Brain structure, cognition, and brain age in schizophrenia, bipolar disorder, and healthy controls.

Schizophrenia and bipolar disorder (BD) may be disorders of accelerated aging. Direct comparison of healthy aging populations with schizophrenia and BD patients across the adult lifespan may help inform this theory. In total, 225 individuals (91 healthy controls, 81 schizophrenia, 53 euthymic BD) underwent 3T T1-weighted magnetic resonance imaging, diffusion tensor imaging, and cognitive testing. We analyzed associations among age, diagnosis, and cognition with cortical thickness and fractional anisotropy (FA) using general linear models. We then assessed "brain age" using a random forest algorithm, which was also assessed in an independent sample (n = 147). Participants with schizophrenia had lower cortical thickness and FA compared with the other two groups, most prominently in fronto-temporal circuitry. These brain changes were more evident in younger participants than in older ones, yet were associated with cognitive performance independent of diagnosis. Predicted age was 8 years greater than chronological age in individuals with schizophrenia in the first sample and 6 years greater in the second sample. Predicted and chronological age were not different in BD. Differences in brain circuitry are present from illness onset most prominently in schizophrenia and to a lesser extent in BD. These results support a non-progressive "early hit" hypothesis/etiology of illness in the major psychoses. Brain age differences support the hypothesized early aging mechanism in schizophrenia but not in BD.

Serotonin transporter promoter methylation in peripheral cells and neural responses to negative stimuli: A study of adolescent monozygotic twins.

Several studies have examined associations between peripheral DNA methylation patterns of the serotonin transporter gene (SLC6A4) promoter and symptoms of depression and anxiety. The SLC6A4 promoter methylation has also been associated with frontal-limbic brain responses to negative stimuli. However, it is unclear how much of this association is confounded by DNA sequence variations. We utilized a monozygotic-twin within-pair discordance design, to test whether DNA methylation at specific CpG sites in the SLC6A4 promoter of peripheral cells is associated with greater frontal-limbic brain responses to negative stimuli (sadness and fear), independently of DNA sequence effects. In total 48 pairs of healthy 15-year-old monozygotic twins from the Quebec Newborn Twin Study, followed regularly since birth, underwent functional magnetic resonance imaging while conducting an emotion-processing task. The SLC6A4 promoter methylation level was assessed in saliva samples using pyrosequencing. Relative to the co-twins with lower SLC6A4 promoter methylation levels, twins with higher peripheral SLC6A4 methylation levels showed greater orbitofrontal cortical (OFC) activity and left amygdala-anterior cingulate cortex (ACC) and left amygdala-right OFC connectivity in response to sadness as well as greater ACC-left amygdala and ACC-left insula connectivity in response to fearful stimuli. By utilising a monozygotic-twin design, we provided evidence that associations between peripheral SLC6A4 promoter methylation and frontal-limbic brain responses to negative stimuli are, in part, independent of DNA sequence variations. Although causality cannot be determined here, SLC6A4 promoter methylation may be one of the mechanisms underlying how environmental factors influence the serotonin system, potentially affecting emotional processing through frontal-limbic areas.

Gray Matter Neuritic Microstructure Deficits in Schizophrenia and Bipolar Disorder.

BACKGROUND: Postmortem studies have demonstrated considerable dendritic pathologies among persons with schizophrenia and to some extent among those with bipolar I disorder. Modeling gray matter (GM) microstructural properties is now possible with a recently proposed diffusion-weighted magnetic resonance imaging modeling technique: neurite orientation dispersion and density imaging. This technique may bridge the gap between neuroimaging and histopathological findings. METHODS: We performed an extended series of multishell diffusion-weighted imaging and other structural imaging series using 3T magnetic resonance imaging. Participants scanned included individuals with schizophrenia (n = 36), bipolar I disorder (n = 29), and healthy controls (n = 35). GM-based spatial statistics was used to compare neurite orientation dispersion and density imaging-driven microstructural measures (orientation dispersion index and neurite density index [NDI]) among groups and to assess their relationship with neurocognitive performance. We also investigated the accuracy of these measures in the prediction of group membership, and whether combining them with cortical thickness and white matter fractional anisotropy further improved accuracy. RESULTS: The GM-NDI was significantly lower in temporal pole, anterior parahippocampal gyrus, and hippocampus of the schizophrenia patients than the healthy controls. The GM-NDI of patients with bipolar I disorder did not differ significantly from either schizophrenia patients or healthy controls, and it was intermediate between the two groups in the post hoc analysis. Regardless of diagnosis, higher performance in spatial working memory was significantly associated with higher GM-NDI mainly in the frontotemporal areas. The addition of GM-NDI to cortical thickness resulted in higher accuracy to predict group membership. CONCLUSIONS: GM-NDI captures brain differences in the major psychoses that are not accessible with other structural magnetic resonance imaging methods. Given the strong association of GM-NDI with disease state and neurocognitive performance, its potential utility for biological subtyping should be further explored.

