RESUMEN
Childhood maltreatment (CM) leads to a lifelong susceptibility to mental ill-health which might be reflected by its effects on adult brain structure, perhaps indirectly mediated by its effects on adult metabolic, immune, and psychosocial systems. Indexing these systemic factors via body mass index (BMI), C-reactive protein (CRP), and rates of adult trauma (AT), respectively, we tested three hypotheses: (H1) CM has direct or indirect effects on adult trauma, BMI, and CRP; (H2) adult trauma, BMI, and CRP are all independently related to adult brain structure; and (H3) childhood maltreatment has indirect effects on adult brain structure mediated in parallel by BMI, CRP, and AT. Using path analysis and data from N = 116,887 participants in UK Biobank, we find that CM is related to greater BMI and AT levels, and that these two variables mediate CM's effects on CRP [H1]. Regression analyses on the UKB MRI subsample (N = 21,738) revealed that greater CRP and BMI were both independently related to a spatially convergent pattern of cortical effects (Spearman's ρ = 0.87) characterized by fronto-occipital increases and temporo-parietal reductions in thickness. Subcortically, BMI was associated with greater volume, AT with lower volume and CPR with effects in both directions [H2]. Finally, path models indicated that CM has indirect effects in a subset of brain regions mediated through its direct effects on BMI and AT and indirect effects on CRP [H3]. Results provide evidence that childhood maltreatment can influence brain structure decades after exposure by increasing individual risk toward adult trauma, obesity, and inflammation.
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Encéfalo , Maltrato a los Niños , Adulto , Humanos , Niño , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Proteína C-Reactiva/metabolismo , Inflamación/metabolismo , Obesidad/complicaciones , Maltrato a los Niños/psicologíaRESUMEN
Adolescent development of human brain structural and functional networks is increasingly recognized as fundamental to emergence of typical and atypical adult cognitive and emotional proodal magnetic resonance imaging (MRI) data collected from N [Formula: see text] 300 healthy adolescents (51%; female; 14 to 26 y) each scanned repeatedly in an accelerated longitudinal design, to provide an analyzable dataset of 469 structural scans and 448 functional MRI scans. We estimated the morphometric similarity between each possible pair of 358 cortical areas on a feature vector comprising six macro- and microstructural MRI metrics, resulting in a morphometric similarity network (MSN) for each scan. Over the course of adolescence, we found that morphometric similarity increased in paralimbic cortical areas, e.g., insula and cingulate cortex, but generally decreased in neocortical areas, and these results were replicated in an independent developmental MRI cohort (N [Formula: see text] 304). Increasing hubness of paralimbic nodes in MSNs was associated with increased strength of coupling between their morphometric similarity and functional connectivity. Decreasing hubness of neocortical nodes in MSNs was associated with reduced strength of structure-function coupling and increasingly diverse functional connections in the corresponding fMRI networks. Neocortical areas became more structurally differentiated and more functionally integrative in a metabolically expensive process linked to cortical thinning and myelination, whereas paralimbic areas specialized for affective and interoceptive functions became less differentiated, as hypothetically predicted by a developmental transition from periallocortical to proisocortical organization of the cortex. Cytoarchitectonically distinct zones of the human cortex undergo distinct neurodevelopmental programs during typical adolescence.
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Imagen por Resonancia Magnética , Neocórtex , Humanos , Adolescente , Femenino , Masculino , Neocórtex/diagnóstico por imagen , Neocórtex/crecimiento & desarrollo , Neocórtex/fisiología , Adulto , Adulto Joven , Mapeo Encefálico/métodos , Desarrollo del Adolescente/fisiología , Red Nerviosa/fisiología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/crecimiento & desarrollo , Encéfalo/diagnóstico por imagen , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiologíaRESUMEN
Brain scans acquired across large, age-diverse cohorts have facilitated recent progress in establishing normative brain aging charts. Here, we ask the critical question of whether cross-sectional estimates of age-related brain trajectories resemble those directly measured from longitudinal data. We show that age-related brain changes inferred from cross-sectionally mapped brain charts can substantially underestimate actual changes measured longitudinally. We further find that brain aging trajectories vary markedly between individuals and are difficult to predict with population-level age trends estimated cross-sectionally. Prediction errors relate modestly to neuroimaging confounds and lifestyle factors. Our findings provide explicit evidence for the importance of longitudinal measurements in ascertaining brain development and aging trajectories.
