William Frans Christiaan Baaré

Background: Children of parents with schizophrenia (SZ) or bipolar disorder (BP) are at familial high risk (FHR) of developing severe mental illnesses. Based on findings in FHR populations and adults with SZ and BP, we hypothesized that children at FHR for schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) would show sex-specific differences in subcortical grey matter volume, particularly in the thalamus, amygdala, and hippocampus, compared with population-based controls (PBC). Methods: We examined eight major subcortical grey matter structures in 108 FHR-SZ, 69 FHR-BP, and 120 PBC children aged 11-12 years from the Danish High Risk and Resilience Study. Structural magnetic resonance imaging (MRI) was used to estimate subcortical volumes and R1, a measure of myelin, iron, water, and macromolecular content. Sex-specific group differences were tested across regions. Results: The thalamus and amygdala, but not hippocampus, showed sex-specific group differences in volume. FHR-SZ males showed smaller thalamic volumes than FHR-BP and PBC males, whereas FHR-BP females showed larger thalamic volumes compared with PBC females. FHR-BP males showed larger relative amygdala volumes (corrected for total brain volume) compared to PBC males. No significant differences were observed for subcortical R1. Conclusions: Children at FHR-SZ and FHR-BP exhibited sex-specific differences in subcortical brain volumes before the typical onset of SZ and BP. These differences may reflect early sex-specific neurodevelopmental correlates of familial risk and highlight the importance of modelling sex-specific effects in developmental neuropsychiatric research. Longitudinal studies are needed to determine how these volumetric differences evolve and whether they are associated with later clinical outcomes.

BackgroundObsessive-compulsive disorder (OCD) is a severe psychiatric disorder typically emerging in childhood or adolescence. OCD models link the disorder to cortico-striato-thalamo-cortical pathway imbalances, favoring habitual over goal-directed behavior. Neuroanatomical alterations in unmedicated pediatric OCD studies have reported cortical thinning in the superior and inferior parietal cortices, lower grey matter density and lower white matter volume in the anterior cingulate cortex (ACC), and larger thalamic volume.

Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leverages 13 longitudinal datasets, including 3737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimer’s Disease. Both factors are associated with accelerated brain decline, yet it remains unclear whether memory loss is exacerbated beyond what atrophy alone would predict. Additionally, we assess whether memory decline aligns with a global pattern of atrophy or stems from distinct regional contributions. Our mega-analysis reveals a nonlinear relationship between memory decline and brain atrophy, primarily affecting individuals with above-average brain structural decline. The associations are stronger in the hippocampus but also spread across diverse cortical and subcortical regions. The associations strengthen with age, reaching moderate associations in participants in their eighties. While APOE ε4 carriers exhibit steeper brain and memory loss, genetic risk has no effect on the change-change associations. These findings support the presence of common biological macrostructural substrates underlying memory function in older age which are vulnerable to multiple age-related factors, even in the absence of overt pathological changes.

Short sleep is held to cause poorer brain health, but is short sleep associated with higher rates of brain structural decline? Analysing 8,153 longitudinal MRIs from 3,893 healthy adults, we found no evidence for an association between sleep duration and brain atrophy. In contrast, cross-sectional analyses (51,295 observations) showed inverse U-shaped relationships, where a duration of 6.5 (95% confidence interval, (5.7, 7.3)) hours was associated with the thickest cortex and largest volumes relative to intracranial volume. This fits converging evidence from research on mortality, health and cognition that points to roughly seven hours being associated with good health. Genome-wide association analyses suggested that genes associated with longer sleep for below-average sleepers were linked to shorter sleep for above-average sleepers. Mendelian randomization did not yield evidence for causal impacts of sleep on brain structure. The combined results challenge the notion that habitual short sleep causes brain atrophy, suggesting that normal brains promote adequate sleep duration—which is shorter than current recommendations.

Introduction: Stakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain—organized in a separate work package—included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project.Methods: Stakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses.Results: Consortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders.Conclusion: Stakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities.Public Contribution: Patient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration.

Background and hypotheses: Impaired interference control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired interference control as well as aberrant brain activation compared to population-based control (PBC) children. Study design: Using a flanker task, we examined interference control together with functional magnetic resonance imaging (fMRI) in 11-to-12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and population-based control (PBC) children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study – VIA 11. Study results: We included 85 (44 % female) FHR-SZ, 63 (52 % female) FHR-BP and 98 (50 % female) PBC in the analyses. Interference effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CV _RT ), revealed a group effect with similarly higher CV _RT in FHR-BP and FHR-SZ compared to PBC (BF ₁₀ = 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post-hoc analyses excluding children with psychiatric illness yielded same results. Conclusion: FHR-SZ and FHR-BP at age 11-to-12 show intact ability to resolve a spatial visuo-motor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk.

It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.

The question of how much sleep is best for the brain attracts scientific and public interest, and there is concern that insuficient sleep leads to poorer brain health. However, it is unknown how much sleep is sufficient and how much is too much. We analyzed 51,295 brain magnetic resonnance images from 47,039 participants, and calculated the self-reported sleep duration associated with the largest regional volumes and smallest ventricles relative to intracranial volume (ICV) and thickest cortex. 6.8 hours of sleep was associated with the most favorable brain outcome overall. Critical values, defined by 95% confidence intervals, were 5.7 and 7.9 hours. There was regional variation, with for instance the hippocampus showing largest volume at 6.3 hours. Moderately long sleep (> 8 hours) was more strongly associated with smaller relative volumes, thinner cortex and larger ventricles than even very short sleep (< 5 hours), but effect sizes were modest. People with larger ICV reported longer sleep (7.5 hours), so not correcting for ICV yielded longer durations associated with maximal volume. Controlling for socioeconomic status, body mass index and depression symptoms did not alter the associations. Genetic analyses showed that genes related to longer sleep in short sleepers were related to shorter sleep in long sleepers. This may indicate a genetically controlled homeostatic regulation of sleep duration. Mendelian randomization analyses did not suggest sleep duration to have a causal impact on brain structure in the analyzed datasets. The findings challenge the notion that habitual short sleep is negatively related to brain structure.

Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging.