Self-regulation in the pre-adolescent brain.

Self-regulation refers to the ability to monitor and modulate emotions, behavior, and cognition, which in turn allows us to achieve goals and adapt to ever changing circumstances. This trait develops from early infancy well into adulthood, and features both low-level executive functions such as reactive inhibition, as well as higher level executive functions such as proactive inhibition. Development of self-regulation is linked to brain maturation in adolescence and adulthood. However, how self-regulation in daily life relates to brain functioning in pre-adolescent children is not known. To this aim, we have analyzed data from 640 children aged 8-11, who performed a stop-signal anticipation task combined with functional magnetic resonance imaging, in addition to questionnaire data on self-regulation. We find that pre-adolescent boys and girls who display higher levels of self-regulation, are better able to employ proactive inhibitory control strategies, exhibit stronger frontal activation and more functional coupling between cortical and subcortical areas of the brain. Furthermore, we demonstrate that pre-adolescent children show significant activation in areas of the brain that were previously only associated with reactive and proactive inhibition in adults and adolescents. Thus, already in pre-adolescent children, frontal-striatal brain areas are active during self-regulatory behavior.

Publisher Correction: Associations between subjective well-being and subcortical brain volumes.

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Genetic vulnerability to DUSP22 promoter hypermethylation is involved in the relation between in utero famine exposure and schizophrenia.

Epigenetic changes may account for the doubled risk to develop schizophrenia in individuals exposed to famine in utero. We therefore investigated DNA methylation in a unique sample of patients and healthy individuals conceived during the great famine in China. Subsequently, we examined two case-control samples without famine exposure in whole blood and brain tissue. To shed light on the causality of the relation between famine exposure and DNA methylation, we exposed human fibroblasts to nutritional deprivation. In the famine-exposed schizophrenia patients, we found significant hypermethylation of the dual specificity phosphatase 22 (DUSP22) gene promoter (Chr6:291687-293285) (N = 153, p = 0.01). In this sample, DUSP22 methylation was also significantly higher in patients independent of famine exposure (p = 0.025), suggesting that hypermethylation of DUSP22 is also more generally involved in schizophrenia risk. Similarly, DUSP22 methylation was also higher in two separate case-control samples not exposed to famine using DNA from whole blood (N = 64, p = 0.03) and postmortem brains (N = 214, p = 0.007). DUSP22 methylation showed strong genetic regulation across chromosomes by a region on chromosome 16 which was consistent with new 3D genome interaction data. The presence of a direct link between famine and DUSP22 transcription was supported by data from cultured human fibroblasts that showed increased methylation (p = 0.048) and expression (p = 0.019) in response to nutritional deprivation (N = 10). These results highlight an epigenetic locus that is genetically regulated across chromosomes and that is involved in the response to early-life exposure to famine and that is relevant for a major psychiatric disorder.

Associations between subjective well-being and subcortical brain volumes.

To study the underpinnings of individual differences in subjective well-being (SWB), we tested for associations of SWB with subcortical brain volumes in a dataset of 724 twins and siblings. For significant SWB-brain associations we probed for causal pathways using Mendelian Randomization (MR) and estimated genetic and environmental contributions from twin modeling. Another independent measure of genetic correlation was obtained from linkage disequilibrium (LD) score regression on published genome-wide association summary statistics. Our results indicated associations of SWB with hippocampal volumes but not with volumes of the basal ganglia, thalamus, amygdala, or nucleus accumbens. The SWB-hippocampus relations were nonlinear and characterized by lower SWB in subjects with relatively smaller hippocampal volumes compared to subjects with medium and higher hippocampal volumes. MR provided no evidence for an SWB to hippocampal volume or hippocampal volume to SWB pathway. This was in line with twin modeling and LD-score regression results which indicated non-significant genetic correlations. We conclude that low SWB is associated with smaller hippocampal volume, but that genes are not very important in this relationship. Instead other etiological factors, such as exposure to stress and stress hormones, may exert detrimental effects on SWB and the hippocampus to bring about the observed association.

A study of genetic and environmental contributions to structural brain changes over time in twins concordant and discordant for bipolar disorder.

