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1.
Psychol Med ; : 1-10, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31736455

RESUMO

BACKGROUND: Subclinical adolescent alcohol use is highly prevalent and may have deleterious effects on important psychosocial and brain outcomes. Prior research has focused on identifying endophenotypes of pathological drinking, and the predictors of normative drinking remain understudied. This study investigated the incremental predictive value of two potential psychophysiological endophenotypes, P3 amplitude (an index of decision making) and midfrontal theta power (a correlate of attentional control), for prospectively predicting the expression and initiation of alcohol use emerging in adolescence. METHODS: A large (N = 594) epidemiological sample was prospectively assessed at ages 11/14/17. Alcohol/substance use was assessed at all ages via a computerized self-report inventory. EEG was recorded at age-14 during a visual oddball task to elicit P3 and theta. RESULTS: Reduced target-related P3 and theta at age-14 prospectively predicted drinking at age-17 independent of one another. Among alcohol-naive individuals at age-14, attenuated P3 and theta increased the odds of new-onset alcohol behaviors 3 years later. Importantly, the endophenotypes provided significant incremental predictive power of future non-clinical alcohol use beyond relevant risk factors (prior alcohol use; tobacco/illicit drug initiation; parental alcohol use disorder). CONCLUSIONS: The current report is the first of our knowledge to demonstrate that deviations in parietal P3 and midfrontal theta prospectively predict the emergence of normative/non-pathological drinking. P3 and theta provide modest yet significant explanatory variance beyond prominent self-report and familial risk measures. Findings offer strong evidence supporting the predictive utility of P3 and theta as candidate endophenotypes for adolescent drinking.

2.
Nat Commun ; 10(1): 4679, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616000

RESUMO

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.

3.
Twin Res Hum Genet ; 22(5): 290-296, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31559947

RESUMO

Genetically informative research designs are becoming increasingly popular as a way to strengthen causal inference with their ability to control for genetic and shared environmental confounding. Co-twin control (CTC) models, a special case of these designs using twin samples, decompose the overall effect of exposure on outcome into a within- and between-twin-pair term. Ideally, the within-twin-pair term would serve as an estimate of the exposure effect controlling for genetic and shared environmental factors, but it is often confounded by factors not shared within a twin-pair. Previous simulation work has shown that if twins are less similar on an unmeasured confounder than they are on an exposure, the within-twin-pair estimate will be a biased estimate of the exposure effect, even more biased than the individual, unpaired estimate. The current study uses simulation and analytical derivations to show that while incorporating a covariate related to the nonshared confounder in CTC models always reduces bias in the within-pair estimate, it will be less biased than the individual estimate only in a narrow set of circumstances. The best case for bias reduction in the within-pair estimate occurs when the within-twin-pair correlation in exposure is less than the correlation in the confounder and the twin-pair correlation in the covariate is high. Additionally, the form of covariate inclusion is compared between adjustment for only one's own covariate value and adjustment for the deviation of one's own value from the covariate twin-pair mean. Results show that adjusting for the deviation from the twin-pair mean results in equal or reduced bias.

4.
Pediatr Neurol ; 100: 92-96, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31376926

RESUMO

BACKGROUND: Acute hemorrhagic leukoencephalopathy is a rare encephalopathy of unknown etiology, causing fulminant, hemorrhagic central nervous system demyelination with high mortality. It is unclear whether acute hemorrhagic leukoencephalopathy is an entirely distinct entity from acute disseminated encephalomyelitis. PATIENTS AND METHODS: We report two patients with rapidly progressive neurological illness resulting in raised intracranial pressure and coma, with biopsy-proven acute hemorrhagic leukoencephalopathy (perivascular hemorrhages and demyelination, predominantly neutrophil infiltrates). RESULTS: Acute cerebrospinal fluid showed pronounced T cell-associated cytokine elevation (interleukins 6, 8, and 17A) and CCL2 or CCL3, higher than in patients with acute disseminated encephalomyelitis, but no B cell-associated cytokine elevation. CONCLUSION: Improved understanding of the immune process may provide rationale for use of anticytokine biologic agents.

