Autism-related dietary preferences mediate autism-gut microbiome associations.

There is increasing interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). However, previous studies have been underpowered and have not been designed to address potential confounding factors in a comprehensive way. We performed a large autism stool metagenomics study (n = 247) based on participants from the Australian Autism Biobank and the Queensland Twin Adolescent Brain project. We found negligible direct associations between ASD diagnosis and the gut microbiome. Instead, our data support a model whereby ASD-related restricted interests are associated with less-diverse diet, and in turn reduced microbial taxonomic diversity and looser stool consistency. In contrast to ASD diagnosis, our dataset was well powered to detect microbiome associations with traits such as age, dietary intake, and stool consistency. Overall, microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and we caution against claims that the microbiome has a driving role in ASD.

Perceiving and misperceiving speech: lexical and sublexical processing in the superior temporal lobes.

Listeners can use prior knowledge to predict the content of noisy speech signals, enhancing perception. However, this process can also elicit misperceptions. For the first time, we employed a prime-probe paradigm and transcranial magnetic stimulation to investigate causal roles for the left and right posterior superior temporal gyri (pSTG) in the perception and misperception of degraded speech. Listeners were presented with spectrotemporally degraded probe sentences preceded by a clear prime. To produce misperceptions, we created partially mismatched pseudo-sentence probes via homophonic nonword transformations (e.g. The little girl was excited to lose her first tooth-Tha fittle girmn wam expited du roos har derst cooth). Compared to a control site (vertex), inhibitory stimulation of the left pSTG selectively disrupted priming of real but not pseudo-sentences. Conversely, inhibitory stimulation of the right pSTG enhanced priming of misperceptions with pseudo-sentences, but did not influence perception of real sentences. These results indicate qualitatively different causal roles for the left and right pSTG in perceiving degraded speech, supporting bilateral models that propose engagement of the right pSTG in sublexical processing.

Heritability of cerebellar subregion volumes in adolescent and young adult twins.

Twin studies have found gross cerebellar volume to be highly heritable. However, whether fine-grained regional volumes within the cerebellum are similarly heritable is still being determined. Anatomical MRI scans from two independent datasets (QTIM: Queensland Twin IMaging, N = 798, mean age 22.1 years; QTAB: Queensland Twin Adolescent Brain, N = 396, mean age 11.3 years) were combined with an optimised and automated cerebellum parcellation algorithm to segment and measure 28 cerebellar regions. We show that the heritability of regional volumetric measures varies widely across the cerebellum ( h 2 $$ {h}^2 $$ 47%-91%). Additionally, the good to excellent test-retest reliability for a subsample of QTIM participants suggests that non-genetic variance in cerebellar volumes is due primarily to unique environmental influences rather than measurement error. We also show a consistent pattern of strong associations between the volumes of homologous left and right hemisphere regions. Associations were predominantly driven by genetic effects shared between lobules, with only sparse contributions from environmental effects. These findings are consistent with similar studies of the cerebrum and provide a first approximation of the upper bound of heritability detectable by genome-wide association studies.

Right hemispheric structural connectivity and poststroke language recovery.

Poststroke aphasia typically results from brain damage to the left-lateralized language network. The contribution of the right-lateralized homologues in aphasia recovery remains equivocal. In this longitudinal observational study, we specifically investigated the role of right hemisphere structural connectome in aphasia recovery. Twenty-two patients with aphasia after a left hemispheric stroke underwent comprehensive language assessment at the early subacute and chronic stages. A novel structural connectometry approach, using multi-shell diffusion-weighted MRI data collected at the early subacute stage, was used to evaluate the relationship between right hemisphere white matter connectome and language production and comprehension abilities at early subacute stage. Moreover, we evaluated the relationship between early subacute right hemisphere white matter connectome and longitudinal change in language production and comprehension abilities. All results were corrected for multiple comparisons. Connectometry analyses revealed negative associations between early subacute stage right hemisphere structural connectivity and language production, both cross-sectionally and longitudinally (pFDR < .0125). In turn, only positive associations between right hemisphere structural connectivity and language comprehension were observed, both cross-sectionally and longitudinally (pFDR < .0125). Interhemispheric connectivity was highly associated with comprehension scores. Our results shed light on the discordant interpretations of previous findings, by providing evidence that while some right hemisphere white matter pathways may make a maladaptive contribution to the recovery of language, other pathways support the recovery of language, especially comprehension abilities.

Global assessment, cognitive profile, and characteristics of mild cognitive impairment in Parkinson's disease.

BACKGROUND: Cognitive deficits are evident throughout the course of Parkinson's disease (PD), with 24% of patients experiencing subtle cognitive disturbances at the time of diagnosis, and with up to 80% of patients developing PD dementia (PDD) at advanced stages of the disease PD patients with mild cognitive impairment (MCI), an at-risk phenotype of PDD, present with heterogeneous clinical characteristics that complicate the management of PD. OBJECTIVES: This study aims to examine the characteristics of PD-MCI by using the Movement Disorder Society (MDS) diagnostic criteria and evaluate the validity of global cognitive scales in identifying PD-MCI. METHODS: Seventy-nine (79) PD patients completed neuropsychological assessments and a comprehensive cognitive battery. PD-MCI was classified according to the level 2 MDS task force criteria. Mini-Mental State Examination (sMMSE), Montreal Cognitive Assessment (MoCA) and Parkinson's Disease Cognitive Rating Scale (PDCRS) were examined against a level 2 dichotomised PD-MCI diagnosis. Characteristics of PD-MCI were evaluated using logistic regression analysis. RESULTS: Twenty-seven patients met criteria for PD-MCI (34%). The MoCA and PDCRS demonstrated high validity to screen for PD-MCI. Impairments in multiple cognitive domains were observed in 77.8% of PD-MCI patients. There were significantly more males in the PD-MCI group compared to PD patients without MCI (p < 0.01). CONCLUSIONS: PD patients with MCI exhibited impairments in the attention/working memory, executive function and memory domains. Heterogeneous cognitive characteristics in PD warrant further investigation into specific cognitive subtypes to advance understanding and effective evaluation of PD-MCI.

Understanding the Sociocognitive Determinants Underlying Intentions to Exercise for Postconcussion Symptom Relief: An Application of the Theory of Planned Behavior.

CONTEXT: This study investigated individual sociocognitive factors from the theory of planned behavior and their relationship to exercise for postconcussion recovery. DESIGN AND METHODS: Four hundred and fifty-nine Australian adults, two-thirds of whom had no concussion history (66%), completed an online survey of their beliefs and attitudes toward exercise for postconcussion recovery. Secondary questions evaluated program design features that could affect engagement (eg, session frequency). RESULTS: Structured equation modeling found that subjective norms were the strongest significant predictor of intention to participate in exercise for postconcussion recovery. Perceived behavioral control was also a significant predictor of intention to participate but to a lesser extent. Attitude did not predict participation intention. The design features identified as key were personalization and being supervised during the program. CONCLUSIONS: This study found that people's intention to participate in a program of exercise postconcussion recovery is shaped by individual psychological factors and identified program design features that could be adjusted for increased engagement. Program success could be maximized through strategies such as supporting individuals to have a stronger sense of control over their participation through the choice of session timing or frequency and harnessing the influence of significant others via supportive messaging from key professionals.

The effects of physical exercise on structural, functional, and biochemical brain characteristics in individuals with chronic whiplash-associated disorder: A pilot randomized clinical trial.

BACKGROUND: Exercise for people with whiplash associated disorder (WAD) induces hypoalgesic effects in some, but hyperalgesic effects in others. We investigated the exercise-induced neurobiological effects of aerobic and strengthening exercise in individuals with chronic WAD. METHODS: Sixteen participants (8 WAD, 8 pain-free [CON]) were randomised to either aerobic or strengthening exercise. MRI for brain morphometry, functional MRI for brain connectivity, and magnetic resonance spectroscopy for brain biochemistry, were used at baseline and after the 8-week intervention. RESULTS: There were no differences in brain changes between exercise groups in either the WAD or CON group, therefore aerobic and strengthening data were combined to optimise sample size. After the exercise intervention, the CON group demonstrated increased cortical thickness (left parahippocampus: mean difference = 0.04, 95% CI = 0.07-0.00, p = 0.032; and left lateral orbital frontal cortex: mean difference = 0.03, 95% CI = 0.00-0.06, p = 0.048). The WAD group demonstrated an increase in prefrontal cortex (right medial orbital frontal) volume (mean difference = 95.57, 95% CI = 2.30-192.84, p = 0.046). Functional changes from baseline to follow-up between the default mode network and the insula, cingulate cortex, temporal lobe, and somatosensory and motor cortices, were found in the CON group, but not in the WAD group. There were no changes post-exercise in brain biochemistry. CONCLUSION: Aerobic and strengthening exercises did not exert differential effects on brain characteristics, however differences in structural and functional changes were found between WAD and CON groups. This suggests that an altered central pain modulatory response may be responsible for differential effects of exercise in individuals with chronic WAD.