This is the first longitudinal twin study examining genetic and environmental contributions to the association between liability to bipolar disorder (BD) and changes over time in global brain volumes, and global and regional measures of cortical surface area, cortical thickness and cortical volume. A total of 50 twins from pairs discordant or concordant for BD (monozygotic: 8 discordant and 3 concordant pairs, and 1 patient and 3 co-twins from incomplete pairs; dizygotic: 6 discordant and 2 concordant pairs, and 1 patient and 7 co-twins from incomplete pairs) underwent magnetic resonance imaging twice. In addition, 57 twins from healthy twin pairs (15 monozygotic and 10 dizygotic pairs, and 4 monozygotic and 3 dizygotic subjects from incomplete pairs) were also scanned twice. Mean follow-up duration for all twins was 7.5 years (standard deviation: 1.5 years). Data were analyzed using structural equation modeling software OpenMx. The liability to BD was not associated with global or regional structural brain changes over time. Although we observed a subtle increase in cerebral white matter in BD patients, this effect disappeared after correction for multiple comparisons. Heritability of brain changes over time was generally low to moderate. Structural brain changes appear to follow similar trajectories in BD patients and healthy controls. Existing brain abnormalities in BD do not appear to progressively change over time, but this requires additional confirmation. Further study with large cohorts is recommended to assess genetic and environmental influences on structural brain abnormalities in BD, while taking into account the influence of lithium on the brain.

Connectome organization is related to longitudinal changes in general functioning, symptoms and IQ in chronic schizophrenia.

Emerging evidence suggests schizophrenia to involve widespread alterations in the macroscale wiring architecture of the human connectome. Recent findings of attenuated connectome alterations in unaffected siblings of schizophrenia patients suggest that altered connectome organization may relate to the vulnerability to develop the disorder, but whether it relates to progression of illness after disease onset is currently unknown. Here, we examined the interaction between connectome structure and longitudinal changes in general functioning, clinical symptoms and IQ in the 3years following MRI assessment in a group of chronically ill schizophrenia patients. Effects in patients were compared to associations between connectome organization and changes in subclinical symptoms and IQ in healthy controls and unaffected siblings of schizophrenia patients. Analyzing the patient sample revealed a relationship between structural connectivity-particularly among central 'brain hubs'-and progressive changes in general functioning (p=0.007), suggesting that more prominent impairments of hub connectivity may herald future functional decline. Our findings further indicate that affected local connectome organization relates to longitudinal increases in overall PANSS symptoms (p=0.013) and decreases in total IQ (p=0.003), independent of baseline symptoms and IQ. No significant associations were observed in controls and siblings, suggesting that the findings in patients represent effects of ongoing illness, as opposed to normal time-related changes. In all, our findings suggest connectome structure to have predictive value for the course of illness in schizophrenia.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

Genetic and environmental influences on cortical surface area and cortical thickness in bipolar disorder.

BACKGROUND: The risk of developing bipolar disorder (BD) has been linked to structural brain abnormalities. The degree to which genes and environment influence the association of BD with cortical surface area remains to be elucidated. In this twin study, genetic and environmental contributions to the association between liability to develop BD and surface area, thickness and volume of the cortex were examined. METHOD: The study cohort included 44 affected monozygotic (nine concordant, 12 discordant) and dizygotic (four concordant, 19 discordant) twin pairs, and seven twins from incomplete discordant monozygotic and dizygotic discordant twin pairs. In addition, 37 monozygotic and 24 dizygotic healthy control twin pairs, and six twins from incomplete monozygotic and dizygotic control pairs were included. RESULTS: Genetic liability to develop BD was associated with a larger cortical surface in limbic and parietal regions, and a thicker cortex in central and parietal regions. Environmental factors related to BD were associated with larger medial frontal, parietal and limbic, and smaller orbitofrontal surfaces. Furthermore, thinner frontal, limbic and occipital cortex, and larger frontal and parietal, and smaller orbitofrontal volumes were also associated with environmental factors related to BD. CONCLUSIONS: Our results suggest that unique environmental factors play a prominent role in driving the associations between liability to develop BD and cortical measures, particularly those involving cortical thickness. Further evaluation of their influence on the surface and thickness of the cortical mantle is recommended. In addition, cortical volume appeared to be primarily dependent on surface and not thickness.

Reciprocal causation models of cognitive vs volumetric cerebral intermediate phenotypes for schizophrenia in a pan-European twin cohort.