5.
Psychophysiology ; 56(9): e13392, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31081153

RESUMO

Brain mechanisms linked to incorrect response selections made under time pressure during cognitive task performance are poorly understood, particularly in adolescents with attention-deficit hyperactivity disorder (ADHD). Using subject-specific multimodal imaging (electroencephalogram, magnetic resonance imaging, behavior) during flanker task performance by a sample of 94 human adolescents (mean age = 15.5 years, 50% female) with varying degrees of ADHD symptomatology, we examined the degree to which amplitude features of source-resolved event-related potentials (ERPs) from brain-independent component processes within a critical (but often ignored) period in the action selection process, the stimulus-response interval, were associated with motor response errors (across trials) and error rates (across individuals). Response errors were typically preceded by two smaller peaks in both trial-level and trial-averaged ERP projections from posterior medial frontal cortex (pMFC): a frontocentral P3 peaking about 390 ms after stimulus onset, and a premovement positivity (PMP) peaking about 110 ms before the motor response. Separating overlapping stimulus-locked and response-locked ERP contributions using a "regression ERP" approach showed that trial errors and participant error rates were primarily associated with smaller PMP, and not with frontocentral P3. Moreover, smaller PMP mediated the association between larger numbers of errors and ADHD symptoms, suggesting the possible value of using PMP as an intervention target to remediate performance deficits in ADHD.

6.
Psychophysiology ; 56(8): e13383, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31012496

RESUMO

Theoretical and empirical work suggests that problematic substance use (PSU) is associated with individual differences in prefrontal cortex activity. While research has strongly linked parietal P3 amplitude reduction (P3AR) to genetic risk for problematic substance use, few studies have tested whether prefrontal EEG measures are sensitive to this genetic liability. In addition to P3, oddball target detection tasks elicit medial frontal theta power, reflecting attentional allocation, and parietal delta, indexing decision making or stimulus-response link updating. Midfrontal theta and parietal delta may index neurocognitive processes relevant to PSU beyond P3AR. The present investigation examined the etiological relationship between PSU and P3, frontal theta, and parietal delta in a large twin sample (N = 754). EEG was recorded during a visual oddball task. Greater PSU was associated with reduced target P3 amplitude and midfrontal theta/parietal delta power, and increased mean reaction time and reaction time variability (RTV; indexing attentional fluctuations). P3, theta, and RTV, but not delta or mean RT, explained unique variance in PSU (R2  = 0.04). Twin biometric modeling indicated a genetic relationship between PSU and P3, theta, and RTV. Theta accounted for distinct genetic variance in PSU beyond P3 and RTV. Together, 23% of the total additive genetic variance in PSU was explained by the three endophenotypes. Results replicate P3AR as an endophenotype and provide support for additional behavioral (RTV) and neurophysiological (midfrontal theta) endophenotypes of PSU. Reduced theta and greater RTV may reflect variations in a prefrontal attentional network that confers genetic risk for substance use problems.

7.
Neurology ; 92(2): e96-e107, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30541864

RESUMO

OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.


Assuntos
Deficiências do Desenvolvimento/genética , Mutação/genética , Espasmos Infantis/genética , Proteínas Ativadoras de ras GTPase/genética , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encefalopatias/complicações , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico por imagem , Eletroencefalografia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Espasmos Infantis/complicações , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/tratamento farmacológico , Adulto Jovem
8.
Biol Psychol ; 139: 25-38, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30300674

RESUMO

Diminished cognitive control in alcohol use disorder (AUD) is thought to be mediated by prefrontal cortex circuitry dysregulation. Research testing the relationship between AUD and specific cognitive control psychophysiological correlates, such as medial frontal (MF) theta-band EEG power, is scarce, and the etiology of this relationship is largely unknown. The current report tested relationship between pathological alcohol use through young adulthood and reduced conflict-related theta at age 29 in a large prospective population-based twin sample. Greater lifetime AUD symptomatology was associated with reduced MF theta power during response conflict, but not alpha-band visual attention processing. Follow-up analyses using cotwin control analysis and biometric modeling suggested that genetic influences, and not the consequences of sustained AUD symptomatology, explained the theta-AUD association. Results provide strong evidence that AUD is genetically related to diminished conflict-related MF theta, and advance MF theta as a promising electrophysiological correlate of AUD-related dysfunctional frontal circuitry.

