated levels of spontaneous synaptic activity, and decreased neuronal intrinsic excitability. Consistent with these findings, VPA-treated tadpoles also have increased seizure susceptibility and decreased acoustic startle habituation. These findings indicate that the effects of VPA are remarkably conserved across vertebrate species and that changes in neural circuitry resulting from abnormal developmental pruning can cascade into higher-level behavioral deficits.
Langley, Ricky L; Kao, Yimin; Mort, Sandra A.; Bateman, Allen; Simpson, Barbara D.; Reich, Brian J
Aim Heavy metals such as manganese, arsenic and lead can act as neurotoxins. There have been few human studies of neurobehavioral/neurodevelopmental effects of arsenic and manganese on children in the United States. Since 1998, North Carolina has tested all new private wells for manganese, arsenic and lead. This study was conducted to evaluate adverse neurodevelopmental effects (delayed milestones, speech/language disorders and hearing loss) in children and metal concentrations in well water. Methods A quasi-regression model of the number of children (0–35 months of age) with adverse neurodevelopmental effects as outcome measures and aggregate mean metal concentration (arsenic, lead, and manganese) in private well water in each county as exposures. Results Over 70,000 private well water samples from 1998 to 2011 were analyzed for metal content. From 2008 to 2011, an average of 17,000 children was enrolled in the Infant Toddler Program. On average, 1.7% of children in this age range in each county had a speech/language disorder, 0.24% had a diagnosis of delayed milestones, and 0.026% had a diagnosis of hearing loss. The county mean manganese concentration was significantly and positively associated with the prevalence of delayed milestones and hearing loss in the children. No association was found for metal concentrations and speech/language disorders. Conclusion This ecological study indicates that further investigation of manganese in well water and associated neurodevelopmental health outcomes in children is needed. PMID:28344850
Rünker, Annette E; O'Tuathaigh, Colm; Dunleavy, Mark; Morris, Derek W; Little, Graham E; Corvin, Aiden P; Gill, Michael; Henshall, David C; Waddington, John L; Mitchell, Kevin J
Psychiatric disorders such as schizophrenia and autism are characterised by cellular disorganisation and dysconnectivity across the brain and can be caused by mutations in genes that control neurodevelopmental processes. To examine how neurodevelopmental defects can affect brain function and behaviour, we have comprehensively investigated the consequences of mutation of one such gene, Semaphorin-6A, on cellular organisation, axonal projection patterns, behaviour and physiology in mice. These analyses reveal a spectrum of widespread but subtle anatomical defects in Sema6A mutants, notably in limbic and cortical cellular organisation, lamination and connectivity. These mutants display concomitant alterations in the electroencephalogram and hyper-exploratory behaviour, which are characteristic of models of psychosis and reversible by the antipsychotic clozapine. They also show altered social interaction and deficits in object recognition and working memory. Mice with mutations in Sema6A or the interacting genes may thus represent a highly informative model for how neurodevelopmental defects can lead to anatomical dysconnectivity, resulting, either directly or through reactive mechanisms, in dysfunction at the level of neuronal networks with associated behavioural phenotypes of relevance to psychiatric disorders. The biological data presented here also make these genes plausible candidates to explain human linkage findings for schizophrenia and autism.
Languis, Marlin; Naour, Paul
For the individual, gender difference falls along the feminine-masculine continuum with strong neurodevelopmental influences at various points throughout the lifespan. Neurodevelopmental influences are conceptualized in a vector model of sex difference. Vector attributes, direction and magnitude, are influenced initially by differences in levels…
Beck, Kenneth H.; Kasperski, Sarah J.; Caldeira, Kimberly M.; Vincent, Kathryn B.; O'Grady, Kevin E.; Arria, Amelia M.
Background: Alcohol-impaired driving is a major public health problem. National studies indicate that about 25% of college students have driven while intoxicated in the past month and an even greater percentage drive after drinking any alcohol and/or ride with an intoxicated driver. The purpose of this investigation was to examine the change in these various alcohol-related traffic risk behaviors as students progressed through their college experience. Methods: A cohort of 1,253 first-time first-year students attending a large, mid-Atlantic university were interviewed annually for four years. Repeated measures analyses were performed using generalized estimating equations (GEE) to evaluate age-related changes in prevalence and frequency of each behavior (i.e., ages 19 to 22). Results: At age 19, 17% wt of students drove while intoxicated, 42%wt drove after drinking any alcohol, and 38%wt rode with an intoxicated driver. For all three driving behaviors, prevalence and frequency increased significantly at age 21. Males were more likely to engage in these behaviors than females. To understand the possible relationship of these behaviors to changes in drinking patterns, a post-hoc analysis was conducted and revealed that while drinking frequency increased every year, frequency of drunkenness was stable for females, but increased for males. Conclusions: Alcohol-related traffic risk behaviors are quite common among college students, and take a significant upturn when students reach the age of 21. Prevention strategies targeted to the college population are needed to prevent serious consequences of these alcohol-related traffic risk behaviors. PMID:20528819
Daly, Justine B; Campbell, Elizabeth M; Wiggers, John H; Considine, Robyn J
This study aimed to determine the prevalence of responsible hospitality policies in a group of licensed premises associated with alcohol-related harm. During March 1999, 108 licensed premises with one or more police-identified alcohol-related incidents in the previous 3 months received a visit from a police officer. A 30-item audit checklist was used to determine the responsible hospitality policies being undertaken by each premises within eight policy domains: display required signage (three items); responsible host practices to prevent intoxication and under-age drinking (five items); written policies and guidelines for responsible service (three items); discouraging inappropriate promotions (three items); safe transport (two items); responsible management issues (seven items); physical environment (three items) and entry conditions (four items). No premises were undertaking all 30 items. Eighty per cent of the premises were undertaking 20 of the 30 items. All premises were undertaking at least 17 of the items. The proportion of premises undertaking individual items ranged from 16% to 100%. Premises were less likely to report having and providing written responsible hospitality documentation to staff, using door charges and having entry/re-entry rules. Significant differences between rural and urban premises were evident for four policies. Clubs were significantly more likely than hotels to have a written responsible service of alcohol policy and to clearly display codes of dress and conditions of entry. This study provides an indication of the extent and nature of responsible hospitality policies in a sample of licensed premises that are associated with a broad range of alcohol related harms. The finding that a large majority of such premises appear to adopt responsible hospitality policies suggests a need to assess the validity and reliability of tools used in the routine assessment of such policies, and of the potential for harm from licensed premises.
Bekman, Nicole M.; Anderson, Kristen G.; Trim, Ryan S.; Metrik, Jane; Diulio, Andrea R.; Myers, Mark G.; Brown, Sandra A.
Purpose Alcohol-related cognitions, particularly expectancies for drinking and non-drinking and motives for non-drinking, are involved in the initiation, maintenance, and cessation of alcohol use and are hypothesized to play key roles in adolescent decision making. This study explored (a) the relationships between alcohol use expectancies, non-drinking expectancies and non-drinking motives, (b) the roles of these cognitions across hypothesized developmental stages of adolescent alcohol use and (c) the relationships between these cognitions and recent or intended future changes in drinking behavior in a cross-sectional sample. Methods Surveys assessing alcohol use behaviors and attitudes were administered to 1648 high school students. Results Heavier drinkers reported more positive alcohol use expectancies and fewer non-drinking motives than lighter drinkers or non-drinkers, however non-drinking expectancies only differed between non- and rare- drinkers and all subsequent drinking classes. Alcohol use expectancies, non-drinking expectancies and non-drinking motives differentiated students who recently initiated alcohol from those who had not, while non-drinking expectancies and non-drinking motives differentiated binge drinking students who had made recent efforts to reduce/stop their drinking from those who had not. Intentions to initiate or reduce drinking in the coming month were also associated with these alcohol-related cognitions. Conclusion Drinking and non-drinking expectancies, and motives for not drinking may play critical roles in decisions to alter alcohol-use behavior during adolescence. Future exploration of temporal relationships between changes in alcohol-related cognitions and behavioral decision making will be useful in the refinement of effective prevention and intervention strategies. PMID:21534645
Rapley, Tim; May, Carl; Frances Kaner, Eileen
This paper describes general practitioners' (GPs) experiences of detecting and managing alcohol and alcohol-related problems in consultations. We undertook qualitative research in two phases in the North-East of England. Initially, qualitative interviews with 29 GPs explored their everyday work with patients with alcohol-related issues. We then undertook group interviews--two with GPs and one with a primary care team--where they discussed and challenged findings of the interviews. The GPs reported routinely discussing alcohol with patients with a range of alcohol-related problems. GPs believed that this work is important, but felt that until patients were willing to accept that their alcohol consumption was problematic they could achieve very little. They tentatively introduced alcohol as a potential problem, re-introduced the topic periodically, and then waited until the patient decided to change their behaviour. They were aware that they could identify and manage more patients. A lack of time and having to work with the multiple problems that patients brought to consultations were the main factors that stopped GPs managing more risky drinkers. Centrally, we compared the results of our study with [Thom, B., & Tellez, C. (1986). A difficult business-Detecting and managing alcohol-problems in general-practice. British Journal of Addiction, 81, 405-418] seminal study that was undertaken 20 years ago. We show how the intellectual, moral, emotional and practical difficulties that GPs currently face are quite similar to those faced by GPs from 20 years ago. As the definition of what could constitute abnormal alcohol consumption has expanded, so the range of consultations that they may have to negotiate these difficulties in has also expanded.
Nashold, R D; Naor, E M
Analysis of the impact of alcohol as an underlying and non-underlying cause of death in Wisconsin showed a marked increase between 1963 and 1977 in the frequency of deaths reported with mention of alcohol. The rate of deaths for which alcohol was a non-underlying cause rose more sharply during this period (2.4 per 100,000 to 9.3) than that of alcohol-related causes (4.6/100,000 to 9.0). Nearly 90 per cent of alcohol-related deaths at ages 15-24 reported alcohol as a non-underlying cause, compared to 40.7 per cent at ages 45-54 and 57 per cent at ages 75+. This proportion was higher (50.8 per cent) among males than among females (32.8 per cent). Deaths related to alcohol are attributed to a number of underlying causes in addition to alcohol. In 1975-77, nearly half of the reported alcohol-related deaths were attributed to other causes, including accidents (14.8 per cent), heart disease (14.3 per cent), respiratory diseases (4.9 per cent), suicide (3.7 per cent), and cancer (31 per cent). These percentages may reflect substantial underreporting. Comparison of motor vehicle driver death certificates with blood alcohol test reports for these drivers shows 90 per cent underreporting of alcohol on death certificates. This fact, along with other information on underreporting, shows that the approximately 650 deaths now being reported with mention of alcohol annually in Wisconsin, represent only a portion of such deaths. PMID:7294267
Lamis, Dorian A.; Malone, Patrick S.
This study examined the relations among alcohol-related problems, perceived burdensomeness, thwarted belongingness, and suicide proneness in undergraduate college students (N = 996). As hypothesized, alcohol-related problems, perceived burdensomeness, and thwarted belongingness were all significantly and positively correlated with suicide proneness. The relation between experiencing alcohol-related problems and suicide proneness was, in part, accounted for by perceived burdensomeness and thwarted belongingness. Additionally, the mediation via perceived burdensomeness was significantly stronger than the mediation via thwarted belongingness. Results suggest that it would be advisable for clinicians to be aware of students’ experiences with alcohol-related problems in conjunction with their levels of burdensomeness and belongingness when assessing for suicide risk PMID:21883409
Doumas, Diana M; Miller, Raissa; Esp, Susan
This study examined protective behavioral strategies (PBS) as a moderator of the relationship between impulsive sensation seeking and binge drinking and alcohol-related consequences in a sample of high school seniors (N=346). Hierarchical regression analyses indicated that impulsive sensation seeking was a significant predictor of binge drinking and alcohol-related consequences and that PBS moderated these relationships. Specifically, manner of drinking moderated the relationships such that among students with high impulsive sensation seeking, those using strategies related to how they drink (e.g. avoiding rapid and excessive drinking) reported lower levels of binge drinking and alcohol-related consequences than those using fewer of these strategies. Clinical implications are discussed including using personality-targeted interventions that equip high impulsive sensation seeking adolescents with specific strategies to reduce binge drinking and alcohol-related consequences.
