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How do we represent and process abstract and concrete concepts? The "concreteness effect", in which words with more concrete meanings are processed more quickly and accurately across a range of language tasks compared to abstract ones, suggests a differential conceptual organization of these words in the brain. However, concrete words tend to be marked by specific phonotactic features, such as having fewer syllables and more phonological neighbours. It is unclear whether these non-arbitrary form-meaning relationships that systematically denote the concreteness of a word impact language processing. In the current study, we first establish the extent of systematic mappings between phonological/phonetic features and concreteness ratings in a large set of monosyllabic and polysyllabic English words (i.e., concreteness form typicality), then demonstrate that they significantly influence lexical processing using behavioural megastudy datasets. Surface form features predicted a significant proportion of variance in concreteness ratings of monomorphemic words (25 %) which increased with the addition of polymorphemic forms (43 %). In addition, concreteness form typicality was a significant predictor of performance on visual and auditory lexical decision, naming, and semantic (concrete/abstract) decision tasks, after controlling for a range of psycholinguistic variables and concreteness ratings. Overall, our results provide the first evidence that concreteness form typicality influences lexical processing. We discuss theoretical implications for interpretations of the concreteness effect and models of language processing that have yet to incorporate non-arbitrary relationships between form and meaning into their feature sets., Competing Interests: Declaration of competing interest none., (Copyright © 2024. Published by Elsevier B.V.)

It is well-established from fMRI experiments employing gradient echo echo-planar imaging (EPI) sequences that overt speech production introduces signal artefacts compromising accurate detection of task-related responses. Both design and post-processing (denoising) techniques have been proposed and implemented over the years to mitigate the various noise sources. Recently, fMRI studies of speech production have begun to adopt multiband EPI sequences that offer better signal-to-noise ratio (SNR) and temporal resolution allowing adequate sampling of physiological noise sources (e.g., respiration, cardiovascular effects) and reduced scanner acoustic noise. However, these new sequences may also introduce additional noise sources. In this study, we demonstrate the impact of applying several noise-estimation and removal approaches to continuous multiband fMRI data acquired during a naming-to-definition task, including rigid body motion regression and outlier censoring, principal component analysis for removal of cerebrospinal fluid (CSF)/edge-related noise components, and global fMRI signal regression (using two different approaches) compared to a baseline of realignment and unwarping alone. Our results show the strongest and most spatially extensive sources of physiological noise are the global signal fluctuations arising from respiration and muscle action and CSF/edge-related noise components, with residual rigid body motion contributing relatively little variance. Interestingly, denoising approaches tended to reduce and enhance task-related BOLD signal increases and decreases, respectively. Global signal regression using a voxel-wise linear model of the global signal estimated from unmasked data resulted in dramatic improvements in temporal SNR. Overall, these findings show the benefits of combining continuous multiband EPI sequences and denoising approaches to investigate the neurobiology of speech production., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2024 Massachusetts Institute of Technology.)

