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The hippocampus is a complex brain structure with key roles in cognitive and emotional processing and with subregion abnormalities associated with a range of disorders and psychopathologies. Here we combine data from two large independent young adult twin/sibling cohorts to obtain the most accurate estimates to date of genetic covariation between hippocampal subfield volumes and the hippocampus as a single volume. The combined sample included 2148 individuals, comprising 1073 individuals from 627 families (mean age = 22.3 years) from the Queensland Twin IMaging (QTIM) Study, and 1075 individuals from 454 families (mean age = 28.8 years) from the Human Connectome Project (HCP). Hippocampal subfields were segmented using FreeSurfer version 6.0 (CA4 and dentate gyrus were phenotypically and genetically indistinguishable and were summed to a single volume). Multivariate twin modeling was conducted in OpenMx to decompose variance into genetic and environmental sources. Bivariate analyses of hippocampal formation and each subfield volume showed that 10%–72% of subfield genetic variance was independent of the hippocampal formation, with greatest specificity found for the smaller volumes; for example, CA2/3 with 42% of genetic variance being independent of the hippocampus; fissure (63%); fimbria (72%); hippocampus-amygdala transition area (41%); parasubiculum (62%). In terms of genetic influence, whole hippocampal volume is a good proxy for the largest hippocampal subfields, but a poor substitute for the smaller subfields. Additive genetic sources accounted for 49%–77% of total variance for each of the subfields in the combined sample multivariate analysis. In addition, the multivariate analyses were sufficiently powered to identify common environmental influences (replicated in QTIM and HCP for the molecular layer and CA4/dentate gyrus, and accounting for 7%–16% of total variance for 8 of 10 subfields in the combined sample). This provides the clearest indication yet from a twin study that factors such as home environment may influence hippocampal volumes (albeit, with caveats).

On average, men and women differ in brain structure and behavior, raising the possibility of a link between sex differences in brain and behavior. But women and men are also subject to different societal and cultural norms. We navigated this challenge by investigating variability of sex-differentiated brain structure within each sex. Using data from the Queensland Twin IMaging study ( n = 1,040) and Human Connectome Project ( n = 1,113), we obtained data-driven measures of individual differences along a male–female dimension for brain and behavior based on average sex differences in brain structure and behavior, respectively. We found a weak association between these brain and behavioral differences, driven by brain size. These brain and behavioral differences were moderately heritable. Our findings suggest that behavioral sex differences are, to some extent, related to sex differences in brain structure but that this is mainly driven by differences in brain size, and causality should be interpreted cautiously.

Infants born very preterm face a range of neurodevelopmental challenges in cognitive, language, behavioural and/or motor domains. Early accurate identification of those at risk of adverse neurodevelopmental outcomes, through clinical assessment and Magnetic Resonance Imaging (MRI), enables prognostication of outcomes and the initiation of targeted early interventions. This study utilises a prospective cohort of 181 infants born31 weeks gestation, who had 3T MRIs acquired at 29-35 weeks postmenstrual age and a comprehensive neurodevelopmental evaluation at 2 years corrected age (CA). Cognitive, language and motor outcomes were assessed using the Bayley Scales of Infant and Toddler Development - Third Edition and functional motor outcomes using the Neuro-sensory Motor Developmental Assessment. By leveraging advanced structural MRI pre-processing steps to standardise the data, and the state-of-the-art developing Human Connectome Pipeline, early MRI biomarkers of neurodevelopmental outcomes were identified. Using Least Absolute Shrinkage and Selection Operator (LASSO) regression, significant associations between brain structure on early MRIs with 2-year outcomes were obtained (r = 0.51 and 0.48 for motor and cognitive outcomes respectively) on an independent 25% of the data. Additionally, important brain biomarkers from early MRIs were identified, including cortical grey matter volumes, as well as cortical thickness and sulcal depth across the entire cortex. Adverse outcome on the Bayley-III motor and cognitive composite scores were accurately predicted, with an Area Under the Curve of 0.86 for both scores. These associations between 2-year outcomes and patient prognosis and early neonatal MRI measures demonstrate the utility of imaging prior to term equivalent age for providing earlier commencement of targeted interventions for infants born preterm.

