Human Pluripotent Stem Cell-Derived Astrocyte Functionality Compares Favorably with Primary Rat Astrocytes.

Astrocytes are essential for the formation and maintenance of neural networks. However, a major technical challenge for investigating astrocyte function and disease-related pathophysiology has been the limited ability to obtain functional human astrocytes. Despite recent advances in human pluripotent stem cell (hPSC) techniques, primary rodent astrocytes remain the gold standard in coculture with human neurons. We demonstrate that a combination of leukemia inhibitory factor (LIF) and bone morphogenetic protein-4 (BMP4) directs hPSC-derived neural precursor cells to a highly pure population of astroglia in 28 d. Using single-cell RNA sequencing, we confirm the astroglial identity of these cells and highlight profound transcriptional adaptations in cocultured hPSC-derived astrocytes and neurons, consistent with their further maturation. In coculture with human neurons, multielectrode array recordings revealed robust network activity of human neurons in a coculture with hPSC-derived or rat astrocytes [3.63 ± 0.44 min-1 (hPSC-derived), 2.86 ± 0.64 min-1 (rat); p = 0.19]. In comparison, we found increased spike frequency within network bursts of human neurons cocultured with hPSC-derived astrocytes [56.31 ± 8.56 Hz (hPSC-derived), 24.77 ± 4.04 Hz (rat); p < 0.01], and whole-cell patch-clamp recordings revealed an increase of postsynaptic currents [2.76 ± 0.39 Hz (hPSC-derived), 1.07 ± 0.14 Hz (rat); p < 0.001], consistent with a corresponding increase in synapse density [14.90 ± 1.27/100 µm2 (hPSC-derived), 8.39 ± 0.63/100 µm2 (rat); p < 0.001]. Taken together, we show that hPSC-derived astrocytes compare favorably with rat astrocytes in supporting human neural network activity and maturation, providing a fully human platform for investigating astrocyte function and neuronal-glial interactions.

Differential susceptibility of human motor neurons to infection with Usutu and West Nile virus.

West Nile virus (WNV) and Usutu virus (USUV) are closely related flaviviruses with differing capacities to cause neurological disease in humans. WNV is thought to use a transneural route of neuroinvasion along motor neurons and causes severe motor deficits. The potential for use of transneural routes of neuroinvasion by USUV has not been investigated experimentally, and evidence from the few clinical case reports of USUV-associated neuroinvasive disease is lacking. We hypothesised that, compared with WNV, USUV is less able to infect motor neurons, and therefore determined the susceptibility of human induced pluripotent stem cell (iPSC)-derived spinal cord motor neurons to infection. Both viruses could grow to high titres in iPSC-derived neural cultures. However, USUV could not productively infect motor neurons due to restriction by the antiviral response, which was not induced upon WNV infection. Inhibition of the antiviral response allowed for widespread infection and transportation of USUV along motor neurons within a compartmented culture system. These results show a stark difference in the ability of these two viruses to evade initiation of intrinsic antiviral immunity. Our data suggests that USUV cannot infect motor neurons in healthy individuals but in case of immunodeficiency may pose a risk for motor-related neurological disease and transneural invasion.

West Nile virus, but not Usutu virus, can productively infect human motor neurons as a possible route of neuroinvasion.

Prevalence and incidence measures for schizophrenia among commercial health insurance and medicaid enrollees.

