RESUMEN

AIM: The aim of this paper is to determine clinical factors related to hostility and disturbing and aggressive behaviour and to examine the effect of medication on these behaviours in FEP. METHODS: Data from phase I and II of the OPTiMiSE trial are used. Outcome measures are the hostility item of the Positive and Negative Syndrome Scale (PANSS P7) and the disturbing and aggressive behaviour domain of the Personal and Social Performance scale (PSP-D). RESULTS: Moderate, severe or extreme hostility (PANSS P7 > 3) was present in 42 patients (9.4%). The PANSS P7 and PSP-D were low to moderate but significantly associated with the selected PANSS items: delusions, hallucinatory behaviour, excitement, tension, uncooperativeness, unusual thought content, impulsivity, and lack of judgement and insight. In a subsample of 185 patients (41.5%) with baseline PANSS P7 > 1, the PANSS P7 and PSP-D scores improved in the first 4 weeks of amisulpride treatment. This effect remained significant after controlling for baseline positive symptoms (PANSS P1-P6). No significant differences were found between olanzapine and amisulpride in the second phase of the trial. CONCLUSION: Clinical risk factors such as poor impulse control, uncooperativeness and excitement could help clinicians in detecting and treating hostile and aggressive behaviour in FEP. Amisulpride could be an effective antipsychotic choice in the treatment of FEP patients who express hostile or aggressive behaviour. Future research is needed to compare the effects of amisulpride and olanzapine on hostility in FEP during the first weeks of treatment.

Asunto(s)

Antipsicóticos , Trastornos Psicóticos , Esquizofrenia , Antipsicóticos/uso terapéutico , Hostilidad , Humanos , Olanzapina/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Esquizofrenia/tratamiento farmacológico

RESUMEN

BACKGROUND: Cortical thickness and surface area changes have repeatedly been found in schizophrenia. Whether progressive loss in cortical thickness and surface area are mediated by genetic or disease related factors is unknown. Here we investigate to what extent genetic and/or environmental factors contribute to the association between change in cortical thickness and surface area and liability to develop schizophrenia. METHOD: Longitudinal magnetic resonance imaging study over a 5-year interval. Monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia were compared with healthy control twin pairs using repeated measures analysis of variance (RM-ANOVA) and structural equation modeling (SEM). Twins discordant for schizophrenia and healthy control twins were recruited from the twin cohort at the University Medical Centre Utrecht, The Netherlands. A total of 90 individuals from 46 same sex twin pairs were included: 9 MZ and 10 DZ discordant for schizophrenia and 14 MZ and 13 (11 complete and 2 incomplete) DZ healthy twin-pairs. Age varied between 19 and 57years. RESULTS: Higher genetic liability for schizophrenia was associated with progressive global thinning of the cortex, particularly of the left superior temporal cortex. Higher environmental liability for schizophrenia was associated with global attenuated thinning of the cortex, and including of the left superior temporal cortex. Cortical surface area change was heritable, but not significantly associated with higher genetic or environmental liability for schizophrenia. CONCLUSIONS: Excessive cortical thinning, particularly of the left superior temporal cortex, may represent a genetic risk marker for schizophrenia.

Asunto(s)

Corteza Cerebral/diagnóstico por imagen , Enfermedades en Gemelos/diagnóstico por imagen , Esquizofrenia/diagnóstico por imagen , Adulto , Análisis de Varianza , Femenino , Estudios de Seguimiento , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelos Genéticos , Tamaño de los Órganos , Esquizofrenia/tratamiento farmacológico , Gemelos Dicigóticos , Gemelos Monocigóticos , Adulto Joven

RESUMEN

Puberty is characterized by major changes in hormone levels and structural changes in the brain. To what extent these changes are associated and to what extent genes or environmental influences drive such an association is not clear. We acquired circulating levels of luteinizing hormone, follicle stimulating hormone (FSH), estradiol and testosterone and magnetic resonance images of the brain from 190 twins at age 9 [9.2 (0.11) years; 99 females/91 males]. This protocol was repeated at age 12 [12.1 (0.26) years] in 125 of these children (59 females/66 males). Using voxel-based morphometry, we tested whether circulating hormone levels are associated with grey matter density in boys and girls in a longitudinal, genetically informative design. In girls, changes in FSH level between the age of 9 and 12 positively associated with changes in grey matter density in areas covering the left hippocampus, left (pre)frontal areas, right cerebellum, and left anterior cingulate and precuneus. This association was mainly driven by environmental factors unique to the individual (i.e. the non-shared environment). In 12-year-old girls, a higher level of circulating estradiol levels was associated with lower grey matter density in frontal and parietal areas. This association was driven by environmental factors shared among the members of a twin pair. These findings show a pattern of physical and brain development going hand in hand.