In aetiologically complex illnesses such as schizophrenia, there is no direct link between genotype and phenotype. Intermediate phenotypes could help clarify the underlying biology and assist in the hunt for genetic vulnerability variants. We have previously shown that cognition shares substantial genetic variance with schizophrenia; however, it is unknown if this reflects pleiotropic effects, direct causality or some shared third factor that links both, for example, brain volume (BV) changes. We quantified the degree of net genetic overlap and tested the direction of causation between schizophrenia liability, brain structure and cognition in a pan-European schizophrenia twin cohort consisting of 1243 members from 626 pairs. Cognitive deficits lie upstream of the liability for schizophrenia with about a quarter of the variance in liability to schizophrenia explained by variation in cognitive function. BV changes lay downstream of schizophrenia liability, with 4% of BV variation explained directly by variation in liability. However, our power to determine the nature of the relationship between BV deviation and schizophrenia liability was more limited. Thus, while there was strong evidence that cognitive impairment is causal to schizophrenia liability, we are not in a position to make a similar statement about the relationship between liability and BV. This is the first study to demonstrate that schizophrenia liability is expressed partially through cognitive deficits. One prediction of the finding that BV changes lie downstream of the disease liability is that the risk loci that influence schizophrenia liability will thereafter influence BV and to a lesser extent. By way of contrast, cognitive function lies upstream of schizophrenia, thus the relevant loci will actually have a larger effect size on cognitive function than on schizophrenia. These are testable predictions.

Development and heritability of subcortical brain volumes at ages 9 and 12.

Subcortical brain structures are involved in a variety of cognitive and emotional functions and follow different trajectories of increase and decrease in volume from childhood to adulthood. The heritability of development of subcortical brain volumes during adolescence has not been studied comprehensively. In a longitudinal twin study, we estimated to what extent subcortical brain volumes are influenced by genetic factors at ages 9 and 12. In addition, we assessed whether new genes are expressed at age 12 and whether there is evidence for genotype by sex interaction. Brain scans were acquired for 112 and 89 twin pairs at 9 and 12 years of age. In both boys and girls, there was an increase in volumes of the thalamus, hippocampus, amygdala and pallidum, and a decrease in volumes of the caudate and nucleus accumbens. The putamen showed a decrease in boys bilaterally and an increase in girls in the left hemisphere. Heritability was high (>50%) for all structures - except for the left nucleus accumbens - with heritabilities ranging from 0.50 to 0.91 at age 9, and from 0.59 to 0.88 at age 12. There were no significant new genetic effects coming into play at age 12, and there was no evidence for genotype by sex interactions. These findings suggest that despite their sensitivity to environmental effects, the heritability of subcortical brain structures is high from childhood on, resembling estimates found in adult samples.

Longitudinal study of hormonal and physical development in young twins.

CONTEXT AND OBJECTIVE: Information on the correlation of normative reproductive hormone levels with physical development (Tanner stages) during puberty and on the influences of genes and environment on variation in these hormones and Tanner stages is limited. DESIGN, SETTING, AND PARTICIPANTS: One hundred twelve healthy 9-year-old twin pairs (n = 224) took part in a longitudinal study, of which 89 pairs participated again at age 12 years (n = 178). MAIN OUTCOME MEASURES: Morning urinary LH, FSH, estradiol, and salivary testosterone levels, determined by competitive immunoassays, were measured. Tanner stages were determined through physical examination. RESULTS: Over the 3-year interval, all hormone levels showed a 2- to 9-fold increase. LH and FSH at age 9 years predicted sex-specific Tanner stages at age 12 years in both boys and girls. Most of the associations between hormone levels at age 9 years and physical development at 12 years were explained by genetic influences. FSH in 9-year-old boys correlated with all hormone levels and Tanner stages at age 12 years. Moderate to high heritability estimates were found for hormone levels at both ages and in both sexes. In girls a shift from environmental (age 9 years) to genetic influences (age 12 years) was found for estradiol and pubic hair development, and for breast development a shift in the opposite direction was seen. CONCLUSIONS: During development LH and FSH (and testosterone in boys) levels predict secondary sexual characteristics in boys and girls 3 years later. These correlations are largely due to genes that are involved in both early pubertal hormone levels and subsequent physical development.

Confounders of excessive brain volume loss in schizophrenia.