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Envejecimiento , Encéfalo , Humanos , Estudios Transversales , Estudios Longitudinales , Encéfalo/diagnóstico por imagen , Neuroimagen , Imagen por Resonancia MagnéticaRESUMEN
Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.
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Encéfalo , Equidad de Género , Masculino , Adulto , Humanos , Femenino , Encéfalo/diagnóstico por imagen , Factores SexualesRESUMEN
Adolescence is a time of profound changes in the physical wiring and function of the brain. Here, we analyzed structural and functional brain network development in an accelerated longitudinal cohort spanning 14 to 25 y (n = 199). Core to our work was an advanced in vivo model of cortical wiring incorporating MRI features of corticocortical proximity, microstructural similarity, and white matter tractography. Longitudinal analyses assessing age-related changes in cortical wiring identified a continued differentiation of multiple corticocortical structural networks in youth. We then assessed structure-function coupling using resting-state functional MRI measures in the same participants both via cross-sectional analysis at baseline and by studying longitudinal change between baseline and follow-up scans. At baseline, regions with more similar structural wiring were more likely to be functionally coupled. Moreover, correlating longitudinal structural wiring changes with longitudinal functional connectivity reconfigurations, we found that increased structural differentiation, particularly between sensory/unimodal and default mode networks, was reflected by reduced functional interactions. These findings provide insights into adolescent development of human brain structure and function, illustrating how structural wiring interacts with the maturation of macroscale functional hierarchies.
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Desarrollo del Adolescente , Encéfalo , Conectoma , Adolescente , Encéfalo/fisiología , Encéfalo/ultraestructura , Estudios Transversales , Humanos , Imagen por Resonancia Magnética , Red Nerviosa/fisiología , Red Nerviosa/ultraestructuraRESUMEN
Autism is a neurodevelopmental condition involving atypical sensory-perceptual functions together with language and socio-cognitive deficits. Previous work has reported subtle alterations in the asymmetry of brain structure and reduced laterality of functional activation in individuals with autism relative to non-autistic individuals (NAI). However, whether functional asymmetries show altered intrinsic systematic organization in autism remains unclear. Here, we examined inter- and intra-hemispheric asymmetry of intrinsic functional gradients capturing connectome organization along three axes, stretching between sensory-default, somatomotor-visual, and default-multiple demand networks, to study system-level hemispheric imbalances in autism. We observed decreased leftward functional asymmetry of language network organization in individuals with autism, relative to NAI. Whereas language network asymmetry varied across age groups in NAI, this was not the case in autism, suggesting atypical functional laterality in autism may result from altered developmental trajectories. Finally, we observed that intra- but not inter-hemispheric features were predictive of the severity of autistic traits. Our findings illustrate how regional and patterned functional lateralization is altered in autism at the system level. Such differences may be rooted in atypical developmental trajectories of functional organization asymmetry in autism.
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Trastorno del Espectro Autista , Trastorno Autístico , Conectoma , Humanos , Imagen por Resonancia Magnética , Encéfalo , Lateralidad Funcional/fisiología , Mapeo EncefálicoRESUMEN
Higher educational attainment is observationally associated with lower risk of Alzheimer's disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer's disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between educational attainment, structural brain reserve as proxied by MRI phenotypes and Alzheimer's disease. Summary statistics were obtained from genome-wide association studies of educational attainment (n = 1 131 881), late-onset Alzheimer's disease (35 274 cases, 59 163 controls) and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33 211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) educational attainment and Alzheimer's disease; (ii) educational attainment and imaging-derived phenotypes; and (iii) imaging-derived phenotypes and Alzheimer's disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the effect of education on Alzheimer's disease risk. Genetically proxied educational attainment was inversely associated with Alzheimer's disease (odds ratio per standard deviation increase in genetically predicted years of schooling = 0.70, 95% confidence interval 0.60, 0.80). There were positive associations between genetically predicted educational attainment and four cortical metrics (standard deviation units change in imaging phenotype per one standard deviation increase in genetically predicted years of schooling): surface area 0.30 (95% confidence interval 0.20, 0.40); volume 0.29 (95% confidence interval 0.20, 0.37); intrinsic curvature 0.18 (95% confidence interval 0.11, 0.25); local gyrification index 0.21 (95% confidence interval 0.11, 0.31)]; and inverse associations with cortical intracellular volume fraction [-0.09 (95% confidence interval -0.15, -0.03)] and white matter hyperintensities volume [-0.14 (95% confidence interval -0.23, -0.05)]. Genetically proxied levels of surface area, cortical volume and intrinsic curvature were positively associated with educational attainment [standard deviation units change in years of schooling per one standard deviation increase in respective genetically predicted imaging phenotype: 0.13 (95% confidence interval 0.10, 0.16); 0.15 (95% confidence interval 0.11, 0.19) and 0.12 (95% confidence interval 0.04, 0.19)]. We found no evidence of associations between genetically predicted imaging-derived phenotypes and Alzheimer's disease. The inverse association of genetically predicted educational attainment with Alzheimer's disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses. Our results provide support for a protective causal effect of educational attainment on Alzheimer's disease risk, as well as potential bidirectional causal relationships between education and brain macro- and micro-structure. However, we did not find evidence that these structural markers affect risk of Alzheimer's disease. The protective effect of education on Alzheimer's disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.
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Enfermedad de Alzheimer , Reserva Cognitiva , Humanos , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Enfermedad de Alzheimer/genética , Estudio de Asociación del Genoma Completo , EscolaridadRESUMEN
Unravelling the complex events driving grade-specific spatial distribution of brain tumour occurrence requires rich datasets from both healthy individuals and patients. Here, we combined open-access data from The Cancer Genome Atlas, the UK Biobank and the Allen Brain Human Atlas to disentangle how the different spatial occurrences of glioblastoma multiforme and low-grade gliomas are linked to brain network features and the normative transcriptional profiles of brain regions. From MRI of brain tumour patients, we first constructed a grade-related frequency map of the regional occurrence of low-grade gliomas and the more aggressive glioblastoma multiforme. Using associated mRNA transcription data, we derived a set of differential gene expressions from glioblastoma multiforme and low-grade gliomas tissues of the same patients. By combining the resulting values with normative gene expressions from post-mortem brain tissue, we constructed a grade-related expression map indicating which brain regions express genes dysregulated in aggressive gliomas. Additionally, we derived an expression map of genes previously associated with tumour subtypes in a genome-wide association study (tumour-related genes). There were significant associations between grade-related frequency, grade-related expression and tumour-related expression maps, as well as functional brain network features (specifically, nodal strength and participation coefficient) that are implicated in neurological and psychiatric disorders. These findings identify brain network dynamics and transcriptomic signatures as key factors in regional vulnerability for glioblastoma multiforme and low-grade glioma occurrence, placing primary brain tumours within a well established framework of neurological and psychiatric cortical alterations.
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Neoplasias Encefálicas , Conectoma , Glioblastoma , Glioma , Humanos , Glioblastoma/genética , Transcriptoma , Estudio de Asociación del Genoma Completo , Glioma/genética , Neoplasias Encefálicas/metabolismoRESUMEN
Brain structural covariance norms capture the coordination of neurodevelopmental programs between different brain regions. We develop and apply anatomical imbalance mapping (AIM), a method to measure and model individual deviations from these norms, to provide a lifespan map of morphological integration in the human cortex. In cross-sectional and longitudinal data, analysis of whole-brain average anatomical imbalance reveals a reproducible tightening of structural covariance by age 25 y, which loosens after the seventh decade of life. Anatomical imbalance change in development and in aging is greatest in the association cortex and least in the sensorimotor cortex. Finally, we show that interindividual variation in whole-brain average anatomical imbalance is positively correlated with a marker of human prenatal stress (birthweight disparity between monozygotic twins) and negatively correlated with general cognitive ability. This work provides methods and empirical insights to advance our understanding of coordinated anatomical organization of the human brain and its interindividual variation.