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain ageing-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and ADHD. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., Competing Interests: IA received speaker’s honorarium Lundbeck; OAA is a consultant to Cortechs.ai and Precision Health, speaker’s honorarium from Lundbeck, Janssen, Otsuka, Sunovion; HB is an Advisory Board Member or Consultant to Biogen, Eisai, Eli Lilly, Roche, Skin2Neuron, Cranbrook Care and Montefiore Homes; CRKC has received past partial research support from Biogen, Inc. (Boston, USA) for work unrelated to the topic of this manuscript; AMD is the Principal Investigator of a research agreement between General Electric Healthcare and the University of California, San Diego (UCSD); he is a Founder of and hold equity in CorTechs Labs, Inc. I am a member of the Scientific Advisory Board of Human Longevity, Inc., and the Mohn Medical Imaging and Visualization Center in Bergen, Norway. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict-of-interest policies; BF has received educational speaking fees from Medice; HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care; DPH is a full time employee of Genentech, Inc; NH is a shareholder various manufacturers of medical technology; AM-L has received consultant fees from Daimler und Benz Stiftung, EPFL Brain Mind Institute, Fondation FondaMental, Hector Stiftung II, Invisio, Janssen-Cilag GmbH, Lundbeck A/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, Neurotorium, MedinCell, The LOOP Zürich, University Medical Center Utrecht, University of Washington, Verein für Mentales Wohlbefinden, von Behring-Röntgen-Stiftung; speaker fees from Ärztekammer Nordrhein, Caritas, Clarivate, Dt. Gesellschaft für Neurowissenschaftliche Begutachtung, Gentner Verlag, Landesärztekammer Baden-Württemberg, LWL Bochum, Northwell Health, Ruhr University Bochum, Penn State University, Society of Biological Psychiatry, University Prague, Vitos Klinik Rheingau and editorial and/or author fees fromAmerican Association for the Advancement of Science, ECNP, Servier Int., Thieme Verlag; WN is founder of Quantib BV and was scientific lead of Quantib BV until Jan 31, 2023; MMN has received fees for membership in an advisory board from HMG Systems Engineering GmbH (Fürth, Germany), for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt, and for serving as a consultant for EVERIS Belgique SPRL in a project of the European Commission (REFORM/SC2020/029). MMN receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities outside the submitted work; BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; AJS receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, and U19 AG074879). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA, Inc. (Dementia Advisory Board); NIH NHLBI (MESA Observational Study Monitoring Board); Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior); MSreceived funding from Pfizer Inc. for a project not related to this research; ES received speaker fees from bfd buchholz fachinformationsdienst gmbh; PMT receives partial research support from Biogen, Inc., for research unrelated to this manuscript; MWW serves on Editorial Boards for Alzheimer’s & Dementia, and the Journal for Prevention of Alzheimer’s disease. He has served on Advisory Boards for Acumen Pharmaceutical, Alzheon, Inc., Cerecin, Merck Sharp & Dohme Corp., and NC Registry for Brain Health. He also serves on the USC ACTC grant which receives funding from Eisai for the AHEAD study. MWW has provided consulting to Boxer Capital, LLC, Cerecin, Inc., Clario, Dementia Society of Japan, Eisai, Guidepoint, Health and Wellness Partners, Indiana University, LCN Consulting, Merck Sharp & Dohme Corp., NC Registry for Brain Health, Prova Education, T3D Therapeutics, University of Southern California (USC), and WebMD. MWW has acted as a speaker/lecturer for China Association for Alzheimer’s Disease (CAAD) and Taipei Medical University, as well as a speaker/lecturer with academic travel funding provided by: AD/PD Congress, Cleveland Clinic, CTAD Congress, Foundation of Learning; Health Society (Japan), INSPIRE Project; U. Toulouse, Japan Society for Dementia Research, and Korean Dementia Society, Merck Sharp & Dohme Corp., National Center for Geriatrics and Gerontology (NCGG; Japan), University of Southern California (USC). MWW holds stock options with Alzeca, Alzheon, Inc., ALZPath, Inc., and Anven. MWW received support for his research from the following funding sources: National Institutes of Health (NIH)/NINDS/National Institute on Aging (NIA), Department of Defense (DOD), California Department of Public Health (CDPH), University of Michigan, Siemens, Biogen, Hillblom Foundation, Alzheimer’s Association, Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI-BHR), The Stroke Foundation, and the Veterans Administration; AIC is currently employed by the Regeneron Genetics Center, a wholly-owned subsidiary of Regeneron Pharmaceuticals, Inc., and may hold Regeneron stock or stock options. All other authors declare no competing interests.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Across spoken languages, there are some words whose acoustic features resemble the meanings of their referents by evoking perceptual imagery, i.e., they are iconic (e.g., in English, "splash" imitates the sound of an object hitting water). While these sound symbolic form-meaning relationships are well-studied, relatively little work has explored whether the sensory properties of English words also involve systematic (i.e., statistical) form-meaning mappings. We first test the prediction that surface form properties can predict sensory experience ratings for over 5,000 monosyllabic and disyllabic words (Juhasz & Yap, 2013), confirming they explain a significant proportion of variance. Next, we show that iconicity and sensory form typicality, a statistical measure of how well a word's form aligns with its sensory experience rating, are only weakly related to each other, indicating they are likely to be distinct constructs. To determine whether form typicality influences processing of sensory words, we conducted regression analyses using lexical decision, word recognition, naming and semantic decision tasks from behavioral megastudy data sets. Across the data sets, sensory form typicality was able to predict more variance in performance than sensory experience or iconicity ratings. Further, the effects of typicality were consistently inhibitory in comprehension (i.e., more typical forms were responded to more slowly and less accurately), whereas for production the effect was facilitatory. These findings are the first evidence that systematic form-meaning mappings in English sensory words influence their processing. We discuss how language processing models incorporating Bayesian prediction mechanisms might be able to account for form typicality in the lexicon. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