9.
Dev Med Child Neurol ; 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30221764

RESUMO

Myelin oligodendrocyte glycoprotein (MOG) antibodies have a strong association with acute disseminated encephalomyelitis (ADEM) in children, and bilateral and recurrent optic neuritis in children and adults. Recent reports suggest that seizures and encephalopathy may occur in children and adults with MOG antibody-associated disease. We describe the clinical, laboratory, and radiological course of four MOG antibody-positive children who first presented with isolated seizures without fulfilling clinical or radiological criteria for ADEM or other central nervous system demyelination syndromes, who months to years later developed more typical demyelination. This case series highlights a novel observation that isolated seizures in the absence of ADEM may be the index presentation for MOG antibody-associated disease, which should therefore be considered a form of autoimmune epilepsy. It would be reasonable to test for MOG antibodies in children with seizures accompanied by subtle inflammatory changes on magnetic resonance imaging or cerebrospinal fluid analyses, particularly if followed by demyelination, given the clinical and therapeutic implications of an expedited diagnosis in minimizing long-term disability. WHAT THIS PAPER ADDS: Isolated seizures in the absence of acute disseminated encephalomyelitis may be the index presentation for myelin oligodendrocyte glycoprotein antibody-associated demyelination.

10.
J Child Psychol Psychiatry ; 59(10): 1083-1093, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30255500

RESUMO

BACKGROUND: We examined whether increased risk for adolescent tobacco and marijuana problems associated with childhood ADHD is explained by key intermediary influences during adolescence and differs by gender. METHODS: Longitudinal structural equation models examined mediating effects on problems with both substances (or each substance separately) through age-14 peer impairment, internalizing, and adolescent ADHD symptoms in two twin samples, prospectively assessed since age 11 (N = 2,164). Whether these mediators contributed beyond mediating effects of early-adolescent substance use was also considered. Twin difference analyses further illuminated which mediators might be potentially causal. RESULTS: Direct effects of childhood ADHD on age-17 tobacco and marijuana problems (i.e., independent of included mediators) as well as effects of adolescent ADHD symptoms were significant only for females. By contrast, mediation by peer impairment, evident particularly for marijuana, was relatively stronger for males than females. Depression and anxiety were not prospectively associated with age-17 substance problems when earlier substance problems were considered. Consistent with causal influence of early substance use on later problems, monozygotic twins with more severe tobacco or marijuana problems at age 14 than their co-twins were also more likely to have substance problems later in adolescence. CONCLUSIONS: Mediation through peer impairment, continued presence of ADHD symptoms, and early substance use may alter development so that childhood ADHD indirectly contributes to problems with tobacco and marijuana. Targeting gender-sensitive interventions prior to mid-adolescence, before these patterns become established, is essential.

11.
J Stud Alcohol Drugs ; 79(4): 635-643, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30079880

RESUMO

OBJECTIVE: The effect of drinking during adolescence on adult functioning is a public health concern. A variety of mechanisms have been proposed where drinking in adolescence has an adverse impact on later outcomes; unfortunately, few studies have included methodologies that account for confounding influences that might link adolescent drinking with subsequent problems. To address this limitation, the current study used a co-twin control design, which uses members of twin pairs that differ from each other on their adolescent drinking. METHOD: We used a prospective longitudinal sample drawn from the Minnesota Twin Family Study, consisting of 2,764 twins (1,434 female) assessed at regular follow-ups from age 17 to age 29. Adolescent drinking was defined by measures of early initiation of use and a measure of overall consumption at age 17. Adult outcomes included indicators of substance use, antisocial behavior, personality, socioeconomic status, and social functioning. RESULTS: The co-twin control analyses suggested that many of the associations between adolescent drinking and later outcomes were largely influenced by genetic confounding. However, for the measure of adolescent alcohol consumption, results were consistent with a small causal impact of drinking on multiple domains of adult functioning. This pattern was less consistently observed for the measures of early initiation. CONCLUSIONS: These results provide empirical justification for policies designed to alleviate long-term consequences associated with adolescent drinking by reducing the level of alcohol consumption in adolescence. In contrast, the evidence did not suggest that delaying drinking would have a broad impact on later-life adjustment.