Given the chronic nature of schizophrenia, it is important to examine age-specific prevalence and incidence to understand the scope of the burden of schizophrenia across the lifespan. Estimates of lifetime prevalence of schizophrenia have varied widely and have often relied upon community-based data estimates from over two decades ago, while more recent studies have shown considerable promise by leveraging pooled datasets. However, the validity of measures of schizophrenia, particularly new onset schizophrenia, has not been well studied in these large health databases. The current study examines prevalence and validity of incidence measures of new diagnoses of schizophrenia in 2019 using two U.S. administrative health databases: MarketScan, a national database of individuals receiving employer-sponsored commercial insurance (N = 16,365,997), and NYS Medicaid, a large state public insurance program (N = 4,414,153). Our results indicate that the prevalence of schizophrenia is over 10-fold higher, and the incidence two-fold higher, in the NYS Medicaid population compared to the MarketScan database. In addition, prevalence increased over the lifespan in the Medicaid population, but decreased in the employment based MarketScan database beginning in early adulthood. Incident measures of new diagnoses of schizophrenia had excellent validity, with positive predictive values and specificity exceeding 95%, but required a longer lookback period for Medicaid compared to MarketScan. Further work is needed to leverage these findings to develop robust clinical outcome predictors for new onset of schizophrenia within large administrative health data systems.

iPSC-derived healthy human astrocytes selectively load miRNAs targeting neuronal genes into extracellular vesicles.

Astrocytes are in constant communication with neurons during the establishment and maturation of functional networks in the developing brain. Astrocytes release extracellular vesicles (EVs) containing microRNA (miRNA) cargo that regulates transcript stability in recipient cells. Astrocyte released factors are thought to be involved in neurodevelopmental disorders. Healthy astrocytes partially rescue Rett Syndrome (RTT) neuron function. EVs isolated from stem cell progeny also correct aspects of RTT. EVs cross the blood-brain barrier (BBB) and their cargo is found in peripheral blood which may allow non-invasive detection of EV cargo as biomarkers produced by healthy astrocytes. Here we characterize miRNA cargo and sequence motifs in healthy human astrocyte derived EVs (ADEVs). First, human induced Pluripotent Stem Cells (iPSC) were differentiated into Neural Progenitor Cells (NPCs) and subsequently into astrocytes using a rapid differentiation protocol. iPSC derived astrocytes expressed specific markers, displayed intracellular calcium transients and secreted ADEVs. miRNAs were identified by RNA-Seq on astrocytes and ADEVs and target gene pathway analysis detected brain and immune related terms. The miRNA profile was consistent with astrocyte identity, and included approximately 80 miRNAs found in astrocytes that were relatively depleted in ADEVs suggestive of passive loading. About 120 miRNAs were relatively enriched in ADEVs and motif analysis discovered binding sites for RNA binding proteins FUS, SRSF7 and CELF5. miR-483-5p was the most significantly enriched in ADEVs. This miRNA regulates MECP2 expression in neurons and has been found differentially expressed in blood samples from RTT patients. Our results identify potential miRNA biomarkers selectively sorted into ADEVs and implicate RNA binding protein sequence dependent mechanisms for miRNA cargo loading.

Morphological correlates of pyramidal cell axonal myelination in mouse and human neocortex.

The axons of neocortical pyramidal neurons are frequently myelinated. Heterogeneity in the topography of axonal myelination in the cerebral cortex has been attributed to a combination of electrophysiological activity, axonal morphology, and neuronal-glial interactions. Previously, we showed that axonal segment length and caliber are critical local determinants of fast-spiking interneuron myelination. However, the factors that determine the myelination of individual axonal segments along neocortical pyramidal neurons remain largely unexplored. Here, we used structured illumination microscopy to examine the extent to which axonal morphology is predictive of the topography of myelination along neocortical pyramidal neurons. We identified critical thresholds for axonal caliber and interbranch distance that are necessary, but not sufficient, for myelination of pyramidal cell axons in mouse primary somatosensory cortex (S1). Specifically, we found that pyramidal neuron axonal segments with a caliber < 0.24 µm or interbranch distance < 18.10 µm are rarely myelinated. Moreover, we further confirmed that these findings in mice are similar for human neocortical pyramidal cell myelination (caliber < 0.25 µm, interbranch distance < 19.00 µm), suggesting that this mechanism is evolutionarily conserved. Taken together, our findings suggest that axonal morphology is a critical correlate of the topography and cell-type specificity of neocortical myelination.

Running in the FAMILY: understanding and predicting the intergenerational transmission of mental illness.

Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.

Music to prevent deliriUm during neuroSurgerY (MUSYC): a single-centre, prospective randomised controlled trial.

OBJECTIVES: Delirium is a serious complication following neurosurgical procedures. We hypothesise that the beneficial effect of music on a combination of delirium-eliciting factors might reduce delirium incidence following neurosurgery and subsequently improve clinical outcomes. DESIGN: Prospective randomised controlled trial. SETTING: Single centre, conducted at the neurosurgical department of the Erasmus Medical Center, Rotterdam, the Netherlands. PARTICIPANTS: Adult patients undergoing craniotomy were eligible. INTERVENTIONS: Patients in the intervention group received preferred recorded music before, during and after the operation until day 3 after surgery. Patients in the control group were treated according to standard of clinical care. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was presence or absence of postoperative delirium within the first 5 postoperative days measured with the Delirium Observation Screening Scale (DOSS) and, in case of a daily mean score of 3 or higher, a psychiatric evaluation with the latest Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. Secondary outcomes included anxiety, heart rate variability (HRV), depth of anaesthesia, delirium severity and duration, postoperative complications, length of stay and location of discharge. RESULTS: We enrolled 189 patients (music=95, control=94) from July 2020 through September 2021. Delirium, as assessed by the DOSS, was less common in the music (n=11, 11.6%) than in the control group (n=21, 22.3%, OR:0.49, p=0.048). However, after DSM-5 confirmation, differences in delirium were not significant (4.2% vs 7.4%, OR:0.47, p=0.342). Moreover, music increased the HRV (root mean square of successive differences between normal heartbeats, p=0.012). All other secondary outcomes were not different between groups. CONCLUSION: Our results support the efficacy of music in reducing the incidence of delirium after craniotomy, as found with DOSS but not after DSM-5 confirmation, substantiated by the effect of music on preoperative autonomic tone. Delirium screening tools should be validated and the long-term implications should be evaluated after craniotomy. TRIAL REGISTRATION NUMBER: Trialregister.nl: NL8503 and ClinicalTrials.gov: NCT04649450.

Psychotic experiences, suicidality and non-suicidal self-injury in adolescents: Independent findings from two cohorts.

BACKGROUND: Prior studies have shown that psychotic experiences are prospectively associated with an increased risk of suicidality. However, it is unclear whether this association is causal or arises from shared risk factors. Furthermore, little is known about the association between psychotic experiences and non-suicidal self-injury (NSSI). METHODS: We used data from two independent samples of young adolescents, which we analyzed separately. In a population-based cohort, data on hallucinatory experiences and suicidality were collected at ages 10 and 14 years (N = 3435). In a cross-sectional study of a population oversampled for elevated psychopathology levels, psychotic experiences, suicidality, and NSSI were assessed at age 15 years (N = 910). Analyses were adjusted for sociodemographic covariates, maternal psychopathology, intelligence, childhood adversity, and mental health problems. RESULTS: Psychotic experiences were prospectively associated with an increased risk of suicidality, even when considering self-harm ideation at baseline. Furthermore, persistent and incident, but not remittent, patterns of psychotic experiences were related to an increased burden of suicidality. Self-harm ideation was also prospectively associated with the risk for psychotic experiences, although of smaller magnitude and only by self-report. Among at-risk adolescents, psychotic experiences were cross-sectionally associated with a greater burden of suicidality and a higher frequency of NSSI events, with more extensive tissue damage. CONCLUSION: Psychotic experiences are longitudinally associated with suicidality beyond the effects of shared risk factors. We also found modest support for reverse temporality, which warrants further investigation. Overall, our findings highlight the importance of assessing psychotic experiences as an index of risk for suicidality and NSSI.

A simplified protocol for the generation of cortical brain organoids.