A number of studies have provided evidence of limited non-arbitrary associations between the phonological forms and meanings of affective words, a finding referred to as affective sound symbolism. Here, we explored whether the affective connotations of Spanish words might have more extensive statistical relationships with phonological/phonetic features, or affective form typicality . After eliminating words with poor affective rating agreement and morphophonological redundancies (e.g., negating prefixes), we found evidence of significant form typicality for emotional valence, emotionality, and arousal in a large sample of monosyllabic and polysyllabic words. These affective form-meaning mappings remained significant even when controlling for a range of lexico-semantic variables. We show that affective variables and their corresponding form typicality measures are able to significantly predict lexical decision performance using a megastudy dataset. Overall, our findings provide new evidence that affective form typicality is a statistical property of the Spanish lexicon., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

A century of research has provided evidence of limited size sound symbolism in English, that is, certain vowels are non-arbitrarily associated with words denoting small versus large referents (e.g., /i/ as in teensy and /ɑ/ as in tall ). In the present study, we investigated more extensive statistical regularities between surface form properties of English words and ratings of their semantic size, that is, form typicality , and its impact on language and memory processing. Our findings provide the first evidence of significant word form typicality for semantic size. In five empirical studies using behavioural megastudy data sets of performance on written and auditory lexical decision, reading aloud, semantic decision, and recognition memory tasks, we show that form typicality for size is a stronger and more consistent predictor of lexical access during word comprehension and production than semantic size, in addition to playing a significant role in verbal memory. The empirical results demonstrate that statistical information about non-arbitrary form-size mappings is accessed automatically during language and verbal memory processing, unlike semantic size that is largely dependent on task contexts that explicitly require participants to access size knowledge. We discuss how a priori knowledge about non-arbitrary form-meaning associations in the lexicon might be incorporated in models of language processing that implement Bayesian statistical inference., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure., Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference., Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness., Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment., (Copyright © 2023. Published by Elsevier Inc.)

It is generally accepted that a word's emotional valence (i.e., whether a word is perceived as positive, negative, or neutral) influences how it is accessed and remembered. There is also evidence that the affective content of some words is represented in nonarbitrary sound-meaning associations (i.e., emotional sound symbolism). We investigated whether more extensive statistical relationships exist between the surface form properties of English words and ratings of their emotional valence, that is, form typicality. We found significant form typicality for both valence and extremity of valence (the absolute distance from the midpoint of the rating scale, regardless of polarity). Next, using behavioral megastudy data sets, we show that measures of emotional form typicality are significant predictors of lexical access during written and auditory lexical decision and reading aloud tasks in addition to recognition memory performance. These findings show nonarbitrary form-valence mappings in English are accessed automatically during language and verbal memory processing. We discuss how these findings might be incorporated into theoretical accounts that implement Bayesian statistical inference. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Left-hemisphere intraparenchymal primary brain tumor patients are at risk of developing reading difficulties that may be stable, improve or deteriorate after surgery. Previous studies examining language organization in brain tumor patients have provided insights into neural plasticity supporting recovery. Only a single study, however, has examined the role of white matter tracts in preserving reading ability post-surgery and none have examined the functional reading network. The current study aimed to investigate the regional spontaneous brain activity associated with reading performance in a group of 36 adult patients 6-24 months following left-hemisphere tumor resection. Spontaneous brain activity was assessed using resting-state fMRI (rs-fMRI) regional homogeneity (ReHo) and fractional amplitude low frequency fluctuation (fALFF) metrics, which measure local functional connectivity and activity, respectively. ReHo in the left occipito-temporal and right superior parietal regions was negatively correlated with reading performance. fALFF in the putamen bilaterally and the left cerebellum was negatively correlated with reading performance, and positively correlated in the right superior parietal gyrus. These findings are broadly consistent with reading networks reported in healthy participants, indicating that reading ability following brain tumor surgery might not involve substantial functional re-organization., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Semantic context effects are well established using both words and pictures as stimuli. One such effect, semantic interference, is observed in naming latencies when a categorically related distractor word or picture is presented together with a target picture (e.g., dog-LION). Recently, this effect has also been shown to occur when an environmental sound (e.g., a dog barking ) is presented as an auditory distractor during picture naming and when a distractor picture is presented with a target sound for naming. The purpose of the current study was twofold: (1) to replicate the semantic interference effect in the picture-sound interference ( PSI ) paradigm and (2) determine whether a semantic interference effect is also observable when distractor words are presented with environmental sounds as target auditory objects for naming, using a novel sound-word interference ( SWI ) paradigm. We replicated the semantic interference effect in Experiment 1 with environmental sound distractors. Experiment 2 demonstrated significant semantic interference during an SWI paradigm for the first time. We discuss the implications of these results for our understanding of the origin and locus of the semantic interference effect according to current theories of lexical selection.