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Corteza Cerebral/crecimiento & desarrollo , Imagen por Resonancia Magnética/métodos , Adolescente , Adulto , Variación Biológica Poblacional , Corteza Cerebral/diagnóstico por imagen , Conectoma , Femenino , Humanos , MasculinoRESUMEN
Background Clinically acquired brain MRI scans represent a valuable but underused resource for investigating neurodevelopment due to their technical heterogeneity and lack of appropriate controls. These barriers have curtailed retrospective studies of clinical brain MRI scans compared with more costly prospectively acquired research-quality brain MRI scans. Purpose To provide a benchmark for neuroanatomic variability in clinically acquired brain MRI scans with limited imaging pathology (SLIPs) and to evaluate if growth charts from curated clinical MRI scans differed from research-quality MRI scans or were influenced by clinical indication for the scan. Materials and Methods In this secondary analysis of preexisting data, clinical brain MRI SLIPs from an urban pediatric health care system (individuals aged ≤22 years) were scanned across nine 3.0-T MRI scanners. The curation process included manual review of signed radiology reports and automated and manual quality review of images without gross pathology. Global and regional volumetric imaging phenotypes were measured using two image segmentation pipelines, and clinical brain growth charts were quantitatively compared with charts derived from a large set of research controls in the same age range by means of Pearson correlation and age at peak volume. Results The curated clinical data set included 532 patients (277 male; median age, 10 years [IQR, 5-14 years]; age range, 28 days after birth to 22 years) scanned between 2005 and 2020. Clinical brain growth charts were highly correlated with growth charts derived from research data sets (22 studies, 8346 individuals [4947 male]; age range, 152 days after birth to 22 years) in terms of normative developmental trajectories predicted by the models (median r = 0.979). Conclusion The clinical indication of the scans did not significantly bias the output of clinical brain charts. Brain growth charts derived from clinical controls with limited imaging pathology were highly correlated with brain charts from research controls, suggesting the potential of curated clinical MRI scans to supplement research data sets. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Ertl-Wagner and Pai in this issue.
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Encéfalo , Gráficos de Crecimiento , Humanos , Masculino , Niño , Recién Nacido , Estudios Retrospectivos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , CabezaRESUMEN
The vast net of fibres within and underneath the cortex is optimised to support the convergence of different levels of brain organisation. Here, we propose a novel coordinate system of the human cortex based on an advanced model of its connectivity. Our approach is inspired by seminal, but so far largely neglected models of cortico-cortical wiring established by postmortem anatomical studies and capitalises on cutting-edge in vivo neuroimaging and machine learning. The new model expands the currently prevailing diffusion magnetic resonance imaging (MRI) tractography approach by incorporation of additional features of cortical microstructure and cortico-cortical proximity. Studying several datasets and different parcellation schemes, we could show that our coordinate system robustly recapitulates established sensory-limbic and anterior-posterior dimensions of brain organisation. A series of validation experiments showed that the new wiring space reflects cortical microcircuit features (including pyramidal neuron depth and glial expression) and allowed for competitive simulations of functional connectivity and dynamics based on resting-state functional magnetic resonance imaging (rs-fMRI) and human intracranial electroencephalography (EEG) coherence. Our results advance our understanding of how cell-specific neurobiological gradients produce a hierarchical cortical wiring scheme that is concordant with increasing functional sophistication of human brain organisation. Our evaluations demonstrate the cortical wiring space bridges across scales of neural organisation and can be easily translated to single individuals.
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Encéfalo/anatomía & histología , Encéfalo/fisiología , Conectoma/métodos , Adulto , Encéfalo/diagnóstico por imagen , Corteza Cerebral/anatomía & histología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiología , Imagen de Difusión por Resonancia Magnética , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/patología , Epilepsia Refractaria/fisiopatología , Electrocorticografía , Epilepsias Parciales/diagnóstico por imagen , Epilepsias Parciales/patología , Epilepsias Parciales/fisiopatología , Femenino , Neuroimagen Funcional , Humanos , Aprendizaje Automático , Masculino , Modelos Anatómicos , Modelos Neurológicos , Red Nerviosa/anatomía & histología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiología , Adulto JovenRESUMEN
BACKGROUND: Trichotillomania (TTM) and skin picking disorder (SPD) are common and often debilitating mental health conditions, grouped under the umbrella term of body-focused repetitive behaviors (BFRBs). Recent clinical subtyping found that there were three distinct subtypes of TTM and two of SPD. Whether these clinical subtypes map on to any unique neurobiological underpinnings, however, remains unknown. METHODS: Two hundred and fifty one adults [193 with a BFRB (85.5% [n = 165] female) and 58 healthy controls (77.6% [n = 45] female)] were recruited from the community for a multicenter between-group comparison using structural neuroimaging. Differences in whole brain structure were compared across the subtypes of BFRBs, controlling for age, sex, scanning site, and intracranial volume. RESULTS: When the subtypes of TTM were compared, low awareness hair pullers demonstrated increased cortical volume in the lateral occipital lobe relative to controls and sensory sensitive pullers. In addition, impulsive/perfectionist hair pullers showed relative decreased volume near the lingual gyrus of the inferior occipital-parietal lobe compared with controls. CONCLUSIONS: These data indicate that the anatomical substrates of particular forms of BFRBs are dissociable, which may have implications for understanding clinical presentations and treatment response.