Human brain organoid technology has the potential to generate unprecedented insight into normal and aberrant brain development. It opens up a developmental time window in which the effects of gene or environmental perturbations can be experimentally tested. However, detection sensitivity and correct interpretation of phenotypes are hampered by notable batch-to-batch variability and low reproducibility of cell and regional identities. Here, we describe a detailed, simplified protocol for the robust and reproducible generation of brain organoids with cortical identity from feeder-independent induced pluripotent stem cells (iPSCs). This self-patterning approach minimizes media supplements and handling steps, resulting in cortical brain organoids that can be maintained over prolonged periods and that contain radial glial and intermediate progenitors, deep and upper layer neurons, and astrocytes.

Modulating mutational outcomes and improving precise gene editing at CRISPR-Cas9-induced breaks by chemical inhibition of end-joining pathways.

Gene editing through repair of CRISPR-Cas9-induced chromosomal breaks offers a means to correct a wide range of genetic defects. Directing repair to produce desirable outcomes by modulating DNA repair pathways holds considerable promise to increase the efficiency of genome engineering. Here, we show that inhibition of non-homologous end joining (NHEJ) or polymerase theta-mediated end joining (TMEJ) can be exploited to alter the mutational outcomes of CRISPR-Cas9. We show robust inhibition of TMEJ activity at CRISPR-Cas9-induced double-strand breaks (DSBs) using ART558, a potent polymerase theta (PolÏ´) inhibitor. Using targeted sequencing, we show that ART558 suppresses the formation of microhomology-driven deletions in favor of NHEJ-specific outcomes. Conversely, NHEJ deficiency triggers the formation of large kb-sized deletions, which we show are the products of mutagenic TMEJ. Finally, we show that combined chemical inhibition of TMEJ and NHEJ increases the efficiency of homology-driven repair (HDR)-mediated precise gene editing. Our work reports a robust strategy to improve the fidelity and safety of genome engineering.

Brain development after intrauterine exposure to lithium: A magnetic resonance imaging study in school-age children.

OBJECTIVE: Lithium is often continued during pregnancy to reduce the risk of perinatal mood episodes for women with bipolar disorder. However, little is known about the effect of intrauterine lithium exposure on brain development. The aim of this study was to investigate brain structure in children after intrauterine exposure to lithium. METHODS: Participants were offspring, aged 8-14 years, of women with a diagnosis of bipolar spectrum disorder. In total, 63 children participated in the study: 30 with and 33 without intrauterine exposure to lithium. Global brain volume outcomes and white matter integrity were assessed using structural MRI and diffusion tensor imaging, respectively. Primary outcomes were total brain, cortical and subcortical gray matter, cortical white matter, lateral ventricles, cerebellum, hippocampus and amygdala volumes, cortical thickness, cortical surface area and global fractional anisotropy, and mean diffusivity. To assess how our data compared to the general population, global brain volumes were compared to data from the Generation R study (N = 3243). RESULTS: In our primary analyses, we found no statistically significant associations between intrauterine exposure to lithium and structural brain measures. There was a non-significant trend toward reduced subcortical gray matter volume. Compared to the general population, lithium-exposed children showed reduced subcortical gray and cortical white matter volumes. CONCLUSION: We found no differences in brain structure between lithium-exposed and non-lithium-exposed children aged 8-14 years following correction for multiple testing. While a rare population to study, future and likely multi-site studies with larger datasets are required to validate and extend these initial findings.