We describe the Queensland Twin Adolescent Brain (QTAB) dataset and provide a detailed methodology and technical validation to facilitate data usage. The QTAB dataset comprises multimodal neuroimaging, as well as cognitive and mental health data collected in adolescent twins over two sessions (session 1: N = 422, age 9-14 years; session 2: N = 304, 10-16 years). The MRI protocol consisted of T1-weighted (MP2RAGE), T2-weighted, FLAIR, high-resolution TSE, SWI, resting-state fMRI, DWI, and ASL scans. Two fMRI tasks were added in session 2: an emotional conflict task and a passive movie-watching task. Outside of the scanner, we assessed cognitive function using standardised tests. We also obtained self-reports of symptoms for anxiety and depression, perceived stress, sleepiness, pubertal development measures, and risk and protective factors. We additionally collected several biological samples for genomic and metagenomic analysis. The QTAB project was established to promote health-related research in adolescence., (© 2023. The Author(s).)

Surgical resection of brain tumours is associated with an increased risk of aphasia. However, relatively little is known about outcomes in the chronic phase (i.e., >6 months). Using voxel-based lesion symptom mapping (VLSM) in 46 patients, we investigated whether chronic language impairments are related to the location of surgical resection, residual tumour characteristics (e.g., peri-resection treatment effects, progressive infiltration, oedema) or both. Approximately 72% of patients scored below the cut-off for aphasia. Action naming and spoken sentence comprehension deficits were associated with lesions in the left anterior temporal and inferior parietal lobes, respectively. Voxel-wise analyses revealed significant associations between ventral language pathways and action naming deficits. Reading impairments were also associated with increasing disconnection of cerebellar pathways. The results indicate chronic post-surgical aphasias reflect a combination of resected tissue and tumour infiltration of language-related white matter tracts, implicating progressive disconnection as the critical mechanism of impairment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Autism omics research has historically been reductionist and diagnosis centric, with little attention paid to common co-occurring conditions (for example, sleep and feeding disorders) and the complex interplay between molecular profiles and neurodevelopment, genetics, environmental factors and health. Here we explored the plasma lipidome (783 lipid species) in 765 children (485 diagnosed with autism spectrum disorder (ASD)) within the Australian Autism Biobank. We identified lipids associated with ASD diagnosis (n = 8), sleep disturbances (n = 20) and cognitive function (n = 8) and found that long-chain polyunsaturated fatty acids may causally contribute to sleep disturbances mediated by the FADS gene cluster. We explored the interplay of environmental factors with neurodevelopment and the lipidome, finding that sleep disturbances and unhealthy diet have a convergent lipidome profile (with potential mediation by the microbiome) that is also independently associated with poorer adaptive function. In contrast, ASD lipidome differences were accounted for by dietary differences and sleep disturbances. We identified a large chr19p13.2 copy number variant genetic deletion spanning the LDLR gene and two high-confidence ASD genes (ELAVL3 and SMARCA4) in one child with an ASD diagnosis and widespread low-density lipoprotein-related lipidome derangements. Lipidomics captures the complexity of neurodevelopment, as well as the biological effects of conditions that commonly affect quality of life among autistic people., (© 2023. The Author(s).)

