All perception is a construction of the brain from sensory input. Our first perceptions begin during gestation, making fetal brain development fundamental to how we experience a diverse world. Hallucinations are percepts without origin in physical reality that occur in health and disease. Despite longstanding research on the brain structures supporting hallucinations and on perinatal contributions to the pathophysiology of schizophrenia, what links these two distinct lines of research remains unclear. Sulcal patterns derived from structural magnetic resonance (MR) images can provide a proxy in adulthood for early brain development. We studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T MR imaging from the United Kingdom and Shanghai, China (n = 181 combined) and 63 healthy controls from Shanghai. Participants were stratified into those with (n = 79 UK; n = 22 Shanghai) and without (n = 43 UK; n = 37 Shanghai) hallucinations from the PANSS P3 scores for hallucinatory behaviour. We quantified the length, depth, and asymmetry indices of the paracingulate and superior temporal sulci (PCS, STS), which have previously been associated with hallucinations in schizophrenia, and constructed cortical folding covariance matrices organized by large-scale functional networks. In both ethnic groups, we demonstrated a significantly shorter left PCS in patients with hallucinations compared to those without, and to healthy controls. Reduced PCS length and STS depth corresponded to focal deviations in their geometry and to significantly increased covariance within and between areas of the salience and auditory networks. The discovery of neurodevelopmental alterations contributing to hallucinations establishes testable models for these enigmatic, sometimes highly distressing, perceptions and provides mechanistic insight into the pathological consequences of prenatal origins.

Interoception concerns the perception of the body's internal state. Despite the importance of this ability for health and aspects of higher-order cognition, its measurement remains problematic. Most studies of interoception employ one of two tasks: the heartbeat counting or heartbeat discrimination task. These tasks are thought to index common abilities, an assertion often used to justify the use of a single measure of cardiac interoception. However, mixed findings regarding the relationship between performance on these tasks raises the question of whether they can be used interchangeably to assess interoceptive accuracy, confidence and awareness ('metacognition'). The present study employed a meta-analytical approach to assess the association between these tasks. Pooled findings from 22 studies revealed a small relationship between accuracy scores on the measures. Additional analyses demonstrated a moderate relationship between confidence ratings but no association between measures of interoceptive awareness. These findings question the interchangeable use of the two tasks.

Higher educational attainment (EA) is observationally associated with lower risk of Alzheimer’s disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer’s disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between EA, structural brain reserve as proxied by MRI phenotypes, and Alzheimer’s disease. Summary statistics were obtained from genome-wide association studies of EA (n = 1,131,881), late-onset Alzheimer’s disease (35,274 cases, 59,163 controls), and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33,211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) EA and Alzheimer’s disease, (ii) EA and imaging-derived phenotypes, (iii) imaging-derived phenotypes and Alzheimer’s disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the effect of education on Alzheimer’s disease risk. Genetically-proxied EA was inversely associated with Alzheimer’s disease (odds ratio per standard deviation [SD] increase in genetically-predicted years of schooling (YOS) = 0.70, 95% confidence interval [CI] 0.60, 0.80). There were positive associations between genetically-predicted EA and four cortical metrics (SD units change in imaging phenotype per one SD increase in genetically-predicted YOS: surface area 0.30 [95% CI 0.20, 0.40]; volume 0.29 [95% CI 0.20, 0.37]; intrinsic curvature 0.18 [95% CI 0.11, 0.25]; local gyrification index 0.21 [95% CI 0.11, 0.31]), and inverse associations with cortical intracellular volume fraction (-0.09 [95% CI -0.15, -0.03]) and white matter hyperintensities volume (-0.14 [95% CI -0.23, -0.05]). Genetically-proxied levels of surface area, cortical volume and intrinsic curvature were positively associated with EA (SD units change in YOS per one SD increase in respective genetically-predicted imaging phenotype: 0.13 [95% CI 0.10, 0.16]; 0.15 [95% CI 0.11, 0.19]; 0.12 [95% CI 0.04, 0.19]). We found no evidence of associations between genetically-predicted imaging-derived phenotypes and Alzheimer’s disease. The inverse association of genetically-predicted EA with Alzheimer’s disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses. Our results provide support for a protective causal effect of educational attainment on Alzheimer’s disease risk, as well as potential bidirectional causal relationships between education and brain macro- and micro-structure. However, we did not find evidence that these structural markers affect risk of Alzheimer’s disease. The protective effect of education on Alzheimer’s disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.