Birth weight discordance, DNA methylation, and cortical morphology of adolescent monozygotic twins.

BACKGROUND: Several studies have shown that the in utero environment, which can be indexed by birth weight (BW), is associated with cortical morphology in adolescence and adulthood. Work in monozygotic (MZ) twins suggests that this association is driven by non-shared environmental factors. This correlation could be the result of in utero impacts on DNA methylation. The aim of the present study with MZ twins is to replicate the association between discordance in BW and brain morphology and test whether discordance in DNA methylation mediates this relationship. METHODS: One hundred and four adolescent MZ twins (52 pairs, of which 42% were male pairs) who have been followed regularly since birth underwent T1 weighted structural MRI, and epigenome-wide assessment of DNA methylation from saliva at age 15. RESULTS: Co-twins had very similar measures of DNA methylation and cortical morphology. Higher BW members of a twin pair had increased total cortical surface area, and decreased cortical thickness compared to their lower BW sibling. BW Discordance was positively associated with both cortical surface area and cortical volume discordance. Genes involved in neurodevelopment were tentatively identified as mediators of both the BW - cortical volume, and BW- cortical surface area relationships. CONCLUSIONS: The association between BW and cortical morphology in adolescence appears to be attributable to in utero environmental effects, and DNA methylation may play a role in mediating this relationship. Hum Brain Mapp 38:2037-2050, 2017. © 2017 Wiley Periodicals, Inc.

The Impact of the in utero and Early Postnatal Environments on Grey and White Matter Volume: A Study with Adolescent Monozygotic Twins.

Prenatal and early postnatal adversities have been shown to be associated with brain development. However, we do not know how much of this association is confounded by genetics, nor whether the postnatal environment can moderate the impact of in utero adversity. This study used a monozygotic (MZ) twin design to assess (1) the association between birth weight (BW) and brain volume in adolescence, (2) the association between within-twin-pair BW discordance and brain volume discordance in adolescence, and (3) whether the association between BW and brain volume in adolescence is mediated or moderated by early negative maternal parenting behaviours. These associations were assessed in a sample of 108 MZ twins followed longitudinally since birth and scanned at age 15. The total grey matter (GM) and white matter (WM) volumes were obtained using the Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) toolbox in the Statistical Parametric Mapping version 8 (SPM8). We found that the BW was significantly associated with the total GM and WM volumes, particularly in the superior frontal gyrus and thalamus. Within-twin-pair discordance in BW was also significantly associated with within-pair discordance in both the GM and the WM volumes, supporting the hypothesis that the specific in utero environment is associated with brain development independently of genetics. Early maternal hostile parenting behaviours and depressive symptoms were associated with total GM volume but not WM volume. Finally, greater early maternal hostility may moderate the association between the BW and GM volume in adolescence, since the positive association between the BW and total GM volume appeared stronger at higher levels of maternal hostility (trend). Together, these findings support the importance of the in utero and early environments for brain development.

Genome-wide DNA methylation variability in adolescent monozygotic twins followed since birth.

DNA methylation patterns are characterized by highly conserved developmental programs, but allow for divergent gene expression resulting from stochastic epigenetic drift or divergent environments. Genome-wide methylation studies in monozygotic (MZ) twins are providing insight into the extent of epigenetic variation that occurs, irrespective of genotype. However, little is known about the variability of DNA methylation patterns in adolescence, a period involving significant and rapid physical, emotional, social, and neurodevelopmental change. Here, we assessed genome-wide DNA methylation using the 450 K Illumina BeadChip in a sample of 37 MZ twin pairs followed longitudinally since birth to investigate: 1) the extent of variation in DNA methylation in identical genetic backgrounds in adolescence and; 2) whether these variations are randomly distributed or enriched in particular functional pathways. We also assessed stability of DNA methylation over 3-6 months to distinguish stable trait-like and variable state-like genes. A pathway analysis found high within-pair variability in genes associated with development, cellular mechanisms, tissue and cell morphology, and various disorders. Test-retest analyses performed in a sub-sample of 8 twin pairs demonstrated enrichment in gene pathways involved in organismal development, cellular growth and proliferation, cell signaling, and particular disorders. The variability found in functional gene pathways may plausibly underlie phenotypic differences in this adolescent MZ twin sample. Furthermore, we assessed stability of methylation over 3-6 months and found that some genes were stable while others were unstable, suggesting that the methylome remains dynamic in adolescence and that dynamic sites tend to be organized in certain gene pathways.

Looking beyond the DNA sequence: the relevance of DNA methylation processes for the stress-diathesis model of depression.