Cole, Jon C; Andretta, James R; McKay, Michael T
Time perspective is an individual difference variable which assesses the extent to which orientation to the past, present and future affects current behaviors. The present study investigated the viability of temporal profiles and the degree (if any) to which these predict meaningful differences in alcohol-related problems. Participants were undergraduates recruited from a University in the North West of England. Full survey data were available for 455 individuals (aged 18-25; 49.7% male) on (a) time perspective, and (b) alcohol-related problems. Four profiles emerged and were labeled Future-Positive, Present, Past Negative-Future, and Ambivalent. As hypothesized, the Future-Positive profile was associated with the best alcohol-related outcomes. The Present profile was associated with the worst outcomes. This study demonstrates that temporal profiles are associated with alcohol-related problems.
Background Excess alcohol consumption has serious adverse effects on health and violence-related harm. In the UK around 37% of men and 29% of women drink to excess and 20% and 13% report binge drinking. The potential impact on population health from a reduction in consumption is considerable. One proposed method to reduce consumption is to reduce availability through controls on alcohol outlet density. In this study we investigate the impact of a change in the density of alcohol outlets on alcohol consumption and alcohol-related harms to health in the community. Methods/Design A natural experiment of the effect of change in outlet density between 2005–09, in Wales, UK; population 2.4 million aged 16 years and over. Data on outlets are held by the 22 local authorities in Wales under The Licensing Act 2003. The study outcomes are change in (1) alcohol consumption using data from annual Welsh Health Surveys, (2) alcohol-related hospital admissions using the Patient Episode Database for Wales, (3) Accident & Emergency department attendances between midnight–6am, and (4) alcohol-related violent crime against the person, using Police data. The data will be anonymously record-linked within the Secure Anonymised Information Linkage Databank at individual and 2001 Census Lower Super Output Area levels. New methods of network analysis will be used to estimate outlet density. Longitudinal statistical analysis will use (1) multilevel ordinal models of consumption and logistic models of admissions and Accident & Emergency attendance as a function of change in individual outlet exposure, adjusting for confounding variables, and (2) spatial models of the change in counts/rates of each outcome measure and outlet density. We will assess the impact on health inequalities and will correct for population migration. Discussion This inter-disciplinary study requires expertise in epidemiology and public health, health informatics, medical statistics, geographical information science
Parrott, Dominic J.; Miller, Cameron A.
A substantial literature has identified risk factors for intoxicated aggression and the mechanisms by which these effects are exerted. This theoretical and empirical foundation is a valuable resource for the development of treatment inventions. In contrast, a comparable literature is not available to guide development of clinical interventions for intoxicated antigay aggression. To address this gap in the literature, the present article 1) identifies risk factors and mechanisms pertinent to alcohol-related antigay aggression, 2) advances predictions regarding how alcohol will increase antigay aggression, and 3) reviews societal- and individual-level considerations for intervention based upon these hypotheses. PMID:19938923
Gilbertson, Troy A
This randomized experiment examines the effects of contextual information on undergraduate college student's levels of alcohol-related incident guardianship at college parties. The research is conceptualized using routine activities theory and the theory of planned behavior. The experiment examines attitudinal variations about heavy drinking differentiated by sex, athletic status, and location of the drinking event. The sex and athletic status variables produce statistically effects on the dependent variables, while location of the drinking event is not significant. The article concludes by discussing the importance of context as it pertains to the social norms marketing strategy utilized in much college alcohol programming, and suggests a more directed marketing approach.
Barker, Jacqueline M; Torregrossa, Mary M; Taylor, Jane R
The factors underlying vulnerability to alcoholism are largely unknown. We identified in rodents an innate endophenotype predicting individual risk for alcohol-related behaviors that was associated with decreased expression of the neuroplasticity-related polysialylated neural cell adhesion molecule (PSA-NCAM). Depletion of PSA-NCAM in the ventromedial prefrontal cortex was sufficient to render mice unable to extinguish alcohol seeking, indicating a causal role of naturally occurring variation. These data suggest a mechanism of aberrant prefrontal neuroplasticity that underlies enhanced propensity for inflexible addiction-related behavior.
Cheah, P S; Ramshaw, H S; Thomas, P Q; Toyo-Oka, K; Xu, X; Martin, S; Coyle, P; Guthridge, M A; Stomski, F; van den Buuse, M; Wynshaw-Boris, A; Lopez, A F; Schwarz, Q P
Complex neuropsychiatric disorders are believed to arise from multiple synergistic deficiencies within connected biological networks controlling neuronal migration, axonal pathfinding and synapse formation. Here, we show that deletion of 14-3-3ζ causes neurodevelopmental anomalies similar to those seen in neuropsychiatric disorders such as schizophrenia, autism spectrum disorder and bipolar disorder. 14-3-3ζ-deficient mice displayed striking behavioural and cognitive deficiencies including a reduced capacity to learn and remember, hyperactivity and disrupted sensorimotor gating. These deficits are accompanied by subtle developmental abnormalities of the hippocampus that are underpinned by aberrant neuronal migration. Significantly, 14-3-3ζ-deficient mice exhibited abnormal mossy fibre navigation and glutamatergic synapse formation. The molecular basis of these defects involves the schizophrenia risk factor, DISC1, which interacts isoform specifically with 14-3-3ζ. Our data provide the first evidence of a direct role for 14-3-3ζ deficiency in the aetiology of neurodevelopmental disorders and identifies 14-3-3ζ as a central risk factor in the schizophrenia protein interaction network.
DiBello, Angelo M; Rodriguez, Lindsey M; Hadden, Benjamin W; Neighbors, Clayton
Previous research suggests that both jealousy and relationship contingent self-esteem (RCSE) are related to alcohol use and alcohol-related problems. No work, however, has examined these two constructs together as they relate to motives for alcohol use and alcohol-related problems. The current study aims to build upon emerging literature examining different types of jealousy (i.e., emotional, cognitive, and behavioral), relationship quality (i.e., satisfaction, commitment, closeness), RCSE, and alcohol use. More specifically, the current study aimed to examine the associations between RCSE and drinking to cope and RCSE and alcohol-related problems, in the context of the different types of jealousy. Moreover, the current study aimed to assess whether the associations between RCSE, jealousy, and drinking outcomes vary as a function of relationship quality. Two hundred and seventy seven individuals (87% female) at a large southern university participated in the study. They completed measures of RCSE, relationship satisfaction, commitment, closeness, and jealousy as well as alcohol-related outcomes. Using PROCESS, moderated mediational analyses were used to evaluate different types of jealousy as mediators of the association between RCSE and drinking to cope/alcohol-related problems. Further, we aimed to examine whether relationship quality moderated the association between RCSE and jealousy in predicting alcohol-related variables. Results indicated that cognitive jealousy mediated the association between both RCSE and drinking to cope and RCSE and alcohol-related problems. Further, relationship satisfaction, commitment, and closeness were all found to moderate the association between RSCE and cognitive jealousy such that at lower, but not higher levels of satisfaction, commitment, and closeness, cognitive jealousy mediated the association between RCSE and drinking to cope and RCSE and alcohol-related problems.
DeMartini, Kelly S.; Carey, Kate B.; Lao, Kristyn; Luciano, Matthew
Perceived drinking norms have received increased attention as one determinant of high levels of college alcohol consumption and alcohol-related problems. Excessive drinking is widely visible on college campuses, and students may therefore assume that it is peer-supported (Kitts, 2003). Research into peer relations indicates that the perceived approval of important others predicts drinking behavior (Neighbors et al., 2007). Neither the use of alcohol-related protective behavioral strategies nor alcohol-related negative consequences have been investigated in terms of their perceived approval. The purpose of this study was to extend previous research on injunctive norms and assess self-other discrepancies in levels of approval for campus drinking patterns, negative alcohol-related consequences, and protective behavioral strategies. Undergraduate volunteers (n = 324, 61% female, 67% Caucasian) completed an online survey of drinking patterns; they rated comfort with overall campus drinking, and the acceptability of alcohol-related consequences and protective strategies for themselves and their close friends. As predicted, students expressed lower acceptance of consequences than their friends, and higher acceptance of alcohol-related protective strategies. We observed main effects of gender and year in school. Males and upperclassmen expressed higher acceptance of negative consequences for both self and others, and lower acceptance of protective strategies for both self and others. Implications for prevention programs are discussed. PMID:21236586
Miller, Joseph; Prichard, Ivanka; Hutchinson, Amanda; Wilson, Carlene
Consuming an unhealthy level of alcohol is a significant problem for some young women. Potential determinants of excess consumption include perceptions of usual consumption among peers-perceptions of what is "normal." The present study examined whether perceptions of social normative endorsement of drinking, operationalized by measures of perceived alcohol consumption of close friends (proximal norms), the consumption of the "average student" (distal norms), and the extent of alcohol-related content posted by peers on Facebook were related to alcohol-related attitudes and self-reported consumption. Female university students (n=129; Mage=21.48 years, SD=3.00) completed an online questionnaire assessing Facebook use, perceived alcohol-related norms, and self-reported alcohol attitudes and consumption. Perceptions of the consumption of the average female student were a negative predictor of attitudes. Positive alcohol attitudes, extent of own alcohol-related photographic posts on Facebook, average female student alcohol consumption, and report of male close friend consumption predicted self-report of own alcohol consumption. Interestingly, female close friend norms failed to predict consumption, whereas male close friend norms predicted consumption but not attitudes, suggesting the possibility of separate cognitive pathways for alcohol-related attitudes and behavior. This study builds on existing research by casting new light on predictors of alcohol-related attitudes, as well as describing the potential role of social networking sites such as Facebook in the formation of social norms and the modulation of drinking behavior.
Martens, Matthew P; Pedersen, Eric R; Smith, Ashley E; Stewart, Sherry H; O'Brien, Kerry
Research has shown that college students participating in athletics drink more than other students, yet relatively few studies have examined variables that are associated with alcohol-related outcomes among this population. The purpose of this study was to examine the relationships among trait urgency, general drinking motives and sport-related drinking motives, and both alcohol use and alcohol-related problems. Data were collected from 198 college students participating in either intercollegiate or recreational athletics at three U.S. universities. Structural equation modeling was used to examine a series of theoretically derived explanatory models. All variables included in the model were directly associated with alcohol use and/or alcohol-related problems. The specific patterns of relationships differed across the motives and trait urgency variables. Sport-related coping motives, sport-related positive reinforcement motives, and general enhancement motives had direct relationships with alcohol use, while trait urgency, general coping motives, and sport-related positive reinforcement motives had direct relationships with alcohol-related problems. Several indirect effects on alcohol use and alcohol-related problems were also found. This study suggests that general drinking motives, sport-related drinking motives, and trait urgency all serve as important predictors of alcohol-related outcomes in college athletes.
Beeghly, M.; Ware, J.; Soul, J.; Plessis, A. Du; Khwaja, O.; Senapati, G. M.; Robson, C. D.; Robertson, R. L.; Poussaint, T. Y.; Barnewolt, C. E.; Feldman, H. A.; Estroff, J. A.; Levine, D.