Asunto(s)

Sustancia Gris/crecimiento & desarrollo , Hormonas/sangre , Adolescente , Encéfalo/crecimiento & desarrollo , Cerebelo/crecimiento & desarrollo , Niño , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Genética Conductual , Humanos , Estudios Longitudinales , Hormona Luteinizante/sangre , Imagen por Resonancia Magnética , Masculino , Polimorfismo de Nucleótido Simple , Pubertad , Testosterona/sangre , Gemelos Dicigóticos , Gemelos Monocigóticos

RESUMEN

It has been shown that brain volume and general intellectual ability are to a significant extent influenced by the same genetic factors. Several cortical regions of the brain also show a genetic correlation with intellectual ability, demonstrating that intellectual functioning is probably represented in a heritable distributed network of cortical regions throughout the brain. This study is the first to investigate a genetic association between subcortical volumes and intellectual ability, taking into account the thalamus, caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, and nucleus accumbens using an extended twin design. Genetic modeling was performed on a healthy adult twin sample consisting of 106 twin pairs and 30 of their siblings, IQ data was obtained from 132 subjects. Our results demonstrate that of all subcortical volumes measured, only thalamus volume is significantly correlated with intellectual functioning. Importantly, the association found between thalamus volume and intellectual ability is significantly influenced by a common genetic factor. This genetic factor is also implicated in cerebral brain volume. The thalamus, with its widespread cortical connections, may thus play a key role in human intelligence.

Asunto(s)

Inteligencia , Modelos Genéticos , Tálamo/anatomía & histología , Adulto , Encéfalo/anatomía & histología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Pruebas de Inteligencia , Imagen por Resonancia Magnética , Masculino , Tamaño de los Órganos , Caracteres Sexuales , Hermanos

RESUMEN

The human brain undergoes structural changes in children entering puberty, while simultaneously children increase in height. It is not known if brain changes are under genetic control, and whether they are related to genetic factors influencing the amount of overall increase in height. Twins underwent magnetic resonance imaging brain scans at age 9 (N = 190) and 12 (N = 125). High heritability estimates were found at both ages for height and brain volumes (49-96%), and high genetic correlation between ages were observed (r(g) > 0.89). With increasing age, whole brain (+1.1%), cerebellum (+4.2%), cerebral white matter (+5.1%), and lateral ventricle (+9.4%) volumes increased, and third ventricle (-4.0%) and cerebral gray matter (-1.6%) volumes decreased. Children increased on average 13.8 cm in height (9.9%). Genetic influences on individual difference in volumetric brain and height changes were estimated, both within and across traits. The same genetic factors influenced both cerebral (20% heritable) and cerebellar volumetric changes (45%). Thus, the extent to which changes in cerebral and cerebellar volumes are heritable in children entering puberty are due to the same genes that influence change in both structures. The increase in height was heritable (73%), and not associated with cerebral volumetric change, but positively associated with cerebellar volume change (r(p) = 0.24). This association was explained by a genetic correlation (r(g) = 0.48) between height and cerebellar change. Brain and body each expand at their own pace and through separate genetic pathways. There are distinct genetic processes acting on structural brain development, which cannot be explained by genetic increase in height.

Asunto(s)

Estatura/genética , Encéfalo/anatomía & histología , Encéfalo/crecimiento & desarrollo , Desarrollo Infantil/fisiología , Modelos Genéticos , Mapeo Encefálico , Niño , Intervalos de Confianza , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Análisis Multivariante , Gemelos Dicigóticos , Gemelos Monocigóticos

