The genetic basis and human-specific character of schizophrenia has led to the hypothesis that human brain evolution may have played a role in the development of the disorder. We examined ...schizophrenia-related changes in brain connectivity in the context of evolutionary changes in human brain wiring by comparing in vivo neuroimaging data from humans and chimpanzees, one of our closest living evolutionary relatives and a species with which we share a very recent common ancestor. We contrasted the connectome layout between the chimpanzee and human brain and compared differences with the pattern of schizophrenia-related changes in brain connectivity as observed in patients. We show evidence of evolutionary modifications of human brain connectivity to significantly overlap with the cortical pattern of schizophrenia-related dysconnectivity (P < 0.001, permutation testing). We validated these effects in three additional, independent schizophrenia datasets. We further assessed the specificity of effects by examining brain dysconnectivity patterns in seven other psychiatric and neurological brain disorders (including, among others, major depressive disorder and obsessive-compulsive disorder, arguably characterized by behavioural symptoms that are less specific to humans), which showed no such associations with modifications of human brain connectivity. Comparisons of brain connectivity across humans, chimpanzee and macaques further suggest that features of connectivity that evolved in the human lineage showed the strongest association to the disorder, that is, brain circuits potentially related to human evolutionary specializations. Taken together, our findings suggest that human-specific features of connectome organization may be enriched for changes in brain connectivity related to schizophrenia. Modifications in human brain connectivity in service of higher order brain functions may have potentially also rendered the brain vulnerable to brain dysfunction.
•The risk of an episode was studied in women with bipolar I disorder during the perinatal period.•Episode risk was six times higher after delivery when compared to the risk during pregnancy, with a ...peak in the early postpartum period.•Risk of an episode was highest after live childbirth and lower but still substantial after abortion and miscarriage.•The risk of bipolar episodes in subsequent pregnancies increased after a previous perinatal episode.•Preventive strategies are particularly important after delivery, given the high recurrence risk within 4 weeks postpartum.
Women with bipolar I disorder are at high risk for severe episodes after childbirth, but there is no study that provides an overview on bipolar episode risk both during pregnancy and after childbirth, miscarriage and induced abortion. The aim of this study was to determine the episode risk during all pregnancy outcomes subdivided by first and subsequent pregnancies.
Participants were 436 women with bipolar I disorder from the Dutch Bipolar Cohort, having 919 pregnancies of which 762 resulted in a live childbirth, 118 ended in a miscarriage and 39 ended in induced abortion. Women reported on the occurrence of manic or depressed episodes during the perinatal period. Information about medication use was obtained by questionnaires.
Episode risk was 5.2% during pregnancy, and 30.1% in the postpartum period, with a peak in the early postpartum period. Risk of an episode was highest after live birth (34.4%), and lower after miscarriage (15.2%) and induced abortion (27.8%). Women with an episode during pregnancy or postpartum were less likely to have a second child compared to women with an uneventful first pregnancy (cOR=0.34; 95%CI: 0.22-0.51; p<0.001); if they had a second child their risk of an episode was significantly elevated with a subsequent pregnancy (cOR=6.17; 95%CI: 3.64-10.45; p<0.001).
Retrospective cross-sectional design with assessment (partial) through self-report in a homogeneous population.
Women with bipolar I disorder have a six times higher risk of an episode after delivery compared to during pregnancy, therefore preventive strategies are particularly important immediately after delivery.
Purpose
Both increased as well as decreased cancer mortality among psychiatric patients has been reported, but competing death causes were not included in the analyses. This study aims to investigate ...whether observed cancer mortality in patients with psychiatric disorders might be biased by competing death causes.
Method
In this retrospective cohort study on data from the Psychiatric Case Register Middle Netherlands linked to the death register of Statistics Netherlands, the risk of cancer death among patients with schizophrenia (
N
= 4,590), bipolar disorder (
N
= 2,077), depression (
N
= 15,130) and their matched controls (
N
= 87,405) was analyzed using a competing risk model.
Results
Compared to controls, higher hazards of cancer death were found in patients with schizophrenia (HR = 1.61, 95 % CI 1.26–2.06), bipolar disorder (HR = 1.20, 95 % CI 0.81–1.79) and depression (HR = 1.26, 95 % CI 1.10–1.44). However, the HRs of death due to suicide and other death causes were more elevated. Consequently, among those who died, the 12-year cumulative risk of cancer death was significantly lower.
Conclusions
Our analysis shows that, compared to the general population, psychiatric patients are at higher risk of dying from cancer, provided that they survive the much more elevated risks of suicide and other death causes.
•Meta-analysis suggests lifetime PTSD severity associated with advanced epigenetic age.•Childhood trauma exposure also associated with advanced epigenetic age.•These effects evident for Hannum but ...not Horvath epigenetic age algorithm.•Sex and white blood cell counts also associated with advanced epigenetic age.•Results highlight importance of studying health consequences of traumatic stress.
Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results.
We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables.
Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps = 0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps < 0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors.
Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD.
Transcriptome studies have revealed age-, disease-, and region-associated microglial phenotypes reflecting changes in microglial function during development, aging, central nervous system ...homeostasis, and pathology. The molecular mechanisms that contribute to these transcriptomic changes are largely unknown. The aim of this study was to characterize the DNA methylation landscape of human microglia and the factors that contribute to variations in the microglia methylome. We hypothesized that both age and brain region would have a large impact on DNA methylation in microglia.
Microglia from postmortem brain tissue of four different brain regions of 22 donors, encompassing 1 patient with schizophrenia, 13 patients with mood disorder pathology, and 8 control subjects, were isolated and assayed using a genome-wide methylation array.
We found that human microglial cells have a methylation profile distinct from bulk brain tissue and neurons, and age explained a considerable part of the variation. Additionally, we showed that interindividual factors had a much larger effect on the methylation landscape of microglia than brain region, which was also seen at the transcriptome level. In our exploratory analysis, we found various differentially methylated regions that were related to disease status (mood disorder vs. control). This included differentially methylated regions that are linked to gene expression in microglia, as well as to myeloid cell function or neuropsychiatric disorders.
Although based on relatively small samples, these findings suggest that the methylation profile of microglia is responsive to interindividual variations and thereby plays an important role in the heterogeneity of microglia observed at the transcriptome level.
The achievement of an HIV cure is dependent on the eradication or permanent silencing of HIV-latent viral reservoirs, including the understudied central nervous system (CNS) reservoir. This requires ...a deep understanding of the molecular mechanisms of HIV's entry into the CNS, latency establishment, persistence, and reversal. Therefore, representative CNS culture models that reflect the intercellular dynamics and pathophysiology of the human brain are urgently needed in order to study the CNS viral reservoir and HIV-induced neuropathogenesis. In this study, we characterized a human cerebral organoid model in which microglia grow intrinsically as a CNS culture model to study HIV infection in the CNS. We demonstrated that both cerebral organoids and isolated organoid-derived microglia (oMG), infected with replication-competent HIVbal reporter viruses, support productive HIV infection via the CCR5 co-receptor. Productive HIV infection was only observed in microglial cells. Fluorescence analysis revealed microglia as the only HIV target cell. Susceptibility to HIV infection was dependent on the co-expression of microglia-specific markers and the CD4 and CCR5 HIV receptors. Altogether, this model will be a valuable tool within the HIV research community to study HIV-CNS interactions, the underlying mechanisms of HIV-associated neurological disorders (HAND), and the efficacy of new therapeutic and curative strategies on the CNS viral reservoir.
Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering ...mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.
The role of the human microbiome in health and disease is increasingly appreciated. We studied the composition of microbial communities present in blood across 192 individuals, including healthy ...controls and patients with three disorders affecting the brain: schizophrenia, amyotrophic lateral sclerosis, and bipolar disorder. By using high-quality unmapped RNA sequencing reads as candidate microbial reads, we performed profiling of microbial transcripts detected in whole blood. We were able to detect a wide range of bacterial and archaeal phyla in blood. Interestingly, we observed an increased microbial diversity in schizophrenia patients compared to the three other groups. We replicated this finding in an independent schizophrenia case-control cohort. This increased diversity is inversely correlated with estimated cell abundance of a subpopulation of CD8
memory T cells in healthy controls, supporting a link between microbial products found in blood, immunity and schizophrenia.
Electroconvulsive therapy (ECT) in patients with major depression is associated with volume changes and markers of neuroplasticity in the hippocampus, in particular in the dentate gyrus. It is ...unclear if these changes are associated with cognitive side effects.
We investigated whether changes in cognitive functioning after ECT were associated with hippocampal structural changes. It was hypothesized that 1) volume increase of hippocampal subfields and 2) changes in perfusion and diffusion of the hippocampus correlated with cognitive decline.
Using ultra high field (7 T) MRI, intravoxel incoherent motion and volumetric data were acquired and neurocognitive functioning was assessed before and after ECT in 23 patients with major depression. Repeated measures correlation analysis was used to examine the relation between cognitive functioning and structural characteristics of the hippocampus.
Left hippocampal volume, left and right dentate gyrus and right CA1 volume increase correlated with decreases in verbal memory functioning. In addition, a decrease of mean diffusivity in the left hippocampus correlated with a decrease in letter fluency.
Due to methodological restrictions direct study of neuroplasticity is not possible. MRI is used as an indirect measure.
As both volume increase in the hippocampus and MD decrease can be interpreted as indirect markers for neuroplasticity that co-occur with a decrease in cognitive functioning, our results may indicate that neuroplastic processes are affecting cognitive processes after ECT.
•ECT-induced volume change of the hippocampus relate to cognitive decline.•Diffusivity changes in the hippocampus correlate with cognitive changes after ECT.•This study indicates that neuroplasticity after ECT underlies structural changes.
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