Objective To characterize the delivery and postnatal neurodevelopmental outcomes of fetuses referred for ventriculomegaly (VM). Methods Under an internal review board-approved protocol, pregnant women were referred for magnetic resonance imaging (MRI) after sonographic diagnosis of VM and classified into one of four diagnostic groups: Group 1, normal central nervous system (CNS); Group 2, isolated mild VM (10–12 mm); Group 3, isolated VM > 12 mm; and Group 4, other CNS findings. Pregnancy outcome was obtained. Follow-up visits were offered with assessment of neurodevelopmental, adaptive and neurological functioning at 6 months and 1 year and/or 2 years of age. Atrial diameter and VM group differences in developmental outcomes were evaluated using repeated measures logistic regression and Fishers exact test, respectively. Results Of 314 fetuses, 253 (81%) were liveborn and survived the neonatal period. Fetuses in Groups 4 and 3 were less likely to progress to live delivery and to survive the neonatal period (60% and 84%, respectively) than were those in Groups 2 or 1 (93% and 100%, respectively, P < 0.001). Of the 143 fetuses followed postnatally, between 41% and 61% had a Bayley Scales of Infant Development (BSID-II) psychomotor developmental index score in the delayed range (< 85) at the follow-up visits, whereas the BSID-II mental developmental index and Vineland Adaptive Behavior composite scores were generally in line with normative expectations. Among those that were liveborn, neither VM group nor prenatal atrial diameter was related to postnatal developmental outcome. Conclusions Diagnostic category and degree of fetal VM based on ultrasound and MRI measurements are associated with the incidence of live births and thus abnormal outcome. Among those undergoing formal postnatal testing, VM grade is not associated with postnatal developmental outcome, but motor functioning is more delayed than is cognitive or adaptive functioning. PMID:20069560
Mallett, Kimberly A.; Turrisi, Rob; Cleveland, Michael J.; Scaglione, Nichole M.; Reavy, Racheal; Sell, Nichole M.; Varvil-Weld, Lindsey
Objective: Despite showing reductions in college student drinking, interventions have shown some inconsistency in their ability to successfully decrease consequences. With the goal of improving prevention efforts, the purpose of this study was to examine the role of consequence-specific constructs, in addition to drinking, that influence students’ experiences with alcohol-related problems. The study examined how drinking and protective behaviors mediated the relationships between students’ willingness to experience consequences, intentions to avoid them, and four categories of alcohol-related problems (physiological, social, sexual, and academic). Method: First-year college student drinkers (n = 2,024) at a large northeastern university completed surveys during the fall and spring of their freshman year. Results: As expected, different patterns of associations emerged for physiological and nonphysiological consequences. When physiological consequences (e.g., hangover, vomiting) were examined, drinking significantly mediated the effect of willingness on the consequences. Drinking-specific protective behaviors indirectly influenced consequences through drinking behaviors whereas general protective behaviors did not. When nonphysiological (e.g., social, sexual, academic) consequences were examined, drinking and general protective behaviors emerged as significant mediators of the effects of willingness and intentions on the consequences, whereas drinking-specific protective behaviors did not. Conclusions: The results suggest that prevention efforts (e.g., personalized feedback) could be tailored to address specific types of protective behaviors as well as specific types of consequences frequently experienced by college students. PMID:26562594
Dickter, Cheryl L.; Forestell, Catherine A.; Hammett, Patrick J.; Young, Chelsie M.
Rationale Previous work has indicated that implicit attentional biases to alcohol-related cues are indicative of susceptibility to alcohol dependence and escape drinking, or drinking to avoid dysphoric mood or emotions. Objective The goal of the current study was to examine whether alcohol dependence and escape drinking were associated with early neural attentional biases to alcohol cues. Methods EEG data were recorded from 54 college students who reported that they regularly drank alcohol, while they viewed alcohol and control pictures that contained human content (active) or no human content (inactive). Results Those who were alcohol dependent showed more neural attentional bias to the active alcohol-related stimuli than to the matched control stimuli early in processing, as indicated by N1 amplitude. Escape drinkers showed greater neural attention to the active alcohol cues than non-escape drinkers, as measured by larger N2 amplitudes. Conclusions While alcohol dependence is associated with enhanced automatic attentional biases early in processing, escape drinking is associated with more controlled attentional biases to active alcohol cues during a relatively later stage in processing. These findings reveal important information about the time-course of attentional processing in problem drinkers and have important implications for addiction models and treatment. PMID:24292342
Oei, T P; Young, R M
Recent literature showed that expectancies or cognitions have been proposed as a major factor in influencing the amount of alcohol an individual consumes and the behavioral consequences following consumption. However, how alcohol expectancies influence alcohol consumption is unclear; this paper reports two studies of the relationship. Study I examined the relationship between alcohol consumption and alcohol-related positive and negative self-statements in 110 social drinkers. The results showed that, in a nondrinking situation, the alcohol expectancies and variables measuring consumption and alcohol-related problems were correlated. Also, subjects who perceived their "alcoholic sets" as negative consumed more than those who perceived theirs as positive. Study II investigated changes in self-statement responding in 8 light and 8 heavy drinkers in a "normal" pub drinking situation. The results showed that alcohol-dependent self-statements in the light drinkers were relatively stable across time and between drinking and nondrinking environments. However, the alcohol-dependent self-statements of heavy drinkers became more negative during the drinking session. Furthermore, the degree and nature of such changes appeared to be related to alcohol-associated problems and consumption.
Buckner, Julia D; Matthews, Russell A
Individuals with elevated social anxiety appear particularly vulnerable to experiencing alcohol-related problems; yet we know little about factors that may account for this relationship. One possibility is that socially anxious individuals hold beliefs about the impressions they make on others while drinking and these beliefs play an important role in their drinking behaviors. The present study used exploratory factor analysis among participants with clinically elevated social anxiety (n=166) to develop a measure, the Social Impressions while Drinking Scale (SIDS), to assess beliefs regarding others' impressions of drinking behaviors that may be particularly relevant to socially anxious individuals. A valuations scale was also developed to assess the importance of each belief. Empirically-derived subscales were identified with adequate reliability. Among socially anxious participants, the Gregarious and Sexual Facilitation subscales were uniquely related to drinking problems and frequency respectively. Individuals with clinically meaningful social anxiety achieved higher scores on all SIDS subscales compared to those with lower social anxiety (n=166). Several SIDS scales mediated the relations between social anxiety group status and drinking problems (Interaction Fears, Observation Fears, Aggression, Gregariousness). Results highlight the importance of examining beliefs specific to high-risk populations in assessing their alcohol-related behaviors.
Nguyen, Van Anh; Le, Tran; Tong, Ming; Mellion, Michelle; Gilchrist, James; de la Monte, Suzanne M.
The mechanisms of alcohol-related peripheral neuropathy (ALPN) are poorly understood. We hypothesize that, like alcohol-related liver and brain degeneration, ALPN may be mediated by combined effects of insulin/IGF resistance and oxidative stress. Adult male Long Evans rats were chronically pair-fed with diets containing 0% or 37% ethanol (caloric), and subjected to nerve conduction studies. Chronic ethanol feeding slowed nerve conduction in the tibial (p = 0.0021) motor nerve, and not plantar sensory nerve, but it did not affect amplitude. Histological studies of the sciatic nerve revealed reduced nerve fiber diameters with increased regenerative sprouts, and denervation myopathy in ethanol-fed rats. qRT-PCR analysis demonstrated reduced mRNA levels of insulin, IGF-1, and IGF-2 polypeptides, IGF-1 receptor, and IRS2, and ELISAs revealed reduced immunoreactivity for insulin and IGF-1 receptors, IRS-1, IRS-4, myelin-associated glycoprotein, and tau in sciatic nerves of ethanol-fed rats (all p < 0.05 or better). The findings suggest that ALPN is characterized by (1) slowed conduction velocity with demyelination, and a small component of axonal degeneration; (2) impaired trophic factor signaling due to insulin and IGF resistance; and (3) degeneration of myelin and axonal cytoskeletal proteins. Therefore, ALPN is likely mediated by molecular and signal transduction abnormalities similar to those identified in alcoholic liver and brain degeneration. PMID:23016131
Jessica, Weafer; Fillmore, Mark T.
Rationale Poor behavioral control and heightened attentional bias toward alcohol-related stimuli have independently received considerable attention in regard to their roles in alcohol abuse. Theoretical accounts have begun to speculate as to potential reciprocal interactions between these two mechanisms that might promote excessive alcohol consumption, yet experimental evidence is lacking. Objectives The objective of the study was to integrate these two lines of research through the development of a novel laboratory task that examines the degree to which alcohol cues serve to disrupt mechanisms of behavioral control. Methods Fifty adult drinkers were recruited to perform the attentional bias–behavioral activation (ABBA) task. The ABBA task, an adaptation of traditional cued go/no-go tasks, is a reaction time model that measures the degree to which alcohol-related stimuli can increase behavioral activation of a drinker and reduce the ability to inhibit inappropriate responses. Participants also completed a novel measure of attentional bias, the scene inspection paradigm (SIP), that measures fixation time on alcohol content imbedded in complex scenes. Results As hypothesized, the proportion of inhibitory failures on the ABBA task was significantly higher following alcohol images compared to neutral images. Correlational analyses showed that heightened attentional bias on the SIP was associated with greater response activation following alcohol images on the ABBA task. Conclusions These findings suggest that alcohol stimuli serve to disrupt mechanisms of behavioral control, and that heightened attentional bias is associated with greater disruption of control mechanisms following alcohol images. PMID:22358851
Hughes, Tonda L.; Wilsnack, Sharon C.; Kantor, Lori Wolfgang
Although there are wide differences in alcohol use patterns among countries, men are consistently more likely than women to be drinkers and to drink heavily. Studies of alcohol use among sexual minorities (SMs), however, reflect a more complex picture. Such research has found higher rates of alcohol use and alcohol-related problems among SM persons than among heterosexuals and greater differences between SM and heterosexual women than between SM and heterosexual men. A variety of factors may contribute to differences in alcohol use and alcohol-related problems between men and women and between SM and heterosexual people. An improved understanding of these factors is important to guide prevention and treatment efforts. Although there is a dearth of literature on use of alcohol by SMs in many parts of the world, especially lower- and middle-income countries, we attempt to review and integrate the sparse data that are available from these lower-resourced countries. The global perspective presented in this article is the first attempt to go beyond a general review of literature in the Western world to document the gender paradox in alcohol use among heterosexuals and SMs in diverse countries worldwide. PMID:27159819
Quinn, Patrick D.; Fromme, Kim
There are important individual differences in acute subjective responses to alcohol, which have often been assessed using self-report measures. There is also evidence of meaningful between-persons variation in alcohol’s disinhibiting effects on behavior, such that some individuals become more impaired on tasks of inhibition than do others after an intoxicating dose. The degree to which subjective alcohol responses correspond with these disinhibition effects is not yet clear. In this study, we tested associations among indices of subjective alcohol responses and their correspondence with sensitivity to alcohol-related disinhibition. We recruited recent-binge-drinking emerging adults (N = 82) for a group-administered, placebo-controlled, within-subject, counterbalanced alcohol challenge in a simulated bar laboratory. Confirmatory factor analyses revealed that a two factor model with several cross-loadings explained associations among the subjective measures well, replicating a differentiation between stimulant-like and sedative-like subjective responses. Controlling sex and placebo performance, participants who reported greater subjective stimulant-like effects—but not sedative-like effects—experienced more alcohol-related disinhibition, as measured by Cued Go/No-Go Task inhibitory failures. This association was small-to-moderate in magnitude. The results of this study highlight the distinction between stimulant-like and sedative-like subjective alcohol effects. They suggest, additionally, that there may be modest commonalities between alcohol’s acute impacts on subjective stimulation and objective disinhibition. PMID:26867000
Quinn, Patrick D; Stappenbeck, Cynthia A; Fromme, Kim
Laboratory-based experimental research has demonstrated that the pharmacological effects of alcohol can increase aggressive responding. Given mixed findings and concerns regarding task validity, however, it remains uncertain whether this effect holds constant across men and women and whether variability in subjective alcohol intoxication contributes to alcohol-related aggression. In this investigation, the authors used 4 years of event-level data in a sample of 1,775 college students (140,618 total observations) to provide a test of laboratory-derived findings on the link between alcohol and aggression in an alternative methodology. They found support for several such findings: (a) Within-person increases in alcohol intoxication, as assessed by estimated blood alcohol concentrations (eBACs), were associated with increases in the probability of aggression at the drinking-episode level; (b) this association was significantly stronger among men than among women; and (c) within-person variability and between-persons individual differences in levels of subjective alcohol intoxication were associated with aggression over and beyond eBACs. Cross-methodological replication can reduce the impact of constraints specific to experimental studies on conclusions regarding alcohol's relation with aggression.