The functioning of the hypothalamic-pituitary-adrenal (HPA) axis and serotonergic (5-HT) system are known to be intertwined with mood. Alterations in these systems are often associated with depression. However, neither are sufficient to cause depression in and of themselves. It is now becoming increasingly clear that the environment plays a crucial role, particularly, the perinatal environment. In this review, we posit that early environmental stress triggers a series of epigenetic mechanisms that adapt the genome and programme the HPA axis and 5-HT system for survival in a harsh environment. We focus on DNA methylation as it is the most stable epigenetic mark. Given that DNA methylation patterns are in large part set within the perinatal period, long-term gene expression programming by DNA methylation is especially vulnerable to environmental insults during this period. We discuss specific examples of genes in the 5-HT system (serotonin transporter) and HPA axis (glucocorticoid receptor and arginine vasopressin enhancer) whose DNA methylation state is associated with early life experience and may potentially lead to depression vulnerability. We conclude with a discussion on the relevance of studying epigenetic mechanisms in peripheral tissue as a proxy for those occurring in the human brain and suggest avenues for future research.

Perinatal effects on in vivo measures of human brain serotonin synthesis in adulthood: a 27-year longitudinal study.

There is an increasing evidence that prenatal and early postnatal stressors have life long impacts on physical and mental health problems. Animal studies have shown that this could include enduring changes to brain serotonin neurotransmission. In the present study, we tested whether perinatal adversity in humans has a long-term impact on brain serotonin neurotransmission in adulthood. Twenty-six healthy males, recruited from a 27-year longitudinal study, underwent a positron emission tomography scan with the tracer alpha-[¹¹C]methyl-L-tryptophan (¹¹C-AMT), as an index of serotonin synthesis capacity. The trapping constant is taken as a proxy for the regional 5-HT synthesis. Birth complications, especially a delivery where the fetus showed signs of physiological distress, predicted lower ¹¹C-AMT trapping in the hippocampus and medial orbitofrontal cortex. Lower ¹¹C-AMT trapping in the medial orbitofrontal cortex was also predicted by maternal smoking and lower birth weight. There were no effects of childhood or recent adversity. This is the first human study reporting associations between perinatal adversity and adult ¹¹C-AMT trapping in the hippocampus and medial orbitofrontal cortex. The associations suggest that limbic serotonin pathways may be particularly vulnerable to environmental challenges during the period when they undergo the most prominent neurodevelopmental changes. In combination with other risk factors, perinatal stressors may contribute to increased vulnerability for psychiatric disorders in which serotonin plays a major role.

Altered patterns of brain activity during transient sadness in children at familial risk for major depression.

INTRODUCTION: We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of sadness, the prevailing mood in major depression (MD), in a prospective, well-documented community sample followed since birth. METHODS: The children, comprising 136 children (65 boys and 71 girls) of mothers with varying levels of depressive symptomatology, were scanned - using a 1.5-Tesla system - while they watched 5 blocks of both sad and neutral film excerpts. Following scanning, they rated the emotions they experienced, and if they identified sadness, they were also asked to rate its intensity. RESULTS: In children whose mothers exhibited higher depressive symptomatology, compared to children whose mothers displayed lower depressive symptomatology, altered neural responses to sad film excerpts were noted in brain regions known to be involved in sadness and MD, notably the insula, anterior cingulate cortex and caudate nucleus, even though the children did not differ in current mood. LIMITATIONS: Whether this represents genetic vulnerability or a consequence of exposure to maternal depressive symptoms at a young age is unknown. DISCUSSION: The results are consistent with the results of studies in healthy adults and MD patients. The present study suggests that an altered pattern of regional brain responses to sad stimuli, is already present in childhood and might represent vulnerability for MD later in life.

Brain serotonin synthesis in adult males characterized by physical aggression during childhood: a 21-year longitudinal study.

BACKGROUND: Adults exhibiting severe impulsive and aggressive behaviors have multiple indices of low serotonin (5-HT) neurotransmission. It remains unclear though whether low 5-HT mediates the behavior or instead reflects a pre-existing vulnerability trait. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, positron emission tomography with the tracer alpha-[(11)C]methyl-L-tryptophan ((11)C-AMT) was used to compare 5-HT synthesis capacity in two groups of adult males from a 21-year longitudinal study (mean age +/- SD: 27.1+/-0.7): individuals with a history of childhood-limited high physical aggression (C-LHPA; N = 8) and individuals with normal (low) patterns of physical aggression (LPA; N = 18). The C-LHPA males had significantly lower trapping of (11)C-AMT bilaterally in the orbitofrontal cortex and self-reported more impulsiveness. Despite this, in adulthood there were no group differences in plasma tryptophan levels, genotyping, aggression, emotional intelligence, working memory, computerized measures of impulsivity, psychosocial functioning/adjustment, and personal and family history of mood and substance abuse disorders. CONCLUSIONS/SIGNIFICANCE: These results force a re-examination of the low 5-HT hypothesis as central in the biology of violence. They suggest that low 5-HT does not mediate current behavior and should be considered a vulnerability factor for impulsive-aggressive behavior that may or may not be expressed depending on other biological factors, experience, and environmental support during development.