There is convincing evidence that schizophrenia is characterised by progressive brain volume changes during the course of the illness. In a large longitudinal study it was shown that different age-related trajectories of brain tissue loss are present in patients compared to healthy subjects, suggesting that brain maturation that occurs in the third and fourth decade of life is abnormal in schizophrenia. However, studies show that medication intake and cannabis use are important confounding factors when interpreting brain volume (change) abnormalities. Indeed, continues use of cannabis, but not cigarette smoking, is associated to a more pronounced loss of grey matter in the anterior cingulated and the prefrontal cortex. Atypical antipsychotics have been found to be related to smaller decreases in tissue loss. Moreover, independent of antipsychotic medication intake, the brain volume abnormalities appear associated to the outcome of the illness.

A meta-analysis of the polyunsaturated fatty acid composition of erythrocyte membranes in schizophrenia.

BACKGROUND: Membrane abnormalities in polyunsaturated fatty acids (PUFAs) have been reported in schizophrenia and have been associated with brain tissue loss in normal ageing. Therefore PUFA may be involved in the excessive brain tissue loss reported in schizophrenia. METHODS: A systematic MEDLINE database search was conducted to identify studies that compared PUFAs in erythrocyte membranes in patients and controls. Patients were categorized by medication regime in medication naive first-episode patients, and patients receiving typical or atypical antipsychotics. SAMPLE: Fourteen studies were included, comprising a total of 429 patients with schizophrenia and 444 healthy control subjects. Cohen's d effect sizes were calculated for PUFAs in erythrocyte membranes using the random-effects model. Combined Cohen's d was calculated separately for patients on different medication regime. RESULTS: Medication-naive patients and patients taking typical antipsychotics showed significantly (p<0.01) decreased concentrations of arachidonic (AA), docosahexaenoic (DHA), and docosapentaenoic (DPA) acid. In addition, patients taking typical antipsychotics showed decreased linoleic (LA), dihomo-γ-linolenic acid (DGLA), eicosapentaenoic (EPA) and docosatetraenoic (DTA) acid (p<0.01). Patients taking atypical antipsychotics showed decreased DHA (p<0.01) only. CONCLUSIONS: PUFA concentrations in erythrocyte membranes are decreased in schizophrenia. Of particular importance in patients are lower concentrations of DHA and AA, two fatty acids that are abundant in the brain and important precursors in the cell-signalling cascade.

Is there change in intelligence quotient in chronically ill schizophrenia patients? A longitudinal study in twins discordant for schizophrenia.

BACKGROUND: Intellectual deficits are commonly found in schizophrenia patients. These intellectual deficits have been found to be heritable. However, whether the intellectual deficits change over time and, if so, whether the change is related with an increased genetic risk for the disease are not known. METHOD: We investigated change of intelligence quotient (IQ) in a twin sample of chronically ill schizophrenia patients, the discordant co-twins and healthy controls during a follow-up period of 5 years. A total of 52 twins completed two IQ assessments: nine patients [three monozygotic (MZ) and six dizygotic (DZ)], 10 unaffected co-twins (three MZ and seven DZ) and 33 healthy control twins (21 MZ and 12 DZ). RESULTS: A significant interaction effect over time was found between IQ measurement and illness (F=4.22, df=1, p<0.05), indicating that change in IQ over time is significantly different between the groups. A stable course in IQ over time was found in the patients with schizophrenia (mean IQ from 109.78 at baseline to 108.44 at follow-up) relative to both the healthy control twins who showed a small increase (from 114.61 at baseline to 119.18 at follow-up) (t=2.06, p<0.05) and the unaffected co-twins (from 111.60 to 117.60, t=-2.32, p<0.05). IQ change in the unaffected co-twins of schizophrenia patients was comparable with that in healthy control twins (t=-0.49, p=0.63). CONCLUSIONS: Patients with schizophrenia in the chronic phase of the disease, but not the discordant co-twins, show a lack of increase in IQ, which is probably due to environmental (non-genetic) factors related to the disease.

White matter development in early puberty: a longitudinal volumetric and diffusion tensor imaging twin study.

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.

Symptom dimensions are associated with progressive brain volume changes in schizophrenia.