12.
Hum Brain Mapp ; 39(11): 4183-4195, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29947131

RESUMO

Oscillatory activity is crucial for information processing in the brain, and has a long history as a biomarker for psychopathology. Variation in oscillatory activity is highly heritable, but current understanding of specific genetic influences remains limited. We performed the largest genome-wide association study to date of oscillatory power during eyes-closed resting electroencephalogram (EEG) across a range of frequencies (delta 1-3.75 Hz, theta 4-7.75 Hz, alpha 8-12.75 Hz, and beta 13-30 Hz) in 8,425 subjects. Additionally, we performed KGG positional gene-based analysis and brain-expression analyses. GABRA2-a known genetic marker for alcohol use disorder and epilepsy-significantly affected beta power, consistent with the known relation between GABAA interneuron activity and beta oscillations. Tissue-specific SNP-based imputation of gene-expression levels based on the GTEx database revealed that hippocampal GABRA2 expression may mediate this effect. Twenty-four genes at 3p21.1 were significant for alpha power (FDR q < .05). SNPs in this region were linked to expression of GLYCTK in hippocampal tissue, and GNL3 and ITIH4 in the frontal cortex-genes that were previously implicated in schizophrenia and bipolar disorder. In sum, we identified several novel genetic variants associated with oscillatory brain activity; furthermore, we replicated and advanced understanding of previously known genes associated with psychopathology (i.e., schizophrenia and alcohol use disorders). Importantly, these psychopathological liability genes affect brain functioning, linking the genes' expression to specific cortical/subcortical brain regions.

13.
Neurol Genet ; 4(3): e236, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29725622

RESUMO

Objective: To determine whether the GNAQ R183Q mutation is present in the forme fruste cases of Sturge-Weber syndrome (SWS) to establish a definitive molecular diagnosis. Methods: We used sensitive droplet digital PCR (ddPCR) to detect and quantify the GNAQ mutation in tissues from epilepsy surgery in 4 patients with leptomeningeal angiomatosis; none had ocular or cutaneous manifestations. Results: Low levels of the GNAQ mutation were detected in the brain tissue of all 4 cases-ranging from 0.42% to 7.1% frequency-but not in blood-derived DNA. Molecular evaluation confirmed the diagnosis in 1 case in which the radiologic and pathologic data were equivocal. Conclusions: We detected the mutation at low levels, consistent with mosaicism in the brain or skin (1.0%-18.1%) of classic cases. Our data confirm that the forme fruste is part of the spectrum of SWS, with the same molecular mechanism as the classic disease and that ddPCR is helpful where conventional diagnosis is uncertain.

14.
J Abnorm Psychol ; 127(4): 339-347, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29745699

RESUMO

The recent inclusion of an alternative model for personality disorders in the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5; American Psychiatric Association, 2013a) highlights the importance of extreme variants of personality for psychopathology. The maladaptive personality traits described in the alternative model comprise 5 higher-order domains and 25 lower-order facets that capture pathological levels of personality. The present report adds to a growing body of research on the implications of maladaptive personality traits for functioning by demonstrating significant associations between each of the higher-order domains (Negative Affect, Detachment, Antagonism, Disinhibition, and Psychoticism) and most of the lower-order facets and lower romantic relationship satisfaction in a population-based sample of 284 monozygotic (MZ) adult twins. We further capitalized upon co-twin differences in levels of personality pathology in a causally informative approach, the MZ co-twin control study design. Co-twin control analyses indicated that higher levels of Negative Affect, Detachment, Disinhibition, and Psychoticism, as well as several lower-order facets, were associated with lower romantic relationship satisfaction even after accounting for the genetic and environmental factors shared by twins that confer liability toward personality pathology and psychosocial dysfunction. The present results lend support to the potentially causal implications of personality pathology for interpersonal functioning, even in a community sample unlikely to be evidencing clinical levels of pathology, by suggesting that extreme variants of personality, manifested by comparably extreme deviations in thinking, feeling, behaving, and interacting with others, may lead to impaired functioning in important domains. (PsycINFO Database Record

15.
Drug Alcohol Depend ; 184: 33-41, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29402677

RESUMO

BACKGROUND: We report whether the etiology underlying associations of childhood ADHD with adolescent alcohol and marijuana involvement is consistent with causal relationships or shared predispositions, and whether it differs by gender. METHODS: In three population-based twin samples (N = 3762; 64% monozygotic), including one oversampling females with ADHD, regressions were conducted with childhood inattentive or hyperactive-impulsive symptoms predicting alcohol and marijuana outcomes by age 17. To determine whether ADHD effects were consistent with causality, twin difference analyses divided effects into those shared between twins in the pair and those differing within pairs. RESULTS: Adolescents with more severe childhood ADHD were more likely to initiate alcohol and marijuana use earlier, escalate to frequent or heavy use, and develop symptoms. While risks were similar across genders, females with more hyperactivity-impulsivity had higher alcohol consumption and progressed further toward daily marijuana use than did males. Monozygotic twins with more severe ADHD than their co-twins did not differ significantly on alcohol or marijuana outcomes, however, suggesting a non-causal relationship. When co-occurring use of other substances and conduct/oppositional defiant disorders were considered, hyperactivity-impulsivity remained significantly associated with both substances, as did inattention with marijuana, but not alcohol. CONCLUSIONS: Childhood ADHD predicts when alcohol and marijuana use are initiated and how quickly use escalates. Shared familial environment and genetics, rather than causal influences, primarily account for these associations. Stronger relationships between hyperactivity-impulsivity and heavy drinking/frequent marijuana use among adolescent females than males, as well as the greater salience of inattention for marijuana, merit further investigation.