RESUMEN

Structural brain abnormalities have consistently been found in patients with schizophrenia. Diffusion tensor imaging (DTI) has been shown to be a useful method to measure white matter (WM) integrity in this illness, but findings in the earlier disease stages are inconclusive. Moreover, the relationship between WM microstructure and the familial risk for developing schizophrenia remains unresolved. From 126 patients with schizophrenia, 123 of their non-psychotic siblings and 109 healthy control subjects, DTI images were acquired on a 1.5 T MRI scanner. Mean fractional anisotropy (FA) was compared along averaged WM tracts, computed for the genu, splenium, left and right uncinate fasciculus, cingulum, inferior fronto-occipital fasciculus, fornix, arcuate fasciculus, and inferior longitudinal fasciculus. Fractional anisotropy (FA) was assessed for its unique environmental and familial (possibly heritable) aspects associated with schizophrenia, using structural equation modeling for these white matter tracts. The results of this study show that young adult (mean age 26.7 years) patients with schizophrenia did not differ in mean FA from healthy controls along WM fibers; siblings of patients showed higher mean FA in the left and right arcuate fasciculus as compared to patients and controls. With increasing age, an excessive decline in mean FA was found in patients as compared to siblings and healthy controls in the genu, left uncinate fasciculus, left inferior fronto-occipital fasciculus, and left inferior longitudinal fasciculus. Moreover, symptom severity was negatively correlated to mean FA in the arcuate fasciculus bilaterally in patients with schizophrenia. In young adult patients with schizophrenia integrity of individual tract-based (corticocortical) fibers can (still) be within normal limits. However, changes in the arcuate fasciculus may be relevant to (the risk to develop) psychosis, while a general and widespread loss of fiber integrity may be related to illness progression.

Asunto(s)

Imagen de Difusión Tensora/métodos , Trastornos Psicóticos , Esquizofrenia/diagnóstico , Esquizofrenia/metabolismo , Hermanos , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esquizofrenia/genética , Adulto Joven

RESUMEN

White matter microstructure and volume show synchronous developmental patterns in children. White matter volume increases considerably during development. Fractional anisotropy, a measure for white matter microstructural directionality, also increases with age. Development of white matter volume and development of white matter microstructure seem to go hand in hand. The extent to which the same or different genetic and/or environmental factors drive these two aspects of white matter maturation is currently unknown. We mapped changes in white matter volume, surface area and diffusion parameters in mono- and dizygotic twins who were scanned at age 9 (203 individuals) and again at age 12 (126 individuals). Over the three-year interval, white matter volume (+6.0%) and surface area (+1.7%) increased, fiber bundles expanded (most pronounced in the left arcuate fasciculus and splenium), and fractional anisotropy increased (+3.0%). Genes influenced white matter volume (heritability ~85%), surface area (~85%), and fractional anisotropy (locally 7% to 50%) at both ages. Finally, volumetric white matter growth was negatively correlated with fractional anisotropy increase (r = -0.62) and this relationship was driven by environmental factors. In children who showed the most pronounced white matter growth, fractional anisotropy increased the least and vice-versa. Thus, white matter development in childhood may reflect a process of both expansion and fiber optimization.

Asunto(s)

Encéfalo/crecimiento & desarrollo , Imagen de Difusión Tensora/métodos , Anisotropía , Encéfalo/anatomía & histología , Niño , Femenino , Humanos , Masculino

RESUMEN

CONTEXT: The nosologic dichotomy between schizophrenia and bipolar disorder (BD) as formulated by Kraepelin is currently being questioned, stimulated by the finding that schizophrenia and BD partly share a common genetic origin. Although both disorders are characterized by changes in brain structure, family studies suggest more segregating than overlapping neuroanatomical abnormalities in both disorders. OBJECTIVES: To investigate whether patients with schizophrenia and patients with BD display overlapping abnormalities in brain volumes and cortical thickness and whether these are caused by shared genetic or environmental influences. DESIGN: Magnetic resonance imaging findings of monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia, twin pairs concordant and discordant for BD, and healthy twin pairs were compared using structural equation modeling. SETTING: The Netherlands Twin Register and University Medical Center Utrecht. PARTICIPANTS: A total of 310 individuals from 158 (152 complete and 6 incomplete) twin pairs were included: 26 pairs discordant for schizophrenia (13 MZ and 13 DZ), 49 pairs with BD (9 MZ and 4 DZ concordant; 14 MZ and 22 DZ discordant), and 83 healthy twin pairs (44 MZ and 39 DZ). MAIN OUTCOME MEASURES: Estimates of additive genetic and unique environmental associations between schizophrenia and BD with overlapping and nonoverlapping volumes and cortical thickness. RESULTS: Higher genetic liabilities for schizophrenia and BD were associated with smaller white matter volume, thinner right (and left) parahippocampus, thinner right orbitofrontal cortex, and thicker temporoparietal and left superior motor cortices; higher environmental liabilities were associated with thinner right medial occipital cortex. Genetic liability for schizophrenia was associated with thicker right parietal cortex; for BD, with larger intracranial volume. CONCLUSIONS: Brain structures reflect overlapping and segregating genetic liabilities for schizophrenia and BD. The overlapping smaller white matter volume and common areas of thinner cortex suggest that both disorders share genetic (neurodevelopmental) roots.