BACKGROUND: There is considerable variation in progressive brain volume changes in schizophrenia. Whether this is related to the clinical heterogeneity that characterizes the illness remains to be determined. This study examines the relationship between change in brain volume over time and individual variation in psychopathology, as measured by five continuous symptom dimensions (i.e. negative, positive, disorganization, mania and depression). METHODS: Global brain volume measurements from 105 schizophrenia patients and 100 healthy comparison subjects, obtained at inclusion and 5-year follow-up, were used in this study. Symptom dimension scores were calculated by factor analysis of clinical symptoms. Using linear regression analyses and independent-samples t-tests, the relationship between symptom dimensions and progressive brain volume changes, corrected for age, gender and intracranial volume, was examined. Antipsychotic medication, outcome and IQ were investigated as potential confounders. RESULTS: In patients, the disorganization dimension was associated with change in total brain (ß=-0.295, p=0.003) and cerebellar (ß=-0.349, p<0.001) volume. Furthermore, higher levels of disorganization were associated with lower IQ, irrespective of psychiatric status (i.e. patient or control). In healthy comparison subjects, disorganization score was not associated with progressive brain volume changes. CONCLUSION: Heterogeneity in progressive brain volume changes in schizophrenia is particularly associated with variation in disorganization. Schizophrenia patients with high levels of disorganization exhibit more progressive decrease of global brain volumes and have lower total IQ. We propose that these patients form a phenotypically and biologically homogenous subgroup that may be useful for etiological (e.g., genetic) studies.

Brain volume reductions in medication-naive patients with schizophrenia in relation to intelligence quotient.

BACKGROUND: Global brain abnormalities such as brain volume loss and grey- and white-matter deficits are consistently reported in first-episode schizophrenia patients and may already be detectable in the very early stages of the illness. Whether these changes are dependent on medication use or related to intelligence quotient (IQ) is still debated. METHOD: Magnetic resonance imaging scans were obtained for 20 medication-naive patients with first-episode schizophrenia and 26 matched healthy subjects. Volume measures of total brain grey and white matter, third and lateral ventricles and cortical thickness/surface were obtained. Differences between the groups were investigated, taking into account the effect of intelligence. RESULTS: Medication-naive patients showed statistically significant reductions in whole-brain volume and cerebral grey- and white-matter volume together with lateral ventricle enlargement compared to healthy subjects. IQ was significantly lower in patients compared to controls and was positively associated with brain and white-matter volume in the whole group. No significant differences in cortical thickness were found between the groups but medication-naive patients had a significantly smaller surface in the left superior temporal pole, Heschl's gyrus and insula compared to controls. CONCLUSIONS: Our findings suggest that brain volume loss is present at illness onset, and can be explained by the reduced surface of the temporal and insular cortex. These abnormalities are not related to medication, but IQ.

Genetic influences on thinning of the cerebral cortex during development.

During development from childhood to adulthood the human brain undergoes considerable thinning of the cerebral cortex. Whether developmental cortical thinning is influenced by genes and if independent genetic factors influence different parts of the cortex is not known. Magnetic resonance brain imaging was done in twins at age 9 (N = 190) and again at age 12 (N = 125; 113 repeated measures) to assess genetic influences on changes in cortical thinning. We find considerable thinning of the cortex between over this three year interval (on average 0.05 mm; 1.5%), particularly in the frontal poles, and orbitofrontal, paracentral, and occipital cortices. Cortical thinning was highly heritable at age 9 and age 12, and the degree of genetic influence differed for the various areas of the brain. One genetic factor affected left inferior frontal (Broca's area), and left parietal (Wernicke's area) thinning; a second factor influenced left anterior paracentral (sensory-motor) thinning. Two factors influenced cortical thinning in the frontal poles: one of decreasing influence over time, and another independent genetic factor emerging at age 12 in left and right frontal poles. Thus, thinning of the cerebral cortex is heritable in children between the ages 9 and 12. Furthermore, different genetic factors are responsible for variation in cortical thickness at ages 9 and 12, with independent genetic factors acting on cortical thickness across time and between various brain areas during childhood brain development.

The course of brain abnormalities in schizophrenia: can we slow the progression?

There is convincing evidence that schizophrenia is characterized by progressive brain volume changes during the course of the illness. In a large longitudinal study it was shown that different age-related trajectories of brain tissue loss are present in patients compared with healthy subjects, suggesting that brain maturation that occurs in the third and fourth decade of life is abnormal in schizophrenia. Studies show that medication intake is an important confounding factor when interpreting brain volume (change) abnormalities. Atypical antipsychotics have been found to be related to smaller decreases in tissue loss. Moreover, independent of antipsychotic medication intake, the brain volume abnormalities appear associated to the outcome of the illness. Before being able to intervene with therapies and prevent the brain from shrinking, one has to understand the underlying mechanism of the progressive changes in the brains of schizophrenia patients.