Neural Correlates of Naturally Occurring Speech Errors during Picture Naming in Healthy Participants.

Most of our knowledge about the neuroanatomy of speech errors comes from lesion-symptom mapping studies in people with aphasia and laboratory paradigms designed to elicit primarily phonological errors in healthy adults, with comparatively little evidence from naturally occurring speech errors. In this study, we analyzed perfusion fMRI data from 24 healthy participants during a picture naming task, classifying their responses into correct and different speech error types (e.g., semantic, phonological, omission errors). Total speech errors engaged a wide set of left-lateralized frontal, parietal, and temporal regions that were almost identical to those involved during the production of correct responses. We observed significant perfusion signal decreases in the left posterior middle temporal gyrus and inferior parietal lobule (angular gyrus) for semantic errors compared to correct trials matched on various psycholinguistic variables. In addition, the left dorsal caudate nucleus showed a significant perfusion signal decrease for omission (i.e., anomic) errors compared with matched correct trials. Surprisingly, we did not observe any significant perfusion signal changes in brain regions proposed to be associated with monitoring mechanisms during speech production (e.g., ACC, superior temporal gyrus). Overall, our findings provide evidence for distinct neural correlates of semantic and omission error types, with anomic speech errors likely resulting from failures to initiate articulatory-motor processes rather than semantic knowledge impairments as often reported for people with aphasia.

SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility.

Mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures is associated with common variation at rs7587026, located in the promoter region of SCN1A. We sought to explore possible underlying mechanisms. SCN1A expression was analysed in hippocampal biopsy specimens of individuals with mesial temporal lobe epilepsy with hippocampal sclerosis who underwent surgical treatment, and hippocampal neuronal cell loss was quantitatively assessed using immunohistochemistry. In healthy individuals, hippocampal volume was measured using MRI. Analyses were performed stratified by rs7587026 type. To study the functional consequences of increased SCN1A expression, we generated, using transposon-mediated bacterial artificial chromosome transgenesis, a zebrafish line expressing exogenous scn1a, and performed EEG analysis on larval optic tecta at 4 day post-fertilization. Finally, we used an in vitro promoter analysis to study whether the genetic motif containing rs7587026 influences promoter activity. Hippocampal SCN1A expression differed by rs7587026 genotype (Kruskal-Wallis test P = 0.004). Individuals homozygous for the minor allele showed significantly increased expression compared to those homozygous for the major allele (Dunn's test P = 0.003), and to heterozygotes (Dunn's test P = 0.035). No statistically significant differences in hippocampal neuronal cell loss were observed between the three genotypes. Among 597 healthy participants, individuals homozygous for the minor allele at rs7587026 displayed significantly reduced mean hippocampal volume compared to major allele homozygotes (Cohen's D = - 0.28, P = 0.02), and to heterozygotes (Cohen's D = - 0.36, P = 0.009). Compared to wild type, scn1lab-overexpressing zebrafish larvae exhibited more frequent spontaneous seizures [one-way ANOVA F(4,54) = 6.95 (P < 0.001)]. The number of EEG discharges correlated with the level of scn1lab overexpression [one-way ANOVA F(4,15) = 10.75 (P < 0.001]. Finally, we showed that a 50 bp promoter motif containing rs7587026 exerts a strong regulatory role on SCN1A expression, though we could not directly link this to rs7587026 itself. Our results develop the mechanistic link between rs7587026 and mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures. Furthermore, we propose that quantitative precision may be important when increasing SCN1A expression in current strategies aiming to treat seizures in conditions involving SCN1A haploinsufficiency, such as Dravet syndrome.