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Tricotilomanía , Adulto , Humanos , Femenino , Tricotilomanía/diagnóstico por imagen , Tricotilomanía/epidemiología , Encéfalo , Conducta Impulsiva , ComorbilidadRESUMEN
Autism spectrum disorder (ASD) and anxiety disorders (ANX) are common neurodevelopmental conditions with several overlapping symptoms. Notably, many children and adolescents with ASD also have an ANX diagnosis, suggesting shared pathological mechanisms. Here, we leveraged structural imaging and phenotypic data from 112 youth (33 ASD, 37 ANX, 42 typically developing controls) to assess shared and distinct cortical thickness patterns of the disorders. ANX was associated with widespread increases in cortical thickness, while ASD related to a mixed pattern of subtle increases and decreases across the cortical mantle. Despite the qualitative difference in the case-control contrasts, the statistical maps from the ANX-vs-controls and ASD-vs-controls analyses were significantly correlated when correcting for spatial autocorrelation. Dimensional analysis, regressing trait anxiety and social responsiveness against cortical thickness measures, partially recapitulated diagnosis-based findings. Collectively, our findings provide evidence for a common axis of neurodevelopmental disturbances as well as distinct effects of ASD and ANX on cortical thickness.
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Trastorno del Espectro Autista , Trastorno Autístico , Adolescente , Ansiedad , Trastornos de Ansiedad , Trastorno del Espectro Autista/diagnóstico por imagen , Trastorno del Espectro Autista/patología , Estudios de Casos y Controles , Niño , Humanos , Imagen por Resonancia Magnética/métodosRESUMEN
Recent discovery of approximately 270 common genetic variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. We hypothesized that normal variation in PRS would be associated with magnetic resonance imaging (MRI) phenotypes of brain morphometry and tissue composition. We used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large sample of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macrostructural MRI metrics measured at each of 180 cortical areas, seven subcortical structures, and 15 major white matter tracts. Linear mixed-effect models were used to investigate associations between PRS and brain structure at global and regional scales, controlled for multiple comparisons. Polygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, five subcortical structures, and 14 white matter tracts. Other microstructural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate, and prefrontal cortical areas, insula, and hippocampus. Post-hoc bidirectional Mendelian randomization analyses provided preliminary evidence in support of a causal relationship between (reduced) thalamic NDI and (increased) risk of schizophrenia. Risk-related reduction in NDI is plausibly indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks. Cortical, subcortical, and white matter microstructure may be linked to the genetic mechanisms of schizophrenia.
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Esquizofrenia , Sustancia Blanca , Encéfalo/patología , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial/genética , Esquizofrenia/patología , Sustancia Blanca/patologíaRESUMEN
While the role of cortical microstructure in organising neural function is well established, it remains unclear how structural constraints can give rise to more flexible elements of cognition. While nonhuman primate research has demonstrated a close structure-function correspondence, the relationship between microstructure and function remains poorly understood in humans, in part because of the reliance on post mortem analyses, which cannot be directly related to functional data. To overcome this barrier, we developed a novel approach to model the similarity of microstructural profiles sampled in the direction of cortical columns. Our approach was initially formulated based on an ultra-high-resolution 3D histological reconstruction of an entire human brain and then translated to myelin-sensitive magnetic resonance imaging (MRI) data in a large cohort of healthy adults. This novel method identified a system-level gradient of microstructural differentiation traversing from primary sensory to limbic regions that followed shifts in laminar differentiation and cytoarchitectural complexity. Importantly, while microstructural and functional gradients described a similar hierarchy, they became increasingly dissociated in transmodal default mode and fronto-parietal networks. Meta-analytic decoding of these topographic dissociations highlighted involvement in higher-level aspects of cognition, such as cognitive control and social cognition. Our findings demonstrate a relative decoupling of macroscale functional from microstructural gradients in transmodal regions, which likely contributes to the flexible role these regions play in human cognition.
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Corteza Cerebral/anatomía & histología , Corteza Cerebral/fisiología , Adulto , Anciano , Femenino , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
Impulsive and compulsive problem behaviours are associated with a variety of mental disorders. Latent phenotyping indicates the expression of impulsive and compulsive problem behaviours is predominantly governed by a transdiagnostic 'disinhibition' phenotype. In a cohort of 117 individuals, recruited as part of the Neuroscience in Psychiatry Network (NSPN), we examined how brain functional connectome and network properties relate to disinhibition. Reduced functional connectivity within a subnetwork of frontal (especially right inferior frontal gyrus), occipital and parietal regions was linked to disinhibition. Findings provide insights into neurobiological pathways underlying the emergence of impulsive and compulsive disorders.