Assuntos
Comportamento do Adolescente , Consumo de Bebidas Alcoólicas/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Fumar Maconha/epidemiologia , Gêmeos , Adolescente , Comportamento do Adolescente/psicologia , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Estudos de Coortes , Feminino , Humanos , Comportamento Impulsivo , Estudos Longitudinais , Masculino , Fumar Maconha/genética , Fumar Maconha/psicologia , Estudos Prospectivos , Fatores Sexuais , Gêmeos/genética , Gêmeos/psicologia
16.
Psychol Med ; 48(10): 1673-1684, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29108528

RESUMO

BACKGROUND: Although there is extensive evidence that problematic alcohol use is associated with smaller hippocampal volume, the typical cross-sectional study design cannot determine whether hippocampal deviations reflect pre-existing liability toward problematic alcohol use or instead reflect an alcohol exposure-related effect. We used the co-twin control study design, which capitalizes upon differences within a twin pair in levels of drinking, to differentiate pre-existing liability from an effect of alcohol exposure. METHODS: The sample included 100 female twins, prospectively assessed from ages 11 to 24. Problematic alcohol use was assessed dimensionally and included indicators of quantity, frequency, and density of alcohol use and intoxication. Hippocampal volume was assessed using magnetic resonance imaging. RESULTS: Problematic alcohol use (proximal and cumulative) was associated with significantly smaller left and right hippocampal volume. Follow-up co-twin control analyses that partitioned individual-level alcohol effects into pre-existing, familial liability and non-shared alcohol exposure-related effects indicated that this association reflected alcohol exposure. Greater alcohol using twins had smaller hippocampal volume relative to lesser alcohol using co-twins, beyond effects of their shared genetic and environmental liability toward problematic alcohol use. Results held accounting for recent alcohol use, other substance use, externalizing and internalizing psychopathology, personality traits, trauma exposure, and menstrual phase. CONCLUSIONS: The association between problematic alcohol use and smaller hippocampal volume likely reflects an alcohol exposure-related effect. Differentiating pre-existing brain deviations that confer risk for problematic alcohol use from those that reflect effects of alcohol on the brain will inform etiological models of addiction and further prevention and intervention efforts.

17.
Epilepsia ; 59(1): e5-e13, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29171013

RESUMO

Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences.


Assuntos
Proteínas de Transporte/genética , Deficiências do Desenvolvimento/genética , Mutação/genética , Espasmos Infantis/complicações , Espasmos Infantis/genética , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Espasmos Infantis/diagnóstico por imagem
18.
Dev Psychol ; 54(4): 689-702, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29154644

RESUMO

Many researchers have used the standard Iowa Gambling Task (IGT) to assess decision-making in adolescence given increased risk-taking during this developmental period. Most studies are cross-sectional and do not observe behavioral trajectories over time, limiting interpretation. This longitudinal study investigated healthy adolescents' and young adults' IGT performance across a 10-year span. A total of 189 individuals (aged 9-23 at baseline) completed a baseline session and were followed at 2-year intervals yielding 5 time-points. IGT deck contingencies were shuffled over time to reduce practice effects. IGT performance (good minus bad decisions) was measured at each assessment point and separated into 3 metrics: overall performance (all blocks), decision-making under ambiguity (blocks 1 and 2), and decision-making under risk (blocks 3, 4, and 5). Covariates included estimated intelligence and affective dispositions as measured by the Behavioral Inhibition and Activation System (BIS/BAS) Scales. A linear effect of age yielded the best fit when comparing linear and quadratic effects of age on overall IGT performance. Age and intelligence positively predicted overall performance, whereas affective approach tendencies (BAS) negatively predicted overall performance. Practice effects were observed and controlled for. Models of ambiguity and risk metrics yielded different patterns of significant predictors. Age predicted better performance and affective approach tendencies predicted worse performance for both metrics. Intelligence was a significant predictor for risk, but not ambiguity. This longitudinal study extends prior work by showing age-related improvements in reward-based decision-making and associating those improvements with cognitive and affective variables. Implications of the results for adolescent development are discussed. (PsycINFO Database Record