In vitro and in vivo differences in neurovirulence between D614G, Delta And Omicron BA.1 SARS-CoV-2 variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism is not fully understood, several studies have shown that neuroinflammation occurs in the acute and post-acute phase. As these studies have predominantly been performed with isolates from 2020, it is unknown if there are differences among SARS-CoV-2 variants in their ability to cause neuroinflammation. Here, we compared the neuroinvasiveness, neurotropism and neurovirulence of the SARS-CoV-2 ancestral strain D614G, the Delta (B.1.617.2) and Omicron BA.1 (B.1.1.529) variants using in vitro and in vivo models. The Omicron BA.1 variant showed reduced neurotropism and neurovirulence compared to Delta and D614G in human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured with astrocytes. Similar differences were obtained in Syrian hamsters inoculated with D614G, Delta and the Omicron BA.1 variant 5 days post infection. Replication in the olfactory mucosa was observed in all hamsters, but most prominently in D614G inoculated hamsters. Furthermore, neuroinvasion into the CNS via the olfactory nerve was observed in D614G, but not Delta or Omicron BA.1 inoculated hamsters. Furthermore, neuroinvasion was associated with neuroinflammation in the olfactory bulb of hamsters inoculated with D614G. Altogether, our findings suggest differences in the neuroinvasive, neurotropic and neurovirulent potential between SARS-CoV-2 variants using in vitro hiPSC-derived neural cultures and in vivo in hamsters during the acute phase of the infection.

Hallucinations and Brain Morphology Across Early Adolescence: A Longitudinal Neuroimaging Study.

BACKGROUND: Psychotic disorders have been widely associated with structural brain abnormalities. However, it is unclear whether brain structure predicts psychotic experiences in youth from the general population, owing to an overall paucity of studies and predominantly cross-sectional designs. Here, the authors investigated longitudinal associations between brain morphology and hallucinations from childhood to early adolescence. METHODS: This study was embedded in the population-based Generation R Study. Children underwent structural neuroimaging at age 10 years (N = 2042); a subsample received a second scan at age 14 years (n = 964). Hallucinations were assessed at ages 10 and 14 years and studied as a binary variable. Cross-lagged panel models and generalized linear mixed-effects models were fitted to examine longitudinal associations between brain morphology and hallucinations. RESULTS: Smaller total gray and white matter volumes and total cortical surface area at baseline were associated with a higher occurrence of hallucinations between ages 10 and 14 years. The regions associated with hallucinations were widespread, including the frontal, parietal, temporal, and occipital lobes, as well as the insula and cingulate cortex. Analyses of subcortical structures revealed that smaller baseline hippocampal volumes were longitudinally associated with hallucinations, although this association was no longer significant following adjustment for intracranial volume. No evidence for reverse temporality was observed (i.e., hallucinations predicting brain differences). CONCLUSIONS: The findings from this longitudinal study suggest that global structural brain differences are associated with the development of hallucinations. These results extend findings from clinical populations and provide evidence for a neurodevelopmental vulnerability across the psychosis continuum.

Dissecting schizophrenia phenotypic variation: the contribution of genetic variation, environmental exposures, and gene-environment interactions.

Schizophrenia is among the leading causes of disability worldwide. Prior studies have conclusively demonstrated that the etiology of schizophrenia contains a strong genetic component. However, the understanding of environmental contributions and gene-environment interactions have remained less well understood. Here, we estimated the genetic and environmental contributions to schizophrenia risk using a unique combination of data sources and mathematical models. We used the administrative health records of 481,657 U.S. individuals organized into 128,989 families. In addition, we employed rich geographically specific measures of air, water, and land quality across the United States. Using models of progressively increasing complexity, we examined both linear and non-linear contributions of genetic variation and environmental exposures to schizophrenia risk. Our results demonstrate that heritability estimates differ significantly when gene-environment interactions are included in the models, dropping from 79% for the simplest model, to 46% in the best-fit model which included the full set of linear and non-linear parameters. Taken together, these findings suggest that environmental factors are an important source of explanatory variance underlying schizophrenia risk. Future studies are warranted to further explore linear and non-linear environmental contributions to schizophrenia risk and investigate the causality of these associations.

The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection is associated with a diverse spectrum of neurological complications during the acute and postacute stages. The pathogenesis of these complications is complex and dependent on many factors. For accurate and consistent interpretation of experimental data in this fast-growing field of research, it is essential to use terminology consistently. In this article, we outline the distinctions between neuroinvasiveness, neurotropism, and neurovirulence. Additionally, we discuss current knowledge of these distinct features underlying the pathogenesis of SARS-CoV-2-associated neurological complications. Lastly, we briefly discuss the advantages and limitations of different experimental models, and how these approaches can further be leveraged to advance the field.