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Early-onset neurodevelopmental conditions (e.g., autism) affect males more frequently than females. Androgens may play a role in this male-bias by sex-differentially impacting early prenatal brain development, particularly neural circuits that later develop specialized roles in social cognition. Here, we find that increasing prenatal testosterone in humans is associated with later reduction of functional connectivity between social brain default mode (DMN) subsystems in adolescent males, but has no effect in females. Since testosterone can work directly via the androgen receptor (AR) or indirectly via the estrogen receptor through aromatase conversion to estradiol, we further examined how a potent non-aromatizable androgen, dihydrotestosterone (DHT), acts via the AR to influence gene expression in human neural stem cells (hNSC)-particularly for genes of high-relevance for DMN circuitry. DHT dysregulates a number of genes enriched for syndromic causes of autism and intellectual disability and for genes that in later development are expressed in anatomical patterns that highly correspond to the cortical midline DMN subsystem. DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation-inhibition balance. Androgens have male-specific prenatal influence over social brain circuitry in humans and may be relevant towards explaining some component of male-bias in early-onset neurodevelopmental conditions.
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Andrógenos , Dihidrotestosterona , Adolescente , Encéfalo , Estradiol , Femenino , Humanos , Masculino , TestosteronaRESUMEN
Ageing is commonly associated with changes to segregation and integration of functional brain networks, but, in isolation, current network-based approaches struggle to elucidate changes across the many axes of functional organisation. However, the advent of gradient mapping techniques in neuroimaging provides a new means of studying functional organisation in a multi-dimensional connectivity space. Here, we studied ageing and behaviourally-relevant differences in a three-dimensional connectivity space using the Cambridge Centre for Ageing Neuroscience cohort (n = 643). Building on gradient mapping techniques, we developed a set of measures to quantify the dispersion within and between functional communities. We detected a strong shift of the visual network across the adult lifespan from an extreme to a more central position in the 3D gradient space. In contrast, the dispersion distance between transmodal communities (dorsal attention, ventral attention, frontoparietal and default mode) did not change. However, these communities themselves were increasingly dispersed with increasing age, reflecting more dissimilar functional connectivity profiles within each community. Increasing dispersion of frontoparietal, attention and default mode networks, in particular, were associated negatively with cognition, measured by fluid intelligence. By using a technique that explicitly captures the ordering of functional systems in a multi-dimensional hierarchical framework, we identified behaviorally-relevant age-related differences of within and between network organisation. We propose that the study of functional gradients across the adult lifespan could provide insights that may facilitate the development of new strategies to maintain cognitive ability across the lifespan in health and disease.
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Envejecimiento/fisiología , Encéfalo/fisiología , Cognición/fisiología , Longevidad/fisiología , Red Nerviosa/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Atención/fisiología , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Differences in cortical morphology-in particular, cortical volume, thickness and surface area-have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected 10-14), driven entirely by downregulated genes (OR = 1.87, Pcorrected 10-15). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism.
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Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Corteza Cerebral/fisiopatología , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Encéfalo/fisiopatología , Mapeo Encefálico/métodos , Niño , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neuroimagen/métodos , Transmisión Sináptica/genética , Transcriptoma/genéticaRESUMEN
Adolescence is a period of dynamic brain remodeling and susceptibility to psychiatric risk factors, mediated by the protracted consolidation of association cortices. Here, we investigated whether longitudinal variation in adolescents' resilience to psychosocial stressors during this vulnerable period is associated with ongoing myeloarchitectural maturation and consolidation of functional networks. We used repeated myelin-sensitive Magnetic Transfer (MT) and resting-state functional neuroimaging (n = 141), and captured adversity exposure by adverse life events, dysfunctional family settings, and socio-economic status at two timepoints, one to two years apart. Development toward more resilient psychosocial functioning was associated with increasing myelination in the anterolateral prefrontal cortex, which showed stabilized functional connectivity. Studying depth-specific intracortical MT profiles and the cortex-wide synchronization of myeloarchitectural maturation, we further observed wide-spread myeloarchitectural reconfiguration of association cortices paralleled by attenuated functional reorganization with increasingly resilient outcomes. Together, resilient/susceptible psychosocial functioning showed considerable intra-individual change associated with multi-modal cortical refinement processes at the local and system-level.