Assuntos
Comportamento do Adolescente/psicologia , Tomada de Decisões , Jogo de Azar , Adolescente , Fatores Etários , Criança , Feminino , Seguimentos , Humanos , Inteligência , Modelos Lineares , Estudos Longitudinais , Masculino , Modelos Psicológicos , Estudos Prospectivos , Testes Psicológicos , Psicologia do Adolescente , Recompensa , Adulto Jovem
19.
Addict Biol ; 23(1): 256-267, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27859998

RESUMO

Research indicates that alcohol misuse is associated with behavioral disinhibition, but the neurophysiological mechanisms governing this relationship remain largely unknown. Recent work suggests that successful inhibition and cognitive control involve electrophysiological theta-band dynamics, including medial frontal cortex (MFC) power enhancement and functional connectivity between the MFC and dorsal prefrontal cortex (dPFC) regions, which may be disrupted by alcohol misuse. In addition, research suggests that, compared to men, women are at heightened risk of experiencing the negative physical and neurocognitive correlates of drinking. The present study tested the hypothesis that alcohol misuse has a deleterious effect on theta-band response inhibition EEG dynamics in a sample of 300 24-year-old same-sex twins. A cotwin control (CTC) design was used to disentangle premorbid risk for alcohol use from the causal effects of alcohol exposure. Drinking was negatively associated with theta-band MFC power and MFC-dPFC connectivity during response inhibition, and this effect was stronger among women. The CTC analysis suggested that, for women, reduced nogo-related theta-band MFC power and MFC-dPFC connectivity were both consistent with the potential deleterious causal effects of alcohol exposure. These findings suggest that diminished theta-band MFC power and MFC-dPFC connectivity may be neurophysiological mechanisms underlying alcohol-related disinhibition. Although preliminary, these results suggest that normative levels of alcohol use during emerging adulthood have potential sex-specific causal effects on response inhibition EEG dynamics, and thus have potentially significant public health implications.

20.
Am J Psychiatry ; 175(1): 63-70, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28838251

RESUMO

OBJECTIVE: This study examined the effects of childhood attention deficit hyperactivity disorder (ADHD) symptoms, both inattention and hyperactivity-impulsivity, on the development of smoking in male and female adolescents. METHOD: Twin difference methods were used to control for shared genetic and environmental confounders in three population-based, same-sex twin samples (N=3,762; 64% monozygotic). One cohort oversampled female adolescents with ADHD beginning in childhood. Regressions of childhood inattentive and hyperactive-impulsive symptoms were conducted to predict smoking outcomes by age 17. ADHD effects were divided into those shared between twins in the pair and those nonshared, or different within pairs. RESULTS: Adolescents who had more severe ADHD symptoms as children were more likely to initiate smoking and to start smoking younger. The association of ADHD symptoms with daily smoking, number of cigarettes per day, and nicotine dependence was greater in females than in males. Monozygotic female twins with greater attentional problems than their co-twins had greater nicotine involvement, consistent with possible causal influence. These effects remained when co-occurring externalizing behaviors and stimulant medication were considered. Hyperactivity-impulsivity, while also more strongly related to smoking for female adolescents, appeared primarily noncausal. CONCLUSIONS: Smoking initiation and escalation are affected differentially by ADHD subtype and gender. The association of inattention with smoking in female adolescents may be causal, whereas hyperactivity-impulsivity appears to act indirectly, through shared propensities for both ADHD and smoking.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Fumar , Tabagismo , Adolescente , Comportamento do Adolescente , Idade de Início , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Causalidade , Criança , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Fatores de Risco , Fatores Sexuais , Fumar/epidemiologia , Fumar/psicologia , Tabagismo/diagnóstico , Tabagismo/epidemiologia , Tabagismo/genética , Tabagismo/psicologia , Gêmeos Monozigóticos/psicologia , Gêmeos Monozigóticos/estatística & dados numéricos , Estados Unidos/epidemiologia
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