Asunto(s)

Trastorno Bipolar/patología , Encéfalo/patología , Enfermedades en Gemelos/patología , Enfermedades en Gemelos/psicología , Modelos Estadísticos , Esquizofrenia/patología , Psicología del Esquizofrénico , Adulto , Atrofia/genética , Atrofia/patología , Trastorno Bipolar/genética , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad/psicología , Humanos , Hipertrofia/genética , Hipertrofia/patología , Imagen por Resonancia Magnética/métodos , Masculino , Fibras Nerviosas Mielínicas/patología , Países Bajos , Neuroimagen/métodos , Neuroimagen/psicología , Neuroimagen/estadística & datos numéricos , Esquizofrenia/genética , Gemelos Dicigóticos/psicología , Gemelos Monocigóticos/psicología

RESUMEN

Human neuronal circuits undergo life-long functional reorganization with profound effects on cognition and behavior. Well documented prolonged development of anatomical brain structures includes white and gray matter changes that continue into the third decade of life. We investigated resting-state EEG oscillations in 1433 subjects from 5 to 71 years. Neuronal oscillations exhibit scale-free amplitude modulation as reflected in power-law decay of autocorrelations--also known as long-range temporal correlations (LRTC)--which was assessed by detrended fluctuation analysis. We observed pronounced increases in LRTC from childhood to adolescence, during adolescence, and even into early adulthood (∼25 years of age) after which the temporal structure stabilized. A principal component analysis of the spatial distribution of LRTC revealed increasingly uniform scores across the scalp. Together, these findings indicate that the scale-free modulation of resting-state oscillations reflects brain maturation, and suggests that scaling analysis may prove useful as a biomarker of pathophysiology in neurodevelopmental disorders such as attention deficit hyperactivity disorder and schizophrenia.

Asunto(s)

Ondas Encefálicas/fisiología , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiología , Neuronas/fisiología , Descanso/fisiología , Adolescente , Adulto , Envejecimiento/fisiología , Niño , Preescolar , Electroencefalografía/métodos , Humanos , Persona de Mediana Edad , Análisis de Componente Principal/métodos , Factores de Tiempo

RESUMEN

During childhood, brain structure and function changes substantially. Recently, graph theory has been introduced to model connectivity in the brain. Small-world networks, such as the brain, combine optimal properties of both ordered and random networks, i.e., high clustering and short path lengths. We used graph theoretical concepts to examine changes in functional brain networks during normal development in young children. Resting-state eyes-closed electroencephalography (EEG) was recorded (14 channels) from 227 children twice at 5 and 7 years of age. Synchronization likelihood (SL) was calculated in three different frequency bands and between each pair of electrodes to obtain SL-weighted graphs. Mean normalized clustering index, average path length and weight dispersion were calculated to characterize network organization. Repeated measures analysis of variance tested for time and gender effects. For all frequency bands mean SL decreased from 5 to 7 years. Clustering coefficient increased in the alpha band. Path length increased in all frequency bands. Mean normalized weight dispersion decreased in beta band. Girls showed higher synchronization for all frequency bands and a higher mean clustering in alpha and beta bands. The overall decrease in functional connectivity (SL) might reflect pruning of unused synapses and preservation of strong connections resulting in more cost-effective networks. Accordingly, we found increases in average clustering and path length and decreased weight dispersion indicating that normal brain maturation is characterized by a shift from random to more organized small-world functional networks. This developmental process is influenced by gender differences early in development.