Caldeira, Valerie; Woodin, Erica M
Alcohol-related partner aggression is a pervasive social problem throughout various life stages, including the transition to parenthood. Previous research shows that alcohol use is associated with partner aggression perpetration for both men and women; however, not all individuals who consume alcohol act aggressively. In this study, the moderating effects of general social support and partner-specific support on the association between prepregnancy alcohol use and recent partner physical aggression are investigated using a community sample of 98 pregnant couples. For men, high levels of general appraisal social support (i.e., someone to talk to about one's problems) increases the strength of the association between alcohol use and aggression perpetration, whereas partner-specific emotional support serves as a buffer. For women, general social support is not a significant moderator, but high levels of partner-specific instrumental support strengthens the association between alcohol use and aggression. These results can be applied to prevention and treatment programs for alcohol-related partner aggression.
Ray, Anne E; Turrisi, Rob; Abar, Beau; Peters, Katherine E
Although heavy episodic drinkers are at risk to experience alcohol-related consequences, studies show that a large percentage of student drinkers do not experience problems as a result of their drinking. The present study was a more in-depth examination of factors beyond just drinking quantity and frequency to explain why students experience consequences. The current research examined the relationship between the use of protective behaviors, alcohol use, and alcohol related consequences, as well as the relationship between attitudinal and cognitive predictors of engaging in protective behaviors when drinking. We hypothesized there would be a significant direct effect of protective behaviors on consequences after taking into account the effect of alcohol use and that cognitive predictors, including perceived self-efficacy, perceived effectiveness, and subjective norm, would be associated with the attitude and frequency of engaging in protective behaviors. Results supported both hypotheses, indicating good model fit for all models and significant paths between constructs (p's<.05). These findings extend the literature on protective behaviors by providing insight as to their utility in preventing harm and why students choose to engage in these behaviors. Implications for interventions are also discussed.
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
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
Guo, Lan; Deng, Jianxiong; He, Yuan; Deng, Xueqing; Huang, Jinghui; Huang, Guoliang; Gao, Xue; Zhang, Wei-Hong; Lu, Ciyong
Alcohol misuse among adolescents is a common issue worldwide and is an emerging problem in China. This study aimed to investigate the prevalence of alcohol drinking and alcohol-related problems among Chinese adolescents and to explore their risk factors and connections.A cross-sectional study using an anonymous questionnaire was conducted among junior and senior high school students between 2010 and 2012. Data on self-reported alcohol use, alcohol-related problems, school factors, family factors, and psychosocial factors were collected. Descriptive analyses were made of the proportions of sociodemographics, family, school, and psychosocial factors. Multilevel logistic regression models were conducted to analyze the risk factors for alcohol drinking and alcohol-related problems.Of the 105,752 students who ranged in age from 9 to 21 years, the prevalence of current drinking among students was 7.3%, and 13.2% students reported having alcohol-related problems. Male students were 1.78 (95% confidence interval [CI] = 1.69-1.87) times more likely to be involved in current drinking and 1.86 (95% CI = 1.79-1.93) times more likely to have alcohol-related problems. Higher grade level students were at a higher risk of current drinking (adjusted odds ratio [AOR] = 1.09, 95% CI = 1.05-1.13) and having alcohol-related problems (AOR = 1.43, 95% CI = 1.42-1.58). Older students were more likely to report current drinking (AOR = 1.06, 95% CI = 1.04-1.17) and having alcohol-related problems (AOR = 1.83, 95% CI = 1.82-1.85). Having poor classmate relations (AOR = 1.28, 95% CI = 1.03-1.37), having poor relationships with teachers (AOR = 1.08, 95% CI = 1.00-1.16), and below average academic achievement (AOR = 1.50, 95% CI = 1.41-1.59) were positively associated with current drinking. Moreover, students with suicidal ideation were at a higher risk of current drinking (AOR = 1.70, 95% CI = 1.61-1.81) and having alcohol-related problems (AOR = 2.08, 95% CI = 1.98-2.16). Having higher Center
Mellert, David J; Williamson, W Ryan; Shirangi, Troy R; Card, Gwyneth M; Truman, James W
Interindividual differences in neuronal wiring may contribute to behavioral individuality and affect susceptibility to neurological disorders. To investigate the causes and potential consequences of wiring variation in Drosophila melanogaster, we focused on a hemilineage of ventral nerve cord interneurons that exhibits morphological variability. We find that late-born subclasses of the 12A hemilineage are highly sensitive to genetic and environmental variation. Neurons in the second thoracic segment are particularly variable with regard to two developmental decisions, whereas its segmental homologs are more robust. This variability "hotspot" depends on Ultrabithorax expression in the 12A neurons, indicating variability is cell-intrinsic and under genetic control. 12A development is more variable and sensitive to temperature in long-established laboratory strains than in strains recently derived from the wild. Strains with a high frequency of one of the 12A variants also showed a high frequency of animals with delayed spontaneous flight initiation, whereas other wing-related behaviors did not show such a correlation and were thus not overtly affected by 12A variation. These results show that neurodevelopmental robustness is variable and under genetic control in Drosophila and suggest that the fly may serve as a model for identifying conserved gene pathways that stabilize wiring in stressful developmental environments. Moreover, some neuronal lineages are variation hotspots and thus may be more amenable to evolutionary change.
Engel, Mareen; Smidt, Marten P; van Hooft, Johannes A
Serotonin (5-hydroxytryptamine, 5-HT), next to being an important neurotransmitter, recently gained attention as a key-regulator of pre- and postnatal development in the mammalian central nervous system (CNS). Several receptors for 5-HT are expressed in the developing brain including a ligand-gated ion channel, the 5-HT3 receptor. Over the past years, evidence has been accumulating that 5-HT3 receptors are involved in the regulation of neurodevelopment by serotonin. Here, we review the spatial and temporal expression patterns of 5-HT3 receptors in the pre- and early postnatal rodent brain and its functional implications. First, 5-HT3 receptors are expressed on GABAergic interneurons in neocortex and limbic structures derived from the caudal ganglionic eminence. Mature inhibitory GABAergic interneurons fine-tune neuronal excitability and thus are crucial for the physiological function of the brain. Second, 5-HT3 receptors are expressed on specific glutamatergic neurons, Cajal-Retzius cells in the cortex and granule cells in the cerebellum, where they regulate morphology, positioning, and connectivity of the local microcircuitry. Taken together, the 5-HT3 receptor emerges as a potential key-regulator of network formation and function in the CNS, which could have a major impact on our understanding of neurodevelopmental disorders in which 5-HT plays a role.
Mertz, Line Granild Bie; Thaulov, Per; Trillingsgaard, Anegen; Christensen, Rikke; Vogel, Ida; Hertz, Jens Michael; Ostergaard, John R
Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, developmental delay, lack of speech, and epileptic seizures. Previous studies have indicated that children with AS due to 15q11.2-q13 deletions have a more severe developmental delay and present more often autistic features than those with AS caused by other genetic etiologies. The present study investigated the neurodevelopmental profiles of the different genetic etiologies of AS, and examined the evolution of mental development and autistic features over a 12-year period in children with a 15q11.2-q13 deletion. This study included 42 children with AS. Twelve had a Class I deletion, 18 had Class II deletions, three showed atypical large deletions, five had paternal uniparental disomy (pUPD) and four had UBE3A mutations. Children with a deletion (Class I and Class II) showed significantly reduced developmental age in terms of visual perception, receptive language, and expressive language when compared to those with a UBE3A mutation and pUPD. Within all subgroups, expressive language performance was significantly reduced when compared to the receptive performance. A follow-up study of seven AS cases with 15q11.2-q13 deletions revealed that over 12 years, the level of autistic features did not change, but both receptive and expressive language skills improved.
Mellert, David J.; Williamson, W. Ryan; Shirangi, Troy R.; Card, Gwyneth M.; Truman, James W.
Interindividual differences in neuronal wiring may contribute to behavioral individuality and affect susceptibility to neurological disorders. To investigate the causes and potential consequences of wiring variation in Drosophila melanogaster, we focused on a hemilineage of ventral nerve cord interneurons that exhibits morphological variability. We find that late-born subclasses of the 12A hemilineage are highly sensitive to genetic and environmental variation. Neurons in the second thoracic segment are particularly variable with regard to two developmental decisions, whereas its segmental homologs are more robust. This variability “hotspot” depends on Ultrabithorax expression in the 12A neurons, indicating variability is cell-intrinsic and under genetic control. 12A development is more variable and sensitive to temperature in long-established laboratory strains than in strains recently derived from the wild. Strains with a high frequency of one of the 12A variants also showed a high frequency of animals with delayed spontaneous flight initiation, whereas other wing-related behaviors did not show such a correlation and were thus not overtly affected by 12A variation. These results show that neurodevelopmental robustness is variable and under genetic control in Drosophila and suggest that the fly may serve as a model for identifying conserved gene pathways that stabilize wiring in stressful developmental environments. Moreover, some neuronal lineages are variation hotspots and thus may be more amenable to evolutionary change. PMID:27223118
Fernandez-Jaen, A; Lopez-Martin, S; Albert, J; Martin Fernandez-Mayoralas, D; Fernandez-Perrone, A L; Calleja-Perez, B; Lopez-Arribas, S
Introduccion. Los trastornos del neurodesarrollo engloban a un grupo heterogeneo de trastornos como la discapacidad intelectual, el trastorno del espectro autista o los trastornos especificos del aprendizaje, entre otros. La reciente inclusion en las clasificaciones internacionales del trastorno por deficit de atencion/hiperactividad (TDAH) dentro de los trastornos del neurodesarrollo parece claramente justificada atendiendo a variables neurobiologicas y clinicas. Desarrollo. El caracter dimensional y la distribucion de diferentes sintomas en la poblacion caracterizan a la mayoria de los trastornos del neurodesarrollo. Se revisan estos aspectos, particularmente desde la sintomatologia y neuropsicologia en el TDAH. El caracter sintomatico dimensional del TDAH contrasta con los criterios diagnosticos de este trastorno de acuerdo a diferentes clasificaciones o guias clinicas. Contrasta igualmente con los datos recogidos a traves de diferentes exploraciones complementarias (escalas, tests...). Conclusiones. El entendimiento del continuo clinico dentro de cada trastorno del neurodesarrollo (incluido el TDAH), entre los diferentes trastornos del neurodesarrollo, y entre los trastornos del neurodesarrollo y la normalidad, es esencial para la investigacion, el diagnostico y el abordaje de todos ellos. El desarrollo de instrumentos que avalen este componente dimensional es igualmente trascendental.
Reeb-Sutherland, Bethany C.; Fox, Nathan A.
Eyeblink conditioning (EBC) is a classical conditioning paradigm typically used to study the underlying neural processes of learning and memory. EBC has a well-defined neural circuitry, is non-invasive, and can be employed in human infants shortly after birth making it an ideal tool to use in both developing and special populations. In addition,…
Schroeder, Stephen R.; Courtemanche, Andrea
There is a very substantial literature over the past 50 years on the advantages of early detection and intervention on the cognitive, communicative, and social-emotional development of infants and toddlers at risk for developmental delay due to premature birth or social disadvantage. Most of these studies excluded children with severe delays or…
Introduccion. La electromiografia de superficie se ha convertido en una tecnica muy utilizada para medir la actividad de distintos grupos musculares. Aunque la fiabilidad y validez de la tecnica se discuten, existe un cuerpo importante de bibliografia cientifica que defiende su uso. Objetivo. Presentar, mediante un estudio de caso, las dos utilidades basicas de la electromiografia de superficie: la medida de la actividad muscular orofacial y su empleo como biofeedback modulador de la propia actividad muscular. Caso clinico. Niña de 10 años con perfil facial dolicocefalico y prognatico, mordida abierta anterior y mordida cruzada bilateral, oclusion clase II de Angle bilateral y deglucion atipica con interposicion lingual. Se utilizo el electromiografo de superficie de ocho canales bipolares MioTool Face, de Miotec Suite 1.0. Se colocaron electrodos de superficie en la musculatura orofacial y los resultados obtenidos se midieron y visualizaron a traves de los programas Miograph y Biotrainer. Conclusiones. Los resultados confirman los obtenidos a traves de la exploracion clinica del paciente y apoyan el uso de estas mediciones para la estimacion y validacion de modelos mecanicos del sistema masticatorio y deglutorio. El biofeedback electromiografico se muestra como una tecnica eficaz para autocontrolar la fuerza que se realiza en grupos musculares claves en actividades primarias como la masticacion y la deglucion.