Grounded or embodied cognition research has employed body-object interaction (BOI; e.g., Pexman et al., 2019) ratings to investigate sensorimotor effects during language processing. We investigated relationships between BOI ratings and nonarbitrary statistical mappings between words' phonological forms and their syntactic category in English; i.e., form systematicity. In Study 1, principal components analysis revealed that BOI and form systematicity measures load on a common component, indicating they convey similar information about the probability of a word belonging to a particular syntactic category. In Studies 2, 3, and 4, form systematicity measures were stronger predictors of English Lexicon Project (ELP; Balota et al., 2007), Auditory English Lexicon Project (AELP; Goh et al., 2020), and English Crowdsourcing Project (ECP; Mandera et al., 2020) performance than BOI. In Study 5, BOI was a stronger predictor of performance from the Calgary Semantic Decision Project (CSDP; Pexman et al., 2017) than form systematicity. In Study 6, only form systematicity significantly predicted performance from the LinguaPix object naming megastudy (Krautz & Keuleers, 2022). Together, these results demonstrate that nonarbitrary statistical relationships in the form of mappings between ortho-phonological information and meaning are accessed automatically during language processing; i.e., even when syntactic category is not relevant to the task, and that sensorimotor simulation mechanisms are only strongly engaged when explicitly demanded by the task. We discuss the implications of these findings for proposals of embodied or grounded cognition and interpretations of neuroimaging data from word recognition tasks. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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., (© 2022 Massachusetts Institute of Technology.)

Accumulating evidence indicates two cortical regions, the left ventral premotor cortex (PMv) and left intraparietal sulcus (IPS), are involved in spoken verb production. Some evidence also indicates these regions may be differentially engaged by transitive (i.e., object-oriented) versus intransitive actions. We explored the role of these regions during action picture naming in two experiments, each employing high frequency (10 Hz) online repetitive Transcranial Magnetic Stimulation (rTMS) in 20 participants. In Experiment 1, participants named intransitive action pictures (e.g., LAUGH) accompanied by active and sham rTMS to the left PMv, left IPS, and right superior parietal lobule (SPL; control site). Application of rTMS to PMv resulted in slower naming latencies compared to sham and control site stimulation, whereas stimulation of the IPS did not result in any significant effects. Experiment 2 employed active and sham rTMS identical to Experiment 1 with transitive action pictures (e.g., PUSH). Stimulation of both regions induced changes in naming latencies compared to sham and control site stimulation, with rTMS applied to PMv slowing responses and IPS stimulation facilitating them. Surprisingly, stimulation of the right SPL control site also slowed naming compared to sham across both Experiments. Overall, these findings indicate different roles for PMv and IPS during action picture naming. Specifically, the divergent effects of PMv and IPS stimulation in the transitive action naming task indicate different processes likely operate in the two regions during verb production. Involvement of the right SPL across both transitive and intransitive action naming might reflect visuospatial or general attention mechanisms rather than language processes per se., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (© 2022. The Author(s).)

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).

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.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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., Competing Interests: Declaration of interests David L.A. Wood and Lutz Krause are employees of Microba Life Sciences. Gene W. Tyson is a co-founder and director of Microba Life Sciences. Gerald Holtmann is on the advisory board of Servatus Biopharmaceuticals. The other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates., (© 2020. The Author(s).)

Background: Neuroimaging studies of suicidal behavior have so far been conducted in small samples, prone to biases and false-positive associations, yielding inconsistent results. The ENIGMA-MDD Working Group aims to address the issues of poor replicability and comparability by coordinating harmonized analyses across neuroimaging studies of major depressive disorder and related phenotypes, including suicidal behavior., Methods: Here, we pooled data from 18 international cohorts with neuroimaging and clinical measurements in 18,925 participants (12,477 healthy control subjects and 6448 people with depression, of whom 694 had attempted suicide). We compared regional cortical thickness and surface area and measures of subcortical, lateral ventricular, and intracranial volumes between suicide attempters, clinical control subjects (nonattempters with depression), and healthy control subjects., Results: We identified 25 regions of interest with statistically significant (false discovery rate < .05) differences between groups. Post hoc examinations identified neuroimaging markers associated with suicide attempt including smaller volumes of the left and right thalamus and the right pallidum and lower surface area of the left inferior parietal lobe., Conclusions: This study addresses the lack of replicability and consistency in several previously published neuroimaging studies of suicide attempt and further demonstrates the need for well-powered samples and collaborative efforts. Our results highlight the potential involvement of the thalamus, a structure viewed historically as a passive gateway in the brain, and the pallidum, a region linked to reward response and positive affect. Future functional and connectivity studies of suicidal behaviors may focus on understanding how these regions relate to the neurobiological mechanisms of suicide attempt risk., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

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.