Cortical Inhibition and Plasticity in Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) is a severe psychiatric disorder that is associated with various cognitive impairments, including learning and memory deficits. As synaptic plasticity is considered an important mechanism underlying learning and memory, deficits in cortical plasticity might play a role in the pathophysiology of patients with MDD. We used Transcranial Magnetic Stimulation (TMS) to assess inhibitory neurotransmission and cortical plasticity in the motor cortex of MDD patients and controls. METHODS: We measured the cortical silent period (CSP) and short interval cortical inhibition (SICI), as well as intermittent theta-burst stimulation (iTBS), in 9 drug-free MDD inpatients and 18 controls. RESULTS: The overall response to the CSP, SICI, and iTBS paradigms was not significantly different between the patient and control groups. iTBS induction resulted in significant potentiation after 20 mins in the control group (t (17) = -2.8, p = 0.01), whereas no potentiation was observed in patients. CONCLUSIONS: Potentiation of MEP amplitudes was not observed within the MDD group. No evidence was found for medium-to-large effect size differences in CSP and SICI measures in severely depressed drug-free patients, suggesting that reduced cortical inhibition is unlikely to be a robust correlate of the pathophysiological mechanism in MDD. However, these findings should be interpreted with caution due to the high inter-subject variability and the small sample size. SIGNIFICANCE: These findings advance our understanding of neurophysiological functioning in drug-free severely depressed inpatients.

Myelination synchronizes cortical oscillations by consolidating parvalbumin-mediated phasic inhibition.

Parvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations, but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here, using toxic and genetic mouse models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals and increases failures, and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during behaviors of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization.

The brain contains billions of neurons that connect with each other via cable-like structures called axons. Axons transmit electrical impulses and are often wrapped in a fatty substance called myelin. This insulation increases the speed of nerve impulses and reduces the energy lost over long distances. Loss or damage of the myelin layer ­ as is the case for multiple sclerosis, a chronic neuroinflammatory and neurodegenerative disease of the central nervous system ­ can cause serious disability. However, a fast-firing neuron within the brain, called PV⁺ interneuron, has short, sparsely myelinated axons. Even so, PV⁺ interneurons are powerful inhibitors that regulate important cognitive processes in gray matter areas, including the outermost parts, in the cortex. Yet it remains unclear how the unusual, patchy myelination affects their function. To examine these questions, Dubey et al. used genetically engineered mice either lacking or losing myelin and studied the impact on PV⁺ interneurons and slow brain waves. As mice progressively lost myelin, the speed of inhibitory signals from PV⁺ interneurons did not change but their signal strength decreased. As a result, the power of slow brain waves, no longer inhibited by PV⁺ interneurons, increased. These waves also triggered spikes of epileptic-like brain activity when the mice were inactive and quiet. Restoring the activity of myelin-deficient PV⁺ interneurons helped to reverse these deficits. This suggests that myelination, however patchy on PV⁺ interneurons, is required to reach their full inhibitory potential. Moreover, the findings shed light on how myelin loss might underpin aberrant brain activity, which have been observed in people with multiple sclerosis. More research could help determine whether these epilepsy-like spikes could be a biomarker of multiple sclerosis and/or a target for developing new therapeutic strategies to limit cognitive impairments.

Long-term association of pregnancy and maternal brain structure: the Rotterdam Study.