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

Systematic review of data-driven cognitive subtypes in Parkinson disease.

BACKGROUND AND PURPOSE: Recent application of the mild cognitive impairment concept to Parkinson disease (PD) has proven valuable in identifying patients at risk of dementia. However, it has sparked controversy regarding the existence of cognitive subtypes. The present review evaluates the current literature pertaining to data-driven subtypes of cognition in PD. METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, systematic literature searches for peer-reviewed articles on the topic of cognitive subtyping in PD were performed. RESULTS: Twenty-two relevant articles were identified in the systematic search. Subtype structures showed either a spectrum of severity or specific domains of impairment. Domain-specific subtypes included amnestic/nonamnestic, memory/executive, and frontal/posterior dichotomies, as well as more complex structures with less definitive groupings. Preliminary longitudinal evidence showed some differences in cognitive progression among subtypes. Neuroimaging evidence provided insight into distinct patterns of brain alterations among subtypes. CONCLUSIONS: Recurring phenotypes in the literature suggest strong clinical relevance of certain cognitive subtypes in PD. Although the current literature is limited, it raises critical questions about the utility of data-driven methods in cognitive research. The results encourage further integration of neuroimaging research to define the latent neural mechanisms behind divergent subtypes. Although there is no consensus, there appears to be growing consistency and inherent value in identifying cognitive subtypes in PD.

The Attention Network Test in Parkinson and Lewy Body Disease: A Systematic Review.

BACKGROUND: The Attention Network Test (ANT) is a well-established measure of efficiency for the alerting, orienting, and executive attentional networks. However, its novel application in Parkinson disease (PD) and Lewy body dementia (LBD) research more broadly has yet to be evaluated systematically. OBJECTIVE: To compare and consolidate the outcomes of studies reporting use of the ANT in PD and LBD groups and to identify the methodological considerations for the conduct of such studies. METHOD: We performed a systematic literature search for articles exploring attention in PD and LBD groups using the ANT. We excluded articles on the basis of irrelevant scope, non-English, and groups other than PD and LBD. Once the full text articles were identified, we extracted the data and assessed the studies' quality. RESULTS: The final sample included 16 articles ranging from low to moderate quality. Behavioral findings suggested a general slowing of responses yet preserved accuracy from the PD group compared with controls. Overall, the evidence was inconclusive regarding the state of the alerting network in the PD and LBD groups, mostly supportive of an intact orienting network, and strongly suggestive of an impaired executive network. Differences in sample stratification, patient symptomatology, and dopaminergic medication levels were identified as influential factors in the attentional results across studies. CONCLUSION: Although sparse, the existing evidence indicates that the ANT is a viable option for measuring attention in PD; it can also be harnessed to explore the impact of symptoms and medications on attentional networks in PD and LBD groups.

Persistence of Anxiety/Depression Symptoms in Early Adolescence: A Prospective Study of Daily Life Stress, Rumination, and Daytime Sleepiness in a Genetically Informative Cohort.

In this prospective study of mental health, we examine the influence of three interrelated traits - perceived stress, rumination, and daytime sleepiness - and their association with symptoms of anxiety and depression in early adolescence. Given the known associations between these traits, an important objective is to determine the extent to which they may independently predict anxiety/depression symptoms. Twin pairs from the Queensland Twin Adolescent Brain (QTAB) project were assessed on two occasions (N = 211 pairs aged 9-14 years at baseline and 152 pairs aged 10-16 years at follow-up). Linear regression models and quantitative genetic modeling were used to analyze the data. Prospectively, perceived stress, rumination, and daytime sleepiness accounted for 8-11% of the variation in later anxiety/depression; familial influences contributed strongly to these associations. However, only perceived stress significantly predicted change in anxiety/depression, accounting for 3% of variance at follow-up after adjusting for anxiety/depression at baseline, although it did not do so independently of rumination and daytime sleepiness. Bidirectional effects were found between all traits over time. These findings suggest an underlying architecture that is shared, to some degree, by all traits, while the literature points to hypothalamic-pituitary-adrenal (HPA) axis and/or circadian systems as potential sources of overlapping influence and possible avenues for intervention.