Autism spectrum disorder (ASD) is more common in males than females and has been linked to male-typical behavior. Accordingly, the "Extreme Male Brain" hypothesis suggests that ASD is associated with an exaggeratedly male-typical brain. To test this hypothesis, we derived a data-driven measure of individual differences along a male-female dimension based on sex differences in subcortical brain shape (i.e., brain maleness) by training our algorithm on two population samples (Queensland Twin IMaging study and Human Connectome Project; combined N = 2153). We then applied this algorithm to two clinical datasets (Autism Brain Imaging Data Exchange I and II; ASD N = 1060; neurotypical controls N = 1166) to obtain a brain maleness score for each individual, representing maleness of their brain on a male-female continuum. Consistent with the Extreme Male Brain hypothesis, we found a higher mean brain maleness score in the ASD group than in controls (d = 0.20 [0.12-0.29]), parallel to higher scores for control males than control females (d = 1.17 [1.05-1.29]). Further, brain maleness was positively associated with autistic symptoms. We tested the possibility this finding was driven by the ASD group's larger brains than controls (d = 0.17 [0.08-0.25]), given that males had larger brains than females (d = 0.96 [0.84-1.07]). Indeed, after adjusting for differences in brain size, the brain maleness difference between the ASD group and controls disappeared, and no association with autistic symptoms remained (after controlling for multiple comparisons), suggesting greater maleness of the autistic brain is driven by brain size. Brain maleness may be influenced by the same factors that influence brain size. LAY SUMMARY: A popular theory proposes that individuals with autistic spectrum disorder (ASD) have an "extreme male brain", but this has not been subject to rigorous, direct tests. We developed a measure of individual differences along a male-female dimension and then derived this measure for 1060 individuals with ASD and 1166 neurotypical controls. Individuals with ASD had slightly more male-type brains. However, this difference is accounted for by males and individuals with ASD having relatively larger brains than females and controls, respectively.

On average, men and women differ in brain structure and behaviour, raising the possibility of a link between sex differences in brain and behaviour. But women and men are also subject to different societal and cultural norms. We navigated this challenge by investigating variability of sex-differentiated brain structure within each sex. Using data from the Queensland Twin IMaging study (N=1,040) and Human Connectome Project (N=1,113), we obtained data-driven measures of individual differences along a male-female dimension for brain and behaviour based on average sex differences in brain structure and behaviour, respectively. We found a weak association between these brain and behavioural differences, driven by brain size. These brain and behavioural differences were moderately heritable. Our findings suggest that behavioural sex differences are to some extent related to sex differences in brain structure, but that this is mainly driven by differences in brain size, and causality should be interpreted cautiously.

The hippocampus is a brain region critical for learning and memory, and is also implicated in several neuropsychiatric disorders that show sex differences in prevalence, symptom expression, and mean age of onset. On average, males have larger hippocampal volumes than females, but findings are inconclusive after adjusting for overall brain size. Although the hippocampus is a heterogenous structure, few studies have focused on sex differences in the hippocampal subfields – with little consensus on whether there are regionally specific sex differences in the hippocampus after adjusting for brain size, or whether it is important to adjust for total hippocampal volume (HPV). Here, using two young adult cohorts from the Queensland Twin IMaging study (QTIM; N ​= ​727) and the Human Connectome Project (HCP; N ​= ​960), we examined differences between males and females in the volumes of 12 hippocampal subfields, extracted using FreeSurfer 6.0. After adjusting the subfield volumes for either HPV or brain size (brain segmentation volume (BSV)) using four controlling methods (allometric, covariate, residual and matching), we estimated the percentage difference of the sex effect (males versus females) and Cohen's d using hierarchical general linear models. Males had larger volumes compared to females in the parasubiculum (up to 6.04%; Cohen's d ​= ​0.46) and fimbria (up to 8.75%; d ​= ​0.54) after adjusting for HPV. These sex differences were robust across the two cohorts and multiple controlling methods, though within cohort effect sizes were larger for the matched approach, due to the smaller sub-sample. Additional sex effects were identified in the HCP cohort and combined (QTIM and HCP) sample (hippocampal fissure (up to 6.79%), presubiculum (up to 3.08%), and hippocampal tail (up to −0.23%)). In contrast, no sex differences were detected for the volume of the cornu ammonis (CA)2/3, CA4, Hippocampus-Amygdala Transition Area (HATA), or the granule cell layer of the dentate gyrus (GCDG). These findings show that, independent of differences in HPV, there are regionally specific sex differences in the hippocampus, which may be most prominent in the fimbria and parasubiculum. Further, given sex differences were less consistent across cohorts after controlling for BSV, adjusting for HPV rather than BSV may benefit future studies. This work may help in disentangling sex effects, and provide a better understanding of the implications of sex differences for behaviour and neuropsychiatric disorders.

This study investigates a method to predict medical outcome of cholinesterase inhibitors in patients with Alzheimer’s disease (AD) and vascular dementia (VaD). Van Gool predicts that patients with cholinergic deficit symptoms will benefit from treatment whereas patients without will experience side effects because of overstimulation of the cholinergic system. We predicted that AD and VaD patients with a longer RT experience fewer side effects than patients with a faster response and that VaD patients have a longer RT than AD patients. A number of 71 patients with AD or VaD diagnosis were included. A sustained attention task was administered, as well as the MMSE and a questionnaire about side effects. Results indicated that VaD patients with a longer RT reported fewer side effects. Furthermore, patients with VaD had a longer RT than patients with AD. MMSE was negatively correlated with RT in the VaD group. Thus, the performance on the attention task seems associated with suffering from side effects and thus tends to predict medical outcome in VaD, but not in AD. Perhaps this attention task was not sensitive enough to measure cholinergic deficit symptoms in AD patients. Furthermore, different doses of medication might confound the effect for the AD group.