Koenig, Claire M; Walker, Cheryl K; Qi, Lihong; Pessah, Isaac N; Berman, Robert F
Misoprostol is a synthetic analogue of prostaglandin E1 that is administered to women at high doses to induce uterine contractions for early pregnancy termination and at low doses to aid in cervical priming during labor. Because of the known teratogenic effects of misoprostol when given during gestation and its effects on axonal growth in vitro, we examined misoprostol for its potential as a neurodevelopmental toxicant when administered to neonatal C57BL6/J mice. Mice were injected subcutaneously (s.c.) with 0.4, 4 or 40 µg/kg misoprostol on postnatal day 7, the approximate developmental stage in mice of human birth, after which neonatal somatic growth, and sensory and motor system development were assessed. These doses were selected to span the range of human exposure used to induce labor. In addition, adult mice underwent a battery of behavioral tests relevant to neurodevelopmental disorders such as autism including tests for anxiety, stereotyped behaviors, social communication and interactions, and learning and memory. No significant effects of exposure were found for any measure of development or behavioral endpoints. In conclusion, the results of the present study in C57BL/6J mice do not provide support for neurodevelopmental toxicity after misoprostol administration approximating human doses and timed to coincide with the developmental stage of human birth.
Vaclav Vojta (1917-2000) developed an early diagnostic method of the neurodevelopmental disorder of infants and came up with therapeutic concept consisting in releasing of global motor complexes by means of the stimulation of proper areas on patients body. In the diagnostics apart from very careful observation of the spontaneous movement of the infant and examination of the reflexes that are characteristic for the first weeks of human's life, Vojta applied the examination of the 7 postural reactions. Presence of the trouble in patterns and dynamics of the postural reactions Vojta called Central Nervous Coordination Disorder--CNCD and regarded as work diagnosis or alarm signal indicating necessity of application of the therapy, especially when asymmetry of the muscle tone and primitive reflexes beyond their physiological appearance period are observed or the number of the abnormal reactions exceeds 5. Global motor complexes as reflex locomotion--crawling and rotation--consist of all the partial motion patterns, which are gradually used by healthy infant in the process of postural and motor ontogenesis. Providing the central nervous system with proper external stimulation allows to, using neuronal plasticity, recreate an access to the human's postural development program and gradually replace pathological motor patterns by those more regular. Exercises repeated several times a day rebuilt support, erectile and vertical mechanisms, improve automatic postural control and phase lower limb movement. Affecting especially on autochtonic muscles of the spine exercises balance synergic cooperation of muscle groups in the trunk and those surrounding key body joints. This way they correct body's posture and peripheral motion and pathology of the outlasted primitive reflexes gradually withdraws.
Ahmed, Rimsha; Hustad, John T.P.; LaSalle, Linda; Borsari, Brian
Objective The purpose of this study is to investigate whether pregaming (i.e., drinking prior to a social event) is a risk factor for hospitalization. Participants Participants (N=516) were undergraduate students with an alcohol-related sanction. Method Participants completed a survey about alcohol use, as well as behaviors and experiences prior to and during the referral event. The dependent variable was whether participants received medical attention at an emergency department during the sanction event. Results Results indicated that older students, females who pregame, students with higher alcohol use screening scores, lighter drinkers, and higher numbers of drinks before the referral event all increased the odds of receiving medical attention. Pregaming alone was not significantly related to receiving medical attention in the multivariate analysis. Conclusions Female students who pregame appear to be at risk for requiring hospitalization after drinking when controlling for the number of drinks consumed. PMID:24635415
Monk, Rebecca L; Heim, Derek
The purpose of this study was to examine the effect of environmental contexts on alcohol norms, expectancies, and efficacy ratings. University students (n = 177) recruited via opportunity sampling completed questionnaires in either university lecture theaters or in a student bar. Positive social, fun, and tension reduction outcome expectancies were higher and social drink refusal self efficacy was lower in those participants questioned in a student bar relative to those questioned in a university lecture theater. These differences were found while controlling for between-groups variations in typical alcohol consumption quantities. Although hitherto largely unexamined by research, context appears to be a potentially important moderator of alcohol-related cognitions. Such findings require further exploration to inform more effective intervention approaches and have implications for the validity of existing literature.
Litt, Dana M; Stock, Michelle L
The present study examined the impact of socially based descriptive norms on willingness to drink alcohol, drinker prototype favorability, affective alcohol attitudes, and perceived vulnerability for alcohol-related consequences within the Prototype Willingness model. Descriptive norms were manipulated by having 189 young adolescents view experimenter-created profile pages from the social networking site Facebook, which either showed older peers drinking or not. The results provided evidence that descriptive norms for alcohol use, as portrayed by Facebook profiles, significantly impact willingness to use, prototypes, attitudes toward use, and perceived vulnerability. A multiple mediation analysis indicated that prototypes, attitudes, and perceptions of use mediated the relationship between the content of the Facebook profile and willingness. These results indicate that adolescents who perceive that alcohol use is normative, as evidenced by Facebook profiles, are at higher risk for cognitions shown to predict alcohol use than adolescents who do not see alcohol use portrayed as frequently on Facebook.
Peel, J L; Dansereau, D F; Dees, S
The goal of the present study was to examine scenarios for using two schematic organizers--schematic knowledge maps and conceptual matrices--in integrating episodic and semantic knowledge about alcohol. Seventy students from undergraduate general psychology classes participated for course credit. Participants were assigned to either a schematic organizer group or an essay writing group. These groups were subdivided further into two treatment sequences: episodic/semantic and semantic/episodic. The episodic activity required participants to complete materials using their own alcohol-related experiences, whereas the semantic activity required participants to annotate expert materials. Assessment measures used were consumer-satisfaction questionnaires and free-recall tests. While no preferences were established for any one scenario, the episodic activities were rated higher than the semantic activities regardless of integration sequence. The semantic/episodic integration scenario did produce higher recall scores for the expert information.
Shell, Duane F.; Huang, Zhaoqing; Qian, Ling
Aim: This paper describes Chinese university students' understanding of the meaning of the alcohol-related flushing response and how they reacted to their own and someone else's flushing in a group drinking situation. Method: The researcher surveyed 530 Chinese university students about their understanding of flushing and their perception of how people respond to a person who visibly flushes while drinking alcohol. Findings: Most students did not know about the physiological cause of flushing. There were significant gender differences in both reactions to and perception of responses to a person who flushes. There was no direct relationship between flushing and drinking behaviour. Conclusions: This description of flushing behaviour and responses to a flushing person is discussed in terms of educational opportunities to change behaviours that could reduce the cancer related risks of this visibly at-risk group. PMID:25983401
Trucks, Holger; Schulz, Herbert; de Kovel, Carolien G.; Kasteleijn-Nolst Trenité, Dorothée; Sonsma, Anja C. M.; Koeleman, Bobby P.; Lindhout, Dick; Weber, Yvonne G.; Lerche, Holger; Kapser, Claudia; Schankin, Christoph J.; Kunz, Wolfram S.; Surges, Rainer; Elger, Christian E.; Gaus, Verena; Schmitz, Bettina; Helbig, Ingo; Muhle, Hiltrud; Stephani, Ulrich; Klein, Karl M.; Rosenow, Felix; Neubauer, Bernd A.; Reinthaler, Eva M.; Zimprich, Fritz; Feucht, Martha; Møller, Rikke S.; Hjalgrim, Helle; De Jonghe, Peter; Suls, Arvid; Lieb, Wolfgang; Franke, Andre; Strauch, Konstantin; Gieger, Christian; Schurmann, Claudia; Schminke, Ulf; Nürnberg, Peter; Sander, Thomas
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes. PMID:25950944
Lal, Dennis; Ruppert, Ann-Kathrin; Trucks, Holger; Schulz, Herbert; de Kovel, Carolien G; Kasteleijn-Nolst Trenité, Dorothée; Sonsma, Anja C M; Koeleman, Bobby P; Lindhout, Dick; Weber, Yvonne G; Lerche, Holger; Kapser, Claudia; Schankin, Christoph J; Kunz, Wolfram S; Surges, Rainer; Elger, Christian E; Gaus, Verena; Schmitz, Bettina; Helbig, Ingo; Muhle, Hiltrud; Stephani, Ulrich; Klein, Karl M; Rosenow, Felix; Neubauer, Bernd A; Reinthaler, Eva M; Zimprich, Fritz; Feucht, Martha; Møller, Rikke S; Hjalgrim, Helle; De Jonghe, Peter; Suls, Arvid; Lieb, Wolfgang; Franke, Andre; Strauch, Konstantin; Gieger, Christian; Schurmann, Claudia; Schminke, Ulf; Nürnberg, Peter; Sander, Thomas
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
Reeb, Ben T; Chan, Sut Yee Shirley; Conger, Katherine J; Martin, Monica J; Hollis, Nicole D; Serido, Joyce; Russell, Stephen T
Research increasingly finds that race/ethnicity needs to be taken into account in the modelling of associations between protective factors and adolescent drinking behaviors in order to understand family effects and promote positive youth development. The current study examined racial/ethnic variation in the prospective effects of family cohesion on adolescent alcohol-related problems using a nationally representative sample. Data were drawn from the first two waves of the National Longitudinal Study of Adolescent to Adult Health and included 10,992 (50% female) non-Hispanic Asian, non-Hispanic Black, Latino, and non-Hispanic White 7th-12th graders. Consistent with Hirschi's social control theory of youth delinquency, higher levels of family cohesion predicted lower levels of future adolescent alcohol-related problems, independent of race/ethnicity, sex, age, baseline alcohol-related problems, and family socioeconomic status. Findings from moderation analyses indicated that the magnitude of associations differed across groups such that the protective effect of family cohesion was strongest among White adolescents. For Latino adolescents, family cohesion was not associated with alcohol-related problems. Future longitudinal cross-racial/ethnic research is needed on common and unique mechanisms underlying differential associations between family processes and adolescent high-risk drinking. Understanding these processes could help improve preventive interventions, identify vulnerable subgroups, and inform health policy aimed at reducing alcohol-related health disparities.
The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformati...
Brieber, Sarah; Neufang, Susanne; Bruning, Nicole; Kamp-Becker, Inge; Remschmidt, Helmut; Herpertz-Dahlmann, Beate; Fink, Gereon R.; Konrad, Kerstin
Background: Although autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) are two distinct neurodevelopmental diseases, they share behavioural, neuropsychological and neurobiological characteristics. For the identification of endophenotypes across diagnostic categories, further investigations of phenotypic overlap…
Nagarajan, Radhakrishnan; Clancy, Barbara
Statistical properties such as distribution and correlation signatures were investigated using a temporal database of common neurodevelopmental events in the three species most frequently used in experimental studies, rat, mouse, and macaque. There was a fine nexus between phylogenetic proximity and empirically derived dates of the occurrences of 40 common events including the neurogenesis of cortical layers and outgrowth milestones of developing axonal projections. Exponential and power-law approximations to the distribution of the events reveal strikingly similar decay patterns in rats and mice when compared to macaques. Subsequent hierarchical clustering of the common event timings also captures phylogenetic proximity, an association further supported by multivariate linear regression data. These preliminary results suggest that statistical analyses of the timing of developmental milestones may offer a novel measure of phylogenetic classifications. This may have added pragmatic value in the specific support it offers for the reliability of rat/mouse comparative modeling, as well as in the broader implications for the potential of meta-analyses using databases assembled from the extensive empirical literature.
Young, Christina B; Wu, Sarah S; Menon, Vinod
Math anxiety is a negative emotional reaction to situations involving mathematical problem solving. Math anxiety has a detrimental impact on an individual's long-term professional success, but its neurodevelopmental origins are unknown. In a functional MRI study on 7- to 9-year-old children, we showed that math anxiety was associated with hyperactivity in right amygdala regions that are important for processing negative emotions. In addition, we found that math anxiety was associated with reduced activity in posterior parietal and dorsolateral prefrontal cortex regions involved in mathematical reasoning. Multivariate classification analysis revealed distinct multivoxel activity patterns, which were independent of overall activation levels in the right amygdala. Furthermore, effective connectivity between the amygdala and ventromedial prefrontal cortex regions that regulate negative emotions was elevated in children with math anxiety. These effects were specific to math anxiety and unrelated to general anxiety, intelligence, working memory, or reading ability. Our study identified the neural correlates of math anxiety for the first time, and our findings have significant implications for its early identification and treatment.
Gropman, Andrea L; Batshaw, Mark L
The diagnostic evaluation of children with intellectual disability (ID) and other neurodevelopmental disabilities (NDD) has become increasingly complex in recent years owing to a number of newly recognized genetic mechanisms and sophisticated methods to diagnose them. Previous studies have attempted to address the diagnostic yield of finding a genetic cause in ID. The results have varied widely from 10% to 81%, with the highest percentage being found in studies using new array comparative genomic hybridization methodology especially in autism. Although many cases of ID/NDD result from chromosomal aneuploidy or structural rearrangements, single gene disorders and new categories of genome modification, including epigenetics and copy number variation play an increasingly important role in diagnosis and testing. Epigenetic mechanisms, such as DNA methylation and modifications to histone proteins, regulate high-order DNA structure and gene expression. Aberrant epigenetic and copy number variation mechanisms are involved in several neurodevelopmental and neurodegenerative disorders including Rett syndrome, fragile X syndrome, and microdeletion syndromes. This review will describe a number of the molecular genetic mechanisms that play a role in disorders leading to ID/NDD and will discuss the categories and technologies for diagnostic testing of these conditions.
Lambe, Laura; Mackinnon, Sean P; Stewart, Sherry H
The motivational model of alcohol use posits that individuals may consume alcohol to cope with negative affect. Conflict with others is a strong predictor of coping motives, which in turn predict alcohol-related problems. Two studies examined links between conflict, coping motives, and alcohol-related problems in emerging adult romantic dyads. It was hypothesized that the association between conflict and alcohol-related problems would be mediated by coping-depression and coping-anxiety motives. It was also hypothesized that this would be true for actor (i.e., how individual factors influence individual behaviors) and partner effects (i.e., how partner factors influence individual behaviors) and at the between- (i.e., does not vary over the study period) and within-subjects (i.e., varies over the study period) levels. Both studies examined participants currently in a romantic relationship who consumed ≥12 alcoholic drinks in the past year. Study 1 was cross-sectional using university students (N = 130 students; 86.9% female; M = 21.02 years old, SD = 3.43). Study 2 used a 4-wave, 4-week longitudinal design with romantic dyads (N = 100 dyads; 89% heterosexual; M = 22.13 years old, SD = 5.67). In Study 2, coping-depression motives emerged as the strongest mediator of the conflict-alcohol-related problems association, and findings held for actor effects but not partner effects. Supplemental analyses revealed that this mediational pathway only held among women. Within any given week, alcohol-related problems changed systematically in the same direction between romantic partners. Interventions may wish to target coping-depression drinking motives within couples in response to conflict to reduce alcohol-related problems.
Bronson, Stefanie L; Bale, Tracy L
Adversity experienced during gestation is a predictor of lifetime neuropsychiatric disease susceptibility. Specifically, maternal stress during pregnancy predisposes offspring to sex-biased neurodevelopmental disorders, including schizophrenia, attention deficit/hyperactivity disorder, and autism spectrum disorders. Animal models have demonstrated disease-relevant endophenotypes in prenatally stressed offspring and have provided unique insight into potential programmatic mechanisms. The placenta has a critical role in the deleterious and sex-specific effects of maternal stress and other fetal exposures on the developing brain. Stress-induced perturbations of the maternal milieu are conveyed to the embryo via the placenta, the maternal–fetal intermediary responsible for maintaining intrauterine homeostasis. Disruption of vital placental functions can have a significant impact on fetal development, including the brain, outcomes that are largely sex-specific. Here we review the novel involvement of the placenta in the transmission of the maternal adverse environment and effects on the developing brain. PMID:26250599
High risk drinking is linked with high rates of physical harm. The reported incidence of alcohol - related trauma among Aboriginal and Torres Strait Islander people in the Northern Territory is the highest in the world. Facial fractures are common among young Aboriginal and Torres Strait Islanders. They are often linked with misuse of alcohol in the Northern Territory and are frequently secondary to assault. This review focuses on alcohol-related trauma in the Territory and draws attention to an urgent need for preventative health approach to address this critical issue. PMID:22862897
Hafsteinsdottir, T; Algra, A; Kappelle, L; Grypdonck, M; on, b
Background: Neurodevelopmental treatment (NDT) is a rehabilitation approach increasingly used in the care of stroke patients, although no evidence has been provided for its efficacy. Objective: To investigate the effects of NDT on the functional status and quality of life (QoL) of patients with stroke during one year after stroke onset. Methods: 324 consecutive patients with stroke from 12 Dutch hospitals were included in a prospective, non-randomised, parallel group study. In the experimental group (n = 223), nurses and physiotherapists from six neurological wards used the NDT approach, while conventional treatment was used in six control wards (n = 101). Functional status was assessed by the Barthel index. Primary outcome was "poor outcome", defined as Barthel index <12 or death after one year. QoL was assessed with the 30 item version of the sickness impact profile (SA-SIP30) and the visual analogue scale. Results: At 12 months, 59 patients (27%) in the NDT group and 24 (24%) in the non-NDT group had poor outcome (corresponding adjusted odds ratio = 1.7 (95% confidence interval, 0.8 to 3.5)). At discharge the adjusted odds ratio was 0.8 (0.4 to 1.5) and after six months it was 1.6 (0.8 to 3.2). Adjusted mean differences in the two QoL measures showed no significant differences between the study groups at six or 12 months after stroke onset. Conclusions: The NDT approach was not found effective in the care of stroke patients in the hospital setting. Health care professionals need to reconsider the use of this approach. PMID:15897499
Autism spectrum disorder is a complex neurodevelopmental disorder, which is accompanied by differences in brain anatomy, functioning and brain connectivity. Due to its neurodevelopmental character, and the large phenotypic heterogeneity among individuals on the autism spectrum, the neurobiology of autism spectrum disorder is inherently difficult…
Navarro, Héctor José; Shakeshaft, Anthony; Doran, Christopher M; Petrie, Dennis J
Approximately half of all alcohol-related crime is violent crime associated with heavy episodic drinking. Multi-component interventions are highly acceptable to communities and may be effective in reducing alcohol-related crime generally, but their impact on alcohol-related violent crime has not been examined. This study evaluated the impact and benefit-cost of a multi-component intervention (increasing community and liquor licensees' awareness, police activity, and feedback) on crimes typically associated with alcohol-related violence. The intervention was tailored to weekends identified as historically problematic in 10 experimental communities in NSW, Australia, relative to 10 control ones. There was no effect on alcohol-related assaults and a small, but statistically significant and cost-beneficial, effect on alcohol-related sexual assaults: a 64% reduction in in the experimental relative to control communities, equivalent to five fewer alcohol-related sexual assaults, with a net social benefit estimated as AUD$3,938,218. The positive benefit-cost ratio was primarily a function of the value that communities placed on reducing alcohol-related harm: the intervention would need to be more than twice as effective for its economic benefits to be comparable to its costs. It is most likely that greater reductions in crimes associated with alcohol-related violence would be achieved by a combination of complementary legislative and community-based interventions.
Andsager, Julie L.; Austin, Erica Weintraub; Pinkleton, Bruce E.
Finds that: (1) perceived realism and themes that students could identify with are important factors in increasing the salience and persuasiveness of alcohol-related public service announcements (PSAs) among undergraduate students; (2) realistic but logic-based PSAs were not as effective as unrealistic but enjoyable ads; and (3) low production…
Pedersen, Eric R.; Skidmore, Jessica R.; Aresi, Giovanni
Objective: Study abroad students are at risk for increased and problematic drinking behavior. As few efforts have been made to examine this at-risk population, the authors predicted drinking and alcohol-related consequences abroad from predeparture and site-specific factors. Participants: The sample consisted of 339 students completing study…
Doumas, Diana M.; Nelson, Kinsey; DeYoung, Amanda; Renteria, Camryn Conrad
This study evaluated the effectiveness of a web-based personalized feedback program using an objective measure of alcohol-related consequences. Participants were assigned to either the intervention group or an assessment-only control group during university orientation. Sanctions received for campus alcohol policy violations were tracked over the…
Durkin, Keith F.; Blackston, Amber; Dowd, Sabrina; Franz, Shalleigh; Eagle, Trevor
The purpose of this study was to examine the comparative influences of various protective and risk factors on the alcohol-related problems of a sample of university students. The conceptualization of these protective and risk factors in the current undertaking was informed by problem behavior theory, and draws heavily on two sociological theories…
Rothman, Emily F.; Dejong, William; Palfai, Tibor; Saitz, Richard
This study investigated the relationship between age of first drink (AFD) and a broad range of negative alcohol-related outcomes among college students exhibiting unhealthy alcohol use. We conducted an anonymous on-line survey to collect self-report data from first-year college students at a large northeastern university. Among 1,792 respondents…
Pearson, Matthew R.; Kite, Benjamin A.; Henson, James M.
In the present study, we examined whether the use of protective behavioral strategies (PBS) mediates the effects of impulsivity-like traits on alcohol-related problems using a sample of 278 college students. Validating the 5-factor model of impulsivity, we showed that each impulsivity-like trait had a distinct pattern of relationships with PBS…
Howard, Elizabeth; And Others
This teacher's manual presents lesson plans for a high-school instructional unit on Fetal Alcohol Syndrome and its less severe manifestations, Alcohol-Related Birth Defects. The lessons cover alcohol's effects during pregnancy, the history of concern about alcohol's effects, consequences of alcohol use in pregnancy, lifestyle risk reduction, and…
Caetano, Raul; Vaeth, Patrice A. C.; Rodriguez, Lori A.
The purpose of this study was to examine the association between acculturation, birthplace, and alcohol-related social problems across Hispanic national groups. A total of 5,224 Hispanic adults (18+ years) were interviewed using a multistage cluster sample design in Miami, New York, Philadelphia, Houston, and Los Angeles. Multivariate analysis…
Mallett, Kimberly A.; Varvil-Weld, Lindsey; Borsari, Brian; Read, Jennifer P.; Neighbors, Clayton; White, Helene R.
The objective of this review is to provide an update on existing research examining alcohol-related consequences among college students with relevance for individual-based interventions. While alcohol-related consequences have been a focus of study for several decades, the literature has evolved into an increasingly nuanced understanding of individual and environmental circumstances that contribute to risk for experiencing consequences. A number of risk factors for experiencing alcohol-related consequences have been identified, including belonging to specific student subgroups (e.g., Greek organizations) or drinking during high-risk periods, such as spring break. In addition, the relationship between students’ evaluations of both negative and positive consequences and their future drinking behavior has become a focus of research. The current review provides an overview of high-risk student subpopulations, high-risk windows and activities, and college students’ subjective evaluations of alcohol related consequences. Future directions for research are discussed and include determining how students’ orientations toward consequences change over time, identifying predictors of membership in high-risk consequence subgroups, and refining existing measures of consequences to address evolving research questions. PMID:23241024
Hummer, Justin F.; Pedersen, Eric R.; Mirza, Tehniat; LaBrie, Joseph W.