Genetic Specificity of Hippocampal Subfield Volumes, Relative to Hippocampal Formation, Identified in 2148 Young Adult Twins and Siblings.

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).

A Sound Explanation for Motor Cortex Engagement during Action Word Comprehension.

Comprehending action words often engages similar brain regions to those involved in perceiving and executing actions. This finding has been interpreted as support for grounding of conceptual processing in motor representations or that conceptual processing involves motor simulation. However, such demonstrations cannot confirm the nature of the mechanism(s) responsible, as word comprehension involves multiple processes (e.g., lexical, semantic, morphological, phonological). In this study, we tested whether this motor cortex engagement instead reflects processing of statistical regularities in sublexical phonological features. Specifically, we measured brain activity in healthy participants using functional magnetic resonance imaging while they performed an auditory lexical decision paradigm involving monosyllabic action words associated with specific effectors (face, arm, and leg). We show that nonwords matched to the action words in terms of their phonotactic probability elicit common patterns of activation. In addition, we show that a measure of the action words' phonological typicality, the extent to which a word's phonology is typical of other words in the grammatical category to which it belongs (i.e., more or less verb-like), is responsible for their activating a significant portion of primary and premotor cortices. These results indicate motor cortex engagement during action word comprehension is more likely to reflect processing of statistical regularities in sublexical phonological features than conceptual processing. We discuss the implications for current neurobiological models of language, all of which implicitly or explicitly assume that the relationship between the sound of a word and its meaning is arbitrary.

Hippocampal correlates of episodic memory in Parkinson's disease: A systematic review of magnetic resonance imaging studies.

The present review asks whether magnetic resonance imaging (MRI) studies are able to define neural correlates of episodic memory within the hippocampus in Parkinson's disease (PD). Systematic searches were performed in PubMed, Web of Science, Medline, CINAHL, and EMBASE using search terms related to structural and functional MRI (fMRI), the hippocampus, episodic memory, and PD. Risk of bias was assessed for each study using the Newtown-Ottawa Scale. Thirty-nine studies met inclusion criteria; eight fMRI, seven diffusion MRI (dMRI), and 24 structural MRI (14 exploring whole hippocampus and 10 exploring hippocampal subfields). Critical analysis of the literature revealed mixed evidence from functional and dMRI, but stronger evidence from sMRI of the hippocampus as a biomarker for episodic memory impairment in PD. Hippocampal subfield studies most often implicated CA1, CA3/4, and subiculum volume in episodic memory and cognitive decline in PD. Despite differences in imaging methodology, study design, and sample characteristics, MRI studies have helped elucidate an important neural correlate of episodic memory impairment in PD with both clinical and theoretical implications. Natural progression of this work encourages future research on hippocampal subfield function as a potential biomarker of, or therapeutic target for, episodic memory dysfunction in PD.

Are Sex Differences in Human Brain Structure Associated With Sex Differences in Behavior?

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.

The Acute Effects of Different Exercise Intensities on Associative Novel Word Learning in Healthy Older Adults: A Randomized Controlled Trial.

Recent studies show positive effects of acute exercise on language learning in young adults with lower baseline learning abilities; however, this is yet to be investigated in older adults. This study investigated the acute effects of different exercise intensities on new word learning in healthy older adults with lower and higher baseline learning abilities. Sixty older adults (mean age = 66.4 (4.6); 43 females) performed either a single bout of stretching exercise, moderate-intensity continuous exercise, or high-intensity interval exercise followed by a word learning task. In lower baseline learners, between-group differences were observed on immediate new word recall success, with the moderate-intensity continuous exercise group performing better than the stretching group. These findings suggest immediate benefits of moderate-intensity continuous exercise that are limited to word learning performance of older adults with lower baseline learning abilities. Further investigation into underlying mechanisms could lead to a better understanding of individual differences in responding to acute exercise.

Region-specific sex differences in the hippocampus.

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 â€‹= â€‹727) and the Human Connectome Project (HCP; N â€‹= â€‹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 â€‹= â€‹0.46) and fimbria (up to 8.75%; d â€‹= â€‹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.