Asunto(s)

Mapeo Encefálico , Ondas Encefálicas/fisiología , Encéfalo/crecimiento & desarrollo , Descanso/fisiología , Análisis de Varianza , Niño , Preescolar , Sincronización Cortical , Electroencefalografía/métodos , Femenino , Humanos , Estudios Longitudinales , Masculino , Red Nerviosa/crecimiento & desarrollo , Vías Nerviosas/crecimiento & desarrollo , Procesamiento de Señales Asistido por Computador , Análisis Espectral , Estudios en Gemelos como Asunto , Gemelos/fisiología

RESUMEN

Multicenter structural MRI studies can have greater statistical power than single-center studies. However, across-center differences in contrast sensitivity, spatial uniformity, etc., may lead to tissue classification or image registration differences that could reduce or wholly offset the enhanced statistical power of multicenter data. Prior work has validated volumetric multicenter MRI, but robust methods for assessing reliability and power of multisite analyses with voxel-based morphometry (VBM) and cortical thickness measurement (CORT) are not yet available. We developed quantitative methods to investigate the reproducibility of VBM and CORT to detect group differences and estimate heritability when MRI scans from different scanners running different acquisition protocols in a multicenter setup are included. The method produces brain maps displaying information such as lowest detectable effect size (or heritability) and effective number of subjects in the multicenter study. We applied the method to a five-site multicenter calibration study using scanners from four different manufacturers, running different acquisition protocols. The reliability maps showed an overall good comparability between the sites, providing a reasonable gain in sensitivity in most parts of the brain. In large parts of the cerebrum and cortex scan pooling improved heritability estimates, with "effective-N" values upto the theoretical maximum. For some areas, "optimal-pool" maps indicated that leaving out a site would give better results. The reliability maps also reveal which brain regions are in any case difficult to measure reliably (e.g., around the thalamus). These tools will facilitate the design and analysis of multisite VBM and CORT studies for detecting group differences and estimating heritability.

Asunto(s)

Mapeo Encefálico/normas , Corteza Cerebral/anatomía & histología , Procesamiento de Imagen Asistido por Computador/normas , Imagen por Resonancia Magnética/normas , Antropometría/métodos , Mapeo Encefálico/métodos , Corteza Cerebral/fisiología , Variación Genética/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/instrumentación , Imagen por Resonancia Magnética/métodos , Tamaño de los Órganos/fisiología

RESUMEN

Structural neuroimaging studies suggest the presence of subtle abnormalities in the brains of patients with bipolar disorder. The influence of genetic and/or environmental factors on these brain abnormalities is unknown. To investigate the contribution of genetic and environmental factors on grey and white matter brain densities in bipolar disorder, monozygotic and dizygotic twins concordant and discordant for bipolar disorder were scanned using 1.5 Tesla magnetic resonance imaging and compared with healthy twin pairs. A total of 232 subjects: 49 affected twin pairs (8 monozygotic concordant, 15 monozygotic discordant, 4 dizygotic concordant, 22 dizygotic discordant) and 67 healthy twin pairs (39 monozygotic and 28 dizygotic) were included. After correcting for the effect of lithium, the liability for bipolar disorder was associated with decreased grey matter density in widespread areas of the brain, but most prominent in frontal and limbic regions, and with decreased white matter density in (frontal parts of) the superior longitudinal fasciculi. The genetic risk to develop bipolar disorder was related to decreased grey matter density in the right medial frontal gyrus, precentral gyrus and insula and with decreased white matter density in the superior longitudinal fasciculi bilaterally. In conclusion, pathology in the frontal lobe, especially in parts of the superior longitudinal fasciculus, may be central to the genetic risk to develop bipolar disorder, while widespread grey matter abnormalities appear related to the illness itself.

Asunto(s)

Trastorno Bipolar/genética , Trastorno Bipolar/patología , Encéfalo/patología , Enfermedades en Gemelos , Adulto , Femenino , Predisposición Genética a la Enfermedad , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fenotipo , Gemelos/genética

RESUMEN

Although the adult brain is considered to be fully developed and stable until senescence when its size steadily decreases, such stability seems at odds with continued human (intellectual) development throughout life. Moreover, although variation in human brain size is highly heritable, we do not know the extent to which genes contribute to individual differences in brain plasticity. In this longitudinal magnetic resonance imaging study in twins, we report considerable thinning of the frontal cortex and thickening of the medial temporal cortex with increasing age and find this change to be heritable and partly related to cognitive ability. Specifically, adults with higher intelligence show attenuated cortical thinning and more pronounced cortical thickening over time than do subjects with average or below average IQ. Genes influencing variability in both intelligence and brain plasticity partly drive these associations. Thus, not only does the brain continue to change well into adulthood, these changes are functionally relevant because they are related to intelligence.