This study contributes to the scarce research on U.S. college students studying abroad by documenting general and sexual negative alcohol-related risks and factors associated with such risk. The manner of drinking (quantity vs. frequency), pre-departure expectations surrounding alcohol use while abroad, culture-related social anxiety, and…
Background The incidence of mandibular fractures in the Northern Territory of Australia is very high, especially among Indigenous people. Alcohol intoxication is implicated in the majority of facial injuries, and substance use is therefore an important target for secondary prevention. The current study tests the efficacy of a brief therapy, Motivational Care Planning, in improving wellbeing and substance misuse in youth and adults hospitalised with alcohol-related facial trauma. Methods and design The study is a randomised controlled trial with 6 months of follow-up, to examine the effectiveness of a brief and culturally adapted intervention in improving outcomes for trauma patients with at-risk drinking admitted to the Royal Darwin Hospital maxillofacial surgery unit. Potential participants are identified using AUDIT-C questionnaire. Eligible participants are randomised to either Motivational Care Planning (MCP) or Treatment as Usual (TAU). The outcome measures will include quantity and frequency of alcohol and other substance use by Timeline Followback. The recruitment target is 154 participants, which with 20% dropout, is hoped to provide 124 people receiving treatment and follow-up. Discussion This project introduces screening and brief interventions for high-risk drinkers admitted to the hospital with facial trauma. It introduces a practical approach to integrating brief interventions in the hospital setting, and has potential to demonstrate significant benefits for at-risk drinkers with facial trauma. Trial Registration The trial has been registered in Australian New Zealand Clinical Trials Registry (ANZCTR) and Trial Registration: ACTRN12611000135910. PMID:23106916
Nguyen, Van Anh; Le, Tran; Tong, Ming; Silbermann, Elizabeth; Gundogan, Fusun; de la Monte, Suzanne M.
Alcohol-related myopathy (Alc-M) is highly prevalent among heavy drinkers, although its pathogenesis is not well understood. We hypothesize that Alc-M is mediated by combined effects of insulin/IGF resistance and oxidative stress, similar to the effects of ethanol on liver and brain. We tested this hypothesis using an established model in which adult rats were pair-fed for 8 weeks with isocaloric diets containing 0% (N = 8) or 35.5% (N = 13) ethanol by caloric content. Gastrocnemius muscles were examined by histology, morphometrics, qRT-PCR analysis, and ELISAs. Chronic ethanol feeding reduced myofiber size and mRNA expression of IGF-1 polypeptide, insulin, IGF-1, and IGF-2 receptors, IRS-1, and IRS-2. Multiplex ELISAs demonstrated ethanol-associated inhibition of insulin, IRS-1, Akt, and p70S6K signaling, and increased activation of GSK-3β. In addition, ethanol-exposed muscles had increased 4-hydroxy-2-nonenal immunoreactivity, reflecting lipid peroxidation, and reduced levels of mitochondrial Complex IV, Complex V, and acetylcholinesterase. These results demonstrate that experimental Alc-M is associated with inhibition of insulin/IGF/IRS and downstream signaling that mediates metabolism and cell survival, similar to findings in alcoholic liver and brain degeneration. Moreover, the increased oxidative stress, which could be mediated by mitochondrial dysfunction, may have led to inhibition of acetylcholinesterase, which itself is sufficient to cause myofiber atrophy and degeneration. PMID:23016132
Miller, Cameron A; Parrott, Dominic J; Giancola, Peter R
This study investigated the mediating effect of trait aggressivity on the relation between agreeableness and alcohol-related aggression in a laboratory setting. Participants were 116 healthy male social drinkers between 21 and 30 years of age. Agreeableness and trait aggressivity were measured using the Big Five Inventory and the Buss-Perry Aggression Questionnaire, respectively. Following the consumption of an alcohol or no-alcohol control beverage, participants completed a modified version of the Taylor Aggression Paradigm, in which electric shocks were received from and administered to a fictitious opponent during a competitive task. Aggression was operationalized as the proportion of the most extreme shocks delivered to the fictitious opponent under conditions of low and high provocation. Results indicated that lower levels of agreeableness were associated with higher levels of trait aggressivity. In turn, higher levels of trait aggressivity predicted extreme aggression in intoxicated, but not sober, participants under low, but not high, provocation. Findings highlight the importance of examining determinants of intoxicated aggression within a broader theoretical framework of personality.
Kenney, Shannon R.; Lac, Andrew; LaBrie, Joseph W.; Hummer,, Justin F.; Pham, Andy
Objective: Poor mental health, sleep problems, drinking motivations, and high-risk drinking are prevalent among college students. However, research designed to explicate the interrelationships among these health risk behaviors is lacking. This study was designed to assess the direct and indirect influences of poor mental health (a latent factor consisting of depression, anxiety, and stress) to alcohol use and alcohol-related consequences through the mediators of global sleep quality and drinking motives in a comprehensive model. Method: Participants were 1,044 heavy-drinking college students (66.3% female) who completed online surveys. Results: A hybrid structural equation model tested hypotheses involving relations leading from poor mental health to drinking motives and poorer global sleep quality to drinking outcomes. Results showed that poor mental health significantly predicted all four subscales of drinking motivations (social, coping, conformity, and enhancement) as well as poor sleep. Most of the drinking motives and poor sleep were found to explain alcohol use and negative alcohol consequences. Poor sleep predicted alcohol consequences, even after controlling for all other variables in the model. The hypothesized mediational pathways were examined with tests of indirect effects. Conclusions: This is the first study to assess concomitantly the relationships among three vital health-related domains (mental health, sleep behavior, and alcohol risk) in college students. Findings offer important implications for college personnel and interventionists interested in reducing alcohol risk by focusing on alleviating mental health problems and poor sleep quality. PMID:24172110
Morgan, M Y; Ross, M G; Ng, C M; Adams, D M; Thomas, H C; Sherlock, S
Ninety-two British, caucasian, alcoholic patients with liver disese were grouped on the basis of hepatic histology into fatty change, hepatitis with or without cirrhosis, and cirrhosis alone. Men with alcoholic hepatitis with or without cirrhosis showed an increased incidence of the histocompatibility antigen HLA-B8 (P less than 0.02). Increased measles antibody titres were found in patients without cirrhosis with or without hepatitis and were associated with the B8 phenotype in both sexes. Rubella antibody titres and percentage DNA-binding were raised in patients with cirrhosis and showed no association with the B8 phenotype. Concentrations of IgM and IgA were were raised in patients with stetosis and with hepatitis, while in patients with cirrhosis IgG concentrations were also increased. Low titres of autoantibodies were found in all histological groups. It is possible that the development of hepatitis in response to alcohol abuse may be influenced, at least in men, by a gene linked to the B locus. Otherwise, immune processes associated with alcohol-related liver disease are probably secondary phenomena. PMID:7400347
Giancola, Peter R; Parrott, Dominic J
The goals of this study were to determine the effects of past-year stimulant and sedative drug use on alcohol-related aggression and to examine whether the relation between stimulant drug use and intoxicated aggression is better accounted for by behavioral disinhibition. Participants were 330 healthy social drinkers (164 men and 166 women) between 21 and 35 years of age. Past-year stimulant and sedative use and behavioral disinhibition were assessed via self-report questionnaires. Following the consumption of either an alcohol or a placebo beverage, participants were tested on a modified version of the Taylor Aggression Paradigm [Taylor, S. (1967). Aggressive behavior and physiological arousal as a function of provocation and the tendency to inhibit aggression. Journal of Personality, 35, 297-310] in which mild electric shocks were received from, and administered to, a fictitious opponent. Aggressive behavior was operationalized as the shock intensities administered to the fictitious opponent under conditions of low and high provocation. Results indicated that alcohol significantly strengthened the relation between stimulant drug use and aggression, but only among men. Behavioral disinhibition did not account for this effect. Regardless of past-year drug use, alcohol did not facilitate aggression among women. The present findings suggest that stimulant drug use may be a risk factor for intoxicated aggression for men. However, the underlying mechanisms accounting for this effect remain unclear.
Balbo, Silvia; Brooks, Philip J
Among various potential mechanisms that could explain alcohol carcinogenicity, the metabolism of ethanol to acetaldehyde represents an obvious possible mechanism, at least in some tissues. The fundamental principle of genotoxic carcinogenesis is the formation of mutagenic DNA adducts in proliferating cells. If not repaired, these adducts can result in mutations during DNA replication, which are passed on to cells during mitosis. Consistent with a genotoxic mechanism, acetaldehyde does react with DNA to form a variety of different types of DNA adducts. In this chapter we will focus more specifically on N2-ethylidene-deoxyguanosine (N2-ethylidene-dG), the major DNA adduct formed from the reaction of acetaldehyde with DNA and specifically highlight recent data on the measurement of this DNA adduct in the human body after alcohol exposure. Because results are of particular biological relevance for alcohol-related cancer of the upper aerodigestive tract (UADT), we will also discuss the histology and cytology of the UADT, with the goal of placing the adduct data in the relevant cellular context for mechanistic interpretation. Furthermore, we will discuss the sources and concentrations of acetaldehyde and ethanol in different cell types during alcohol consumption in humans. Finally, in the last part of the chapter, we will critically evaluate the concept of carcinogenic levels of acetaldehyde, which has been raised in the literature, and discuss how data from acetaldehyde genotoxicity are and can be utilized in physiologically based models to evaluate exposure risk.
Nguyen, Van Anh; Le, Tran; Tong, Ming; Silbermann, Elizabeth; Gundogan, Fusun; de la Monte, Suzanne M
Alcohol-related myopathy (Alc-M) is highly prevalent among heavy drinkers, although its pathogenesis is not well understood. We hypothesize that Alc-M is mediated by combined effects of insulin/IGF resistance and oxidative stress, similar to the effects of ethanol on liver and brain. We tested this hypothesis using an established model in which adult rats were pair-fed for 8 weeks with isocaloric diets containing 0% (N = 8) or 35.5% (N = 13) ethanol by caloric content. Gastrocnemius muscles were examined by histology, morphometrics, qRT-PCR analysis, and ELISAs. Chronic ethanol feeding reduced myofiber size and mRNA expression of IGF-1 polypeptide, insulin, IGF-1, and IGF-2 receptors, IRS-1, and IRS-2. Multiplex ELISAs demonstrated ethanol-associated inhibition of insulin, IRS-1, Akt, and p70S6K signaling, and increased activation of GSK-3β. In addition, ethanol-exposed muscles had increased 4-hydroxy-2-nonenal immunoreactivity, reflecting lipid peroxidation, and reduced levels of mitochondrial Complex IV, Complex V, and acetylcholinesterase. These results demonstrate that experimental Alc-M is associated with inhibition of insulin/IGF/IRS and downstream signaling that mediates metabolism and cell survival, similar to findings in alcoholic liver and brain degeneration. Moreover, the increased oxidative stress, which could be mediated by mitochondrial dysfunction, may have led to inhibition of acetylcholinesterase, which itself is sufficient to cause myofiber atrophy and degeneration.
Background Although there have been a wide range of epidemiological studies examining the impact of patterns of alcohol consumption among adolescents, there remains considerable variability in both defining these patterns and the ability to comprehensively evaluate their relationship to behavioural patterns. This study explores a new procedure for defining and evaluating drinking patterns and integrating well-established indicators. The composite measure is then used to estimate the impact of these patterns on alcohol-related aggressive behaviour among Italian adolescents. Methods Data were collected as part of the 2011 European School Survey Project on Alcohol and other Drugs (ESPAD). A national sample of 14,199 students aged 15–19 years was collected using an anonymous, self-administered questionnaire completed in a classroom setting. Drinking patterns were established using principal component analysis. Alcohol-related aggression was analysed as to its relationship to patterns of drinking, behaviour of friends towards alcohol use, substance use/abuse, school performance, family relationships and leisure activities. Results Several specific drinking patterns were identified: “Drinking to Excess” (DE), “Drinking with Intoxication” (DI) and “Drinking but Not to Excess” (DNE). A higher percentage of males were involved in alcohol-related aggression compared with females. In males, the DE and DI patterns significantly increased the likelihood of alcohol-related aggression, whereas the DNE pattern was negatively associated. Similar results were found in females, although the DI pattern was not significantly associated with alcohol-related aggression. Overall, cigarette smoking, illegal drug use, truancy, limited parental monitoring, frequent evenings spent outside of the home and peer influence associated strongly with alcohol-related aggression. Conclusions Our findings suggest that drinking patterns, as uniquely monitored with an integrated metric
Morriss, Frank H.; Saha, Shampa; Bell, Edward F.; Colaizy, Tarah T.; Stoll, Barbara J.; Hintz, Susan R.; Shankaran, Seetha; Vohr, Betty R.; Hamrick, Shannon E. G.; Pappas, Athina; Jones, Patrick M.; Carlo, Waldemar A.; Laptook, Abbot R.; Van Meurs, Krisa P.; Sánchez, Pablo J.; Hale, Ellen C.; Newman, Nancy S.; Das, Abhik; Higgins, Rosemary D.