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., (© 2019. The Author(s).)

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

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.

Cortical folds help drive the parcellation of the human cortex into functionally specific regions. Variations in the length, depth, width, and surface area of these sulcal landmarks have been associated with disease, and may be genetically mediated. Before estimating the heritability of sulcal variation, the extent to which these metrics can be reliably extracted from in-vivo MRI must be established. Using four independent test-retest datasets, we found high reliability across the brain (intraclass correlation interquartile range: 0.65-0.85). Heritability estimates were derived for three family-based cohorts using variance components analysis and pooled (total N > 3000); the overall sulcal heritability pattern was correlated to that derived for a large population cohort (N > 9000) calculated using genomic complex trait analysis. Overall, sulcal width was the most heritable metric, and earlier forming sulci showed higher heritability. The inter-hemispheric genetic correlations were high, yet select sulci showed incomplete pleiotropy, suggesting hemisphere-specific genetic influences.

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., Competing Interests: Declaration of competing interest None. Paul M. Thompson received grant funding from Biogen, Inc. (Boston, USA) for research unrelated to this manuscript., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities., Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance., Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019., Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort., Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks., Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10 -6 , 1.7 × 10 - 9 , 3.5 × 10 -12 and 1.0 × 10 -4 , respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.

During conversation, speakers monitor their own and others' output so they can alter their production adaptively, including halting it if needed. We investigated the neural mechanisms of monitoring and halting in spoken word production by employing a modified stop signal task during fMRI. Healthy participants named target pictures and withheld their naming response when presented with infrequent auditory words as stop signals. We also investigated whether the speech comprehension system monitors inner (i.e., prearticulatory) speech via the output of phonological word form encoding as proposed by the perceptual loop theory [Levelt, W. J. M. Speaking: From intention to articulation . Cambridge, MA: MIT Press, 1989] by presenting stop signals phonologically similar to the target picture name (e.g., cabbage-CAMEL). The contrast of successful halting versus naming revealed extensive BOLD signal responses in bilateral inferior frontal gyrus, preSMA, and superior temporal gyrus. Successful versus unsuccessful halting of speech was associated with increased BOLD signal bilaterally in the posterior middle temporal, frontal, and parietal lobes and decreases bilaterally in the posterior and left anterior superior temporal gyrus and right inferior frontal gyrus. These results show, for the first time, the neural mechanisms engaged during both monitoring and interrupting speech production. However, we failed to observe any differential effects of phonological similarity in either the behavioral or neural data, indicating monitoring of inner versus external speech might involve different mechanisms.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Comparing estimates of the amount of genetic and environmental variance for different brain structures may elucidate differences in the genetic architecture or developmental constraints of individual brain structures. However, most studies compare estimates of relative genetic (heritability) and environmental variance in brain structure, which do not reflect differences in absolute variance between brain regions. Here we used a population sample of young adult twins and singleton siblings of twins (n = 791; M = 23 years, Queensland Twin IMaging study) to estimate the absolute genetic and environmental variance, standardised by the phenotypic mean, in the size of cortical, subcortical, and ventricular brain structures. Mean-standardised genetic variance differed widely across structures [23.5-fold range 0.52% (hippocampus) to 12.28% (lateral ventricles)], but the range of estimates within cortical, subcortical, or ventricular structures was more moderate (two to fivefold range). There was no association between mean-standardised and relative measures of genetic variance (i.e., heritability) in brain structure volumes. We found similar results in an independent sample (n = 1075, M = 29 years, Human Connectome Project). These findings open important new lines of enquiry: namely, understanding the bases of these variance patterns, and their implications regarding the genetic architecture, evolution, and development of the human brain.