Asunto(s)

Encéfalo/fisiología , Inteligencia/genética , Plasticidad Neuronal/genética , Gemelos/genética , Adulto , Encéfalo/patología , Corteza Cerebral/patología , Corteza Cerebral/fisiología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Red Nerviosa/patología , Red Nerviosa/fisiología , Sistema de Registros , Gemelos/psicología , Adulto Joven

RESUMEN

Overall brain size is strikingly heritable throughout life. The influence of genes on variation in focal gray and white matter density is less pronounced and may vary with age. This paper describes the relative influences of genes and environment on variation in white matter microstructure, measured along fiber tracts with diffusion tensor imaging and magnetization transfer imaging, in a sample of 185 nine-year old children from monozygotic and dizygotic twin pairs. Fractional anisotropy, a measure of microstructural directionality, was not significantly influenced by genetic factors. In contrast, studying longitudinal and radial diffusivity separately, we found significant genetic effects for both radial and longitudinal diffusivity in the genu and splenium of the corpus callosum and the right superior longitudinal fasciculus. Moreover, genetic factors influencing the magnetization transfer ratio (MTR), putatively representing myelination, were most pronounced in the splenium of the corpus callosum and the superior longitudinal fasciculi, located posterior in the brain. The differences in the extent to which genetic and environmental factors influence the various diffusion parameters and MTR, suggest that different physiological mechanisms (either genetic or environmental) underlie these traits at nine years of age.

Asunto(s)

Mapeo Encefálico/métodos , Encéfalo/anatomía & histología , Carácter Cuantitativo Heredable , Gemelos/genética , Niño , Imagen de Difusión Tensora , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Magnetismo , Masculino

RESUMEN

CONTEXT: A monocyte pro-inflammatory state has previously been reported in bipolar disorder (BD). OBJECTIVE: To determine the contribution of genetic and environmental influences on the association between monocyte pro-inflammatory state and BD. DESIGN: A quantitative polymerase chain reaction case-control study of monocytes in bipolar twins. Determination of the influence of additive genetic, common, and unique environmental factors by structural equation modeling (ACE). SETTING: Dutch academic research center. PARTICIPANTS: Eighteen monozygotic BD twin pairs, 23 dizygotic BD twin pairs, and 18 monozygotic and 16 dizygotic healthy twin pairs. MAIN OUTCOME MEASURES: Expression levels of monocytes in the previously reported coherent set of 19 genes (signature) reflecting the pro-inflammatory state. RESULTS: The familial occurrence of the association between the monocyte pro-inflammatory gene-expression signature and BD found in the within-trait/cross-twin correlations (twin correlations) was due to shared environmental factors (ie, both monozygotic and dizygotic ratios in twin correlations approximated 1; ACE modeling data: 94% [95% confidence interval, 53%-99%] explained by common [shared] environmental factors). Although most individual signature genes followed this pattern, there was a small subcluster of genes in which genetic influences could dominate. CONCLUSION: The association of the monocyte pro-inflammatory state with BD is primarily the result of a common shared environmental factor.

Asunto(s)

Trastorno Bipolar/genética , Expresión Génica/genética , Monocitos/fisiología , Adulto , Anciano , Trastorno Bipolar/sangre , Trastorno Bipolar/epidemiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Enfermedades en Gemelos/sangre , Enfermedades en Gemelos/epidemiología , Enfermedades en Gemelos/genética , Ambiente , Femenino , Perfilación de la Expresión Génica/estadística & datos numéricos , Predisposición Genética a la Enfermedad , Humanos , Inflamación/genética , Masculino , Persona de Mediana Edad , Modelos Genéticos , Monocitos/metabolismo , Países Bajos/epidemiología , Factores de Riesgo , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genética