IMPORTANCE Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine. OBJECTIVE To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low birth weight infants. DESIGN Retrospective cohort analysis of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998–2009 and evaluated at 18–22 months’ corrected age. SETTING 22 academic neonatal intensive care units. PARTICIPANTS Inclusion criteria were: birth weight 401–1500 g; survival to 12 hours; available for follow-up. Some conditions were excluded. 12 111 infants were included in analyses, 87% of those eligible. EXPOSURES Surgical procedures; surgery also classified by expected anesthesia type as major (general anesthesia) or minor surgery (non-general anesthesia). MAIN OUTCOME MEASURES Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted means of Bayley Scales of Infant Development, Second Edition, Mental Developmental Index and Psychomotor Developmental Index for patients born before 2006. RESULTS There were 2186 major, 784 minor and 9141 no surgery patients. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% confidence interval 1.08–1.55). For patients who had major surgery compared with those who had no surgery the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% confidence interval 1.24–1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery
Trulioff, Andrey; Ermakov, Alexander; Malashichev, Yegor
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
Thapar, Anita; Cooper, Miriam
Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a prevalence of 1·4-3·0%. It is more common in boys than girls. Comorbidity with childhood-onset neurodevelopmental disorders and psychiatric disorders is substantial. ADHD is highly heritable and multifactorial; multiple genes and non-inherited factors contribute to the disorder. Prenatal and perinatal factors have been implicated as risks, but definite causes remain unknown. Most guidelines recommend a stepwise approach to treatment, beginning with non-drug interventions and then moving to pharmacological treatment in those most severely affected. Randomised controlled trials show short-term benefits of stimulant medication and atomoxetine. Meta-analyses of blinded trials of non-drug treatments have not yet proven the efficacy of such interventions. Longitudinal studies of ADHD show heightened risk of multiple mental health and social difficulties as well as premature mortality in adult life.
Tao, Weiyuan; Lu, Zuneng; Wen, Fang
Neurodevelopmental treatment is an advanced therapeutic approach for the neural rehabilitation of children with cerebral palsy. Cerebral palsy represents a spectrum of neurological disorders primarily affecting gross motor function. The authors investigated the effects of neurodevelopmental treatment on serum levels of transforming growth factor-β1 (TGF-β1), a neuroprotective cytokine, and improvements to motor skills. Serum TGF-β1 levels and total score of the Gross Motor Function Measure-88 (GMFM-88) were significantly higher in children with cerebral palsy who underwent neurodevelopmental treatment compared to untreated patients (P < .01). Furthermore, the improved GMFM-88 total scores after neurodevelopmental treatment were significantly higher in children under the age of 3 with cerebral palsy than in older patients (P < .01). The authors demonstrate that the integration of TGF-β1 levels and GMFM-88 total score could be used to assess the efficacy of neurodevelopmental treatment. Moreover, the findings provide further scientific support for the early intervention and neurological rehabilitation of young children with cerebral palsy.
Iwamoto, Derek Kenji; Kaya, Aylin; Grivel, Margaux; Clinton, Lauren
, traditional norms that may directly pertain to hyperfemininzed Asian-American women, including modesty and sexual fidelity, may protect against heavy episodic drinking (Young et al. 2005). Conversely, the risk for heavy episodic drinking may be enhanced in men who strive to demonstrate traditional notions of masculinity through risk-taking and endorsement of playboy norms (Iwamoto et al. 2010). Although this review has illustrated the contemporary state of research on alcohol use among Asian Americans, it also highlights the significant limitations in this literature. Many of the studies reviewed here have used cross-sectional data, which do not allow researchers to infer causality between the various sociocultural factors and problematic alcohol use. One way of addressing this gap in the existing literature may be to implement longitudinal designs to further understand how the temporal relationship between sociocultural factors, including acculturation and gender norms, may impact alcohol use and alcohol-related problem trajectories. There also is a pressing need to develop greater understanding of within-group differences among U.S.-born and foreign-born Asian Americans as well as among as specific ethnic groups. To date, epidemiological research has largely neglected to examine these significant discrepancies. Given the growing prevalence of alcohol use and alcohol-related problems among Asian-American women (Grant et al. 2004; Iwamoto et al. 2010), studies also should focus on this group and explore how the intersection of gender and culture may influence alcohol use. Finally, the majority of research on this population has been conducted in college samples; therefore, it is important to also examine community samples, including U.S.-born young adults who are not attending college and older adult Asian-American populations.
Skardhamar, Torbjørn; Skirbekk, Vegard
Background Registered offenders are known to have a higher mortality rate, but given the high proportion of offenders with drug-addiction, particularly among offenders with a custodial sentence, higher mortality is expected. While the level of overall mortality compared to the non-criminal population is of interest in itself, we also estimate the risk of death by criminal records related to substance abuse and other types of criminal acts, and separate between those who receive a prison sentence or not. Methods Age-adjusted relative risks of death for 2000–2008 were studied in a population based dataset. Our dataset comprise the total Norwegian population of 2.9 million individuals aged 15–69 years old in 1999, of whom 10% had a criminal record in the 1992–1999 period. Results Individuals with a criminal record have twice the relative risk (RR) of death of the control group (non-offenders). Males with a record of use/possession of drugs and a prison record have an 11.9 RR (females, 15.6); males with a drug record but no prison record have a 6.9 RR (females 10.5). Males imprisoned for driving under the influence of substances have a 4.4 RR (females 5.6); males with a record of driving under the influence but no prison sentence have a 3.2 RR (females 6.5). Other male offenders with a prison record have a 2.8 RR (females 3.7); other male offenders with no prison record have a 1.7 RR (females 2.3). Conclusion Significantly higher mortality was found for people with a criminal record, also for those without any record of drug use. Mortality is much higher for those convicted of substance-related crimes: more so for drug- than for alcohol-related crimes and for women. PMID:24223171
Menary, Kyle R.; Corbin, William R.; Leeman, Robert F.; Fucito, Lisa M.; Toll, Benjamin A.; DeMartini, Kelly; O’Malley, Stephanie S.
Background Although drinking for tension reduction has long been posited as a risk factor for alcohol-related problems, studies investigating anxiety in relation to risk for alcohol problems have returned inconsistent results, leading researchers to search for potential moderators. Negative urgency (the tendency to become behaviorally dysregulated when experiencing negative affect) is a potential moderator of theoretical interest because it may increase risk for alcohol problems among those high in negative affect. The present study tested a cross-sectional mediated moderation hypothesis whereby an interactive effect of anxiety and negative urgency on alcohol problems is mediated through coping-related drinking motives. Method The study utilized baseline data from a hazardously drinking sample of young adults (N = 193) evaluated for participation in a randomized controlled trial of naltrexone and motivational interviewing for drinking reduction. Results The direct effect of anxiety on physiological dependence symptoms was moderated by negative urgency such that the positive association between anxiety and physiological dependence symptoms became stronger as negative urgency increased. Indirect effects of anxiety and negative urgency on alcohol problems (operating through coping motives) were also observed. Conclusions Although results of the current cross-sectional study require replication using longitudinal data, the findings suggest that the simultaneous presence of anxiety and negative urgency may be an important indicator of risk for AUDs via both direct interactive effects and indirect additive effects operating through coping motives. These findings have potentially important implications for prevention/intervention efforts for individuals who become disinhibited in the context of negative emotional states. PMID:26031346
Haighton, Catherine; Wilson, Graeme; Ling, Jonathan; McCabe, Karen; Crosland, Ann; Kaner, Eileen
Aims Epidemiological surveys over the last 20 years show a steady increase in the amount of alcohol consumed by older age groups. Physiological changes and an increased likelihood of health problems and medication use make older people more likely than younger age groups to suffer negative consequences of alcohol consumption, often at lower levels. However, health services targeting excessive drinking tend to be aimed at younger age groups. The aim of this study was to gain an in-depth understanding of experiences of, and attitudes towards, support for alcohol related health issues in people aged 50 and over. Methods Qualitative interviews (n = 24, 12 male/12 female, ages 51–90 years) and focus groups (n = 27, 6 male/21 female, ages 50–95 years) were carried out with a purposive sample of participants who consumed alcohol or had been dependent. Findings Participants’ alcohol misuse was often covert, isolated and carefully regulated. Participants tended to look first to their General Practitioner for help with alcohol. Detoxification courses had been found effective for dependent participants but only in the short term; rehabilitation facilities were appreciated but seen as difficult to access. Activities, informal groups and drop-in centres were endorsed. It was seen as difficult to secure treatment for alcohol and mental health problems together. Barriers to seeking help included functioning at a high level, concern about losing positive aspects of drinking, perceived stigma, service orientation to younger people, and fatalistic attitudes to help-seeking. Facilitators included concern about risk of fatal illness or pressure from significant people. Conclusion Primary care professionals need training on improving the detection and treatment of alcohol problems among older people. There is also a compelling need to ensure that aftercare is in place to prevent relapse. Strong preferences were expressed for support to be provided by those who had experienced
Foroud, T; Bucholz, K K; Edenberg, H J; Goate, A; Neuman, R J; Porjesz, B; Koller, D L; Rice, J; Reich, T; Bierut, L J; Cloninger, C R; Nurnberger, J I; Li, T K; Conneally, P M; Tischfield, J A; Crowe, R; Hesselbrock, V; Schuckit, M; Begleiter, H
There is substantial evidence for a significant genetic component to the risk for alcoholism. In searching for genes that contribute to this risk, the diagnostic criteria for alcohol dependence may not be the optimal phenotype; rather, creation of a more homogeneous phenotype will lead to a more homogeneous genetic etiology. Items from the Semi-Structured Assessment for the Genetics of Alcoholism collected from 830 individuals in 105 alcoholic families were used in a latent class analysis to identify a more homogeneous alcoholism-related phenotype. A four-class solution was chosen: class 1, unaffected group; class 2, mildly problematic group; class 3, moderately affected group; and class 4, severely affected group. Classes 3 and 4 had higher symptom endorsement probabilities than classes 1 and 2 for items reflecting severe alcohol dependence, and were combined to provide enough sibling pairs for genetic linkage analysis. A total of 291 markers distributed throughout the genome, with an average intermarker distance of 14 cM, were genotyped. Linkage analysis was performed to detect loci underlying classes 3 and 4, the moderately and severely affected alcoholics, of whom 88% met the Collaborative Study of the Genetics of Alcoholism, and >99% met ICD-10 criteria for alcohol dependence. Evidence for a locus on chromosome 16, near the marker D16S675, was found with a maximum multipoint lod score of 4.0. Analysis of additional markers on chromosome 16 yielded a lod score of 3.2, narrowed the critical region, and placed the gene between D16S475 and D16S675 in a 15 cM interval.
Bobak, Martin; Malyutina, Sofia; Horvat, Pia; Pajak, Andrzej; Tamosiunas, Abdonas; Kubinova, Ruzena; Simonova, Galina; Topor-Madry, Roman; Peasey, Anne; Pikhart, Hynek; Marmot, Michael G
Alcohol has been implicated in the high mortality in Central and Eastern Europe but the magnitude of its effect, and whether it is due to regular high intake or episodic binge drinking remain unclear. The aim of this paper was to estimate the contribution of alcohol to mortality in four Central and Eastern European countries. We used data from the Health, Alcohol and Psychosocial factors in Eastern Europe is a prospective multi-centre cohort study in Novosibirsk (Russia), Krakow (Poland), Kaunas (Lithuania) and six Czech towns. Random population samples of 34,304 men and women aged 45-69 years in 2002-2005 were followed up for a median 7 years. Drinking volume, frequency and pattern were estimated from the graduated frequency questionnaire. Deaths were ascertained using mortality registers. In 230,246 person-years of follow-up, 2895 participants died from all causes, 1222 from cardiovascular diseases (CVD), 672 from coronary heart disease (CHD) and 489 from pre-defined