The peripartum period is the highest risk interval for the onset or exacerbation of psychiatric illness in women's lives. Notably, pregnancy and childbirth have been associated with short-term structural and functional changes in the maternal human brain. Yet the long-term effects of pregnancy on maternal brain structure remain unknown. We investigated a large population-based cohort to examine the association between parity and brain structure. In total, 2,835 women (mean age 65.2 years; all free from dementia, stroke, and cortical brain infarcts) from the Rotterdam Study underwent magnetic resonance imaging (1.5 T) between 2005 and 2015. Associations of parity with global and lobar brain tissue volumes, white matter microstructure, and markers of vascular brain disease were examined using regression models. We found that parity was associated with a larger global gray matter volume (ß = 0.14, 95% CI = 0.09-0.19), a finding that persisted following adjustment for sociodemographic factors. A non-significant dose-dependent relationship was observed between a higher number of childbirths and larger gray matter volume. The gray matter volume association with parity was globally proportional across lobes. No associations were found regarding white matter volume or integrity, nor with markers of cerebral small vessel disease. The current findings suggest that pregnancy and childbirth are associated with robust long-term changes in brain structure involving a larger global gray matter volume that persists for decades. Future studies are warranted to further investigate the mechanism and physiological relevance of these differences in brain morphology.

Schizophrenia polygenic risk is associated with child mental health problems through early childhood adversity: evidence for a gene-environment correlation.

Previous studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations arise. Here, we explored a possible gene-environment correlation in the association of schizophrenia polygenic risk with mental health problems via childhood adversity. This study was embedded in the population-based Generation R Study, including N = 1901 participants with genotyping for schizophrenia polygenic risk, maternal reporting of childhood adversity, and Child Behaviour Checklist measurement of mental health problems. Independent replication was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3641). Associations were analysed with Poisson regression and statistical mediation analysis. Higher burden of schizophrenia polygenic risk was associated with greater exposure to childhood adversity (P-value threshold < 0.5: Generation R Study, OR = 1.08, 95%CI 1.02-1.15, P = 0.01; ALSPAC, OR = 1.02, 95%CI 1.01-1.03, P < 0.01). Childhood adversities partly explained the relationship of schizophrenia polygenic risk with emotional, attention, and thought problems (proportion explained, range 5-23%). Direct effects of schizophrenia polygenic risk and adversity on mental health outcomes were also observed. In summary, genetic liability to schizophrenia increased the risk for mental health problems in the general paediatric population through childhood adversity. Although this finding could result from a mediated causal relationship between genotype and mental health, we argue that these observations most likely reflect a gene-environment correlation, i.e. adversities are a marker for the genetic risk that parents transmit to children. These and similar recent findings raise important conceptual questions about preventative interventions aimed at reducing childhood adversities.

Long-term outcome of postpartum psychosis: a prospective clinical cohort study in 106 women.

OBJECTIVE: We aimed to investigate the outcome of postpartum psychosis over a four-year follow-up, and to identify potential clinical markers of mood/psychotic episodes outside of the postpartum period. METHODS: One hundred and six women with a diagnosis of first-onset mania or psychosis during the postpartum period were included in this prospective longitudinal study. Women were categorized into either (1) recurrence of non-postpartum mood/psychotic episodes or (2) mania/psychosis limited to the postpartum period. We summarize the longitudinal course of the illness per group. We used a logistic regression model to identify clinical predictors of recurrence of mood/psychotic episodes outside of the postpartum period. RESULTS: Over two thirds of the women included in this study did not have major psychiatric episodes outside of the postpartum period during follow-up. The overall recurrence rate of mood/psychotic episodes outside the postpartum period was ~ 32%. Of these women, most transitioned to a bipolar disorder diagnosis. None of the women fulfilled diagnostic criteria for schizophrenia or schizophreniform disorder. No clinical markers significantly predicted recurrence outside of the postpartum period. CONCLUSIONS: For the majority of women with first-onset postpartum psychosis, the risk of illness was limited to the period after childbirth. For the remaining women, postpartum psychosis was part of a mood/psychotic disorder with severe non-postpartum recurrence, mainly in the bipolar spectrum. No clinical predictors for risk of severe episodes outside the postpartum period emerged. Our findings add to previous evidence suggesting a fundamental link between postpartum psychosis and bipolar disorder, which may represent two distinct diagnoses within the same spectrum.