RESUMEN

Puberty represents the phase of sexual maturity, signaling the change from childhood into adulthood. During childhood and adolescence, prominent changes take place in the brain. Recently, variation in frontal, temporal, and parietal areas was found to be under varying genetic control between 5 and 19 years of age. However, at the onset of puberty, the extent to which variation in brain structures is influenced by genetic factors (heritability) is not known. Moreover, whether a direct link between human pubertal development and brain structure exists has not been studied. Here, we studied the heritability of brain structures at 9 years of age in 107 monozygotic and dizygotic twin pairs (N = 210 individuals) using volumetric MRI and voxel-based morphometry. Children showing the first signs of secondary sexual characteristics (N = 47 individuals) were compared with children without these signs, based on Tanner-stages. High heritabilities of intracranial, total brain, cerebellum, and gray and white matter volumes (up to 91%) were found. Regionally, the posterior fronto-occipital, corpus callosum, and superior longitudinal fascicles (up to 93%), and the amygdala, superior frontal and middle temporal cortices (up to 83%) were significantly heritable. The onset of secondary sexual characteristics of puberty was associated with decreased frontal and parietal gray matter densities. Thus, in 9-year-old children, global brain volumes, white matter density in fronto-occipital and superior longitudinal fascicles, and gray matter density of (pre-)frontal and temporal areas are highly heritable. Pubertal development may be directly involved in the decreases in gray matter areas that accompany the transition of our brains from childhood into adulthood.

Asunto(s)

Encéfalo/anatomía & histología , Genes , Pubertad , Gemelos , Mapeo Encefálico , Niño , Desarrollo Infantil , Estudios de Cohortes , Femenino , Humanos , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Fibras Nerviosas Mielínicas , Tamaño de los Órganos , Fenotipo , Sistema de Registros , Caracteres Sexuales , Gemelos Dicigóticos , Gemelos Monocigóticos

RESUMEN

CONTEXT: Structural neuroimaging studies suggest the presence of subtle abnormalities in the brains of patients with bipolar disorder. The influence of genetic and/or environmental factors on these brain abnormalities is unknown. OBJECTIVE: To investigate the contribution of genetic and environmental factors on brain volume in bipolar disorder. DESIGN: Magnetic resonance imaging (1.5 T) brain scans of monozygotic (MZ) or dizygotic (DZ) twins concordant and discordant for bipolar disorder were compared with healthy twin pairs. SETTING: Subjects were recruited from the population, the Netherlands Twin Register, and the twin pair cohort at the University Medical Center Utrecht, Utrecht, The Netherlands. PARTICIPANTS: A total of 234 subjects including 50 affected twin pairs (9 MZ concordant; 15 MZ discordant; 4 DZ concordant; 22 DZ discordant) and 67 healthy twin pairs (39 MZ and 28 DZ) were included. MAIN OUTCOME MEASURES: Volumes of the intracranium, cerebrum, cerebellum, lateral and third ventricle, and gray and white matter from the cerebrum and frontal, parietal, temporal, and occipital lobes, both with and without correction for lithium use. To estimate the influence of additive genetic, common, and unique environmental factors, structural equation modeling was applied. RESULTS: Bipolar disorder was associated with a decrease in total cortical volume. Decreases in white matter were related to the genetic risk of developing bipolar disorder (bivariate heritability, 77%; 95% confidence interval, 38% to 100%). Significant environmental correlations were found for cortical gray matter. These relationships all became more pronounced when data were corrected for lithium use. CONCLUSIONS: Focusing on genes controlling white matter integrity may be a fruitful strategy in the quest to discover genes implicated in bipolar disorder. Elucidating the mechanism by which lithium attenuates brain matter loss may lead to the development of neuroprotective drugs.

Asunto(s)

Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Encéfalo/patología , Enfermedades en Gemelos/genética , Enfermedades en Gemelos/psicología , Genotipo , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Imagen por Resonancia Magnética , Medio Social , Adulto , Antimaníacos/uso terapéutico , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Corteza Cerebral/patología , Estudios de Cohortes , Enfermedades en Gemelos/diagnóstico , Enfermedades en Gemelos/tratamiento farmacológico , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Carbonato de Litio/uso terapéutico , Masculino , Persona de Mediana Edad , Países Bajos , Tamaño de los Órganos , Fenotipo , Gemelos Dicigóticos/genética , Gemelos Dicigóticos/psicología , Gemelos Monocigóticos/genética , Gemelos Monocigóticos/psicología , Adulto Joven

RESUMEN

OBJECTIVE: Brain volume of boys is larger than that of girls by approximately 10%. Prenatal exposure to testosterone has been suggested in the masculinization of the brain. For example, in litter-bearing mammals intrauterine position increases prenatal testosterone exposure through adjacent male fetuses, resulting in masculinization of brain morphology. DESIGN: The influence of intrauterine presence of a male co-twin on masculinization of human brain volume was studied in 9-year old twins. METHODS: Magnetic resonance imaging brain scans, current testosterone, and estradiol levels were acquired from four groups of dizygotic (DZ) twins: boys from same-sex twin-pairs (SSM), boys from opposite-sex twin-pairs (OSM), girls from opposite-sex twin-pairs (OSF), and girls from same-sex twin-pairs (SSF; n=119 individuals). Data on total brain, cerebellum, gray and white matter volumes were examined. RESULTS: Irrespective of their own sex, children with a male co-twin as compared to children with a female co-twin had larger total brain (+2.5%) and cerebellum (+5.5%) volumes. SSM, purportedly exposed to the highest prenatal testosterone levels, were found to have the largest volumes, followed by OSM, OSF and SSF children. Birth weight partly explained the effect on brain volumes. Current testosterone and estradiol levels did not account for the volumetric brain differences. However, the effects observed in children did not replicate in adult twins. CONCLUSIONS: Our study indicates that sharing the uterus with a DZ twin brother increases total brain volume in 9-year olds. The effect may be transient and limited to a critical period in childhood.

Asunto(s)

Encéfalo/anatomía & histología , Hermanos , Gemelos Dicigóticos/fisiología , Encéfalo/diagnóstico por imagen , Niño , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Tamaño de los Órganos , Radiografía , Factores Sexuales , Testosterona/sangre , Gemelos Dicigóticos/sangre

RESUMEN

Sex steroids exert important organizational effects on brain structure. Early in life, they are involved in brain sexual differentiation. During puberty, sex steroid levels increase considerably. However, to which extent sex steroid production is involved in structural brain development during human puberty remains unknown. The relationship between pubertal rises in testosterone and estradiol levels and brain structure was assessed in 37 boys and 41 girls (10-15 years). Global brain volumes were measured using volumetric-MRI. Regional gray and white matter were quantified with voxel-based morphometry (VBM), a technique which measures relative concentrations ('density') of gray and white matter after individual global differences in size and shape of brains have been removed. Results showed that, corrected for age, global gray matter volume was negatively associated with estradiol levels in girls, and positively with testosterone levels in boys. Regionally, a higher estradiol level in girls was associated with decreases within prefrontal, parietal and middle temporal areas (corrected for age), and with increases in middle frontal-, inferior temporal- and middle occipital gyri. In boys, estradiol and testosterone levels were not related to regional brain structures, nor were testosterone levels in girls. Pubertal sex steroid levels could not explain regional sex differences in regional gray matter density. Boys were significantly younger than girls, which may explain part of the results. In conclusion, in girls, with the progression of puberty, gray matter development is at least in part directly associated with increased levels of estradiol, whereas in boys, who are in a less advanced pubertal stage, such steroid-related development could not (yet) be found. We suggest that in pubertal girls, estradiol may be implicated in neuronal changes in the cerebral cortex during this important period of brain development.

Asunto(s)

Encéfalo/anatomía & histología , Estradiol/metabolismo , Pubertad/fisiología , Testosterona/metabolismo , Adolescente , Factores de Edad , Niño , Estradiol/orina , Femenino , Humanos , Masculino , Pubertad/metabolismo , Saliva/metabolismo , Caracteres Sexuales

RESUMEN

To investigate whether genetic and/or disease-related factors are involved in progressive structural brain changes in schizophrenia, magnetic resonance imaging scans with a 5-year scan interval were acquired in patients, their same-gender siblings and matched healthy controls. Structural equation modelling was applied to assess disease and familial effects. Whole brain and cerebral grey matter volumes decreased excessively in patients compared with their siblings and the controls, suggesting that the progressive brain loss in schizophrenia may be related to the disease process.

Asunto(s)

Corteza Cerebral/patología , Imagen por Resonancia Magnética , Esquizofrenia/patología , Hermanos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Progresión de la Enfermedad , Estudios Epidemiológicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Linaje , Esquizofrenia/genética