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An atlas of age- and sex-related volumetric alterations of grey matter in subcortical regions: The case of 46,111 UK Biobank participants.
Ageing is commonly associated with neuroanatomical changes in brain structure, underscoring the importance of distinguishing normal age-related alterations from those linked to pathological neurodegeneration. Despite this critical need, a standardized benchmark for identifying brain volumetric signatures of ageing remains lacking, and the influence of biological sex on age-related changes in brain volume is not yet fully understood. To address the above-mentioned gaps, we employed T1-weighted MRI images of 46,111 cognitively healthy individuals aged 44-83 from the UK Biobank cohort, and generated comprehensive maps of all the linear and non-linear trajectories of alterations in the grey matter volumes (GMVs) of subcortical regions across males and females. According to our findings, Brainstem, bilateral Amygdala and Hippocampus are the most susceptible subcortical regions to age-related atrophy, with males being generally more prone to such alterations. However, ageing proves to have a dual function as we also observed age-related inflammation in GMVs of Pallidum and Caudate which accelerates during older age and remains consistent across males and females. Our findings guide regenerative strategies and therapeutic interventions by locating subcortical regions most vulnerable to age-related atrophy and inflammation and establish a benchmark for sex-specific typical patterns of subcortical grey matter alterations due to ageing.
Distinct connectivity patterns in clusters of inferior parietal cortex: from a cognitive control hub to modulating cortical areas.
The inferior parietal cortex (IPC) is a complex brain region, composed of the rostral, the middle and the caudal clusters, and functionally connected to several other parts of the brain. Various executive functions are suggested to be governed by the IPC, however, by ignoring the tripartite structure of this region, contradictory research reports abound in the literature. Here, we elaborated on the functional connectivity patterns of the clusters of the IPC, highlighting evidence that only the rostral cluster of this part of the brain is involved in cognitive control, not the entire IPC. We also underscored the unique connectivity profile of the middle and the caudal clusters which are not accommodated by the traditional classification of brain areas as either being task-based or being related to the resting-state functionality of the brain. The middle and the caudal IPC demonstrate negative functional associations with cortical areas involved in general cognitive functions, executive functions, in addition to the precuneus cortex, proportional to cognitive demand, in a modulating manner, while remaining distinct from resting-state related parts of the cortex.
Cognitive demand modulates connectivity patterns of rostral inferior parietal cortex in cognitive control of language.
The inferior parietal cortex (IPC) is involved in different cognitive functions including language. In line with the correlated transmitter receptor-based organization of the IPC, this part of the brain is parcellated into the rostral, the middle and the caudal clusters; however, the tripartite organization of the IPC has not been addressed in studies with a focus on cognitive control of language. Using multiband EPI, in this study we investigated how the rostral IPC contributes to this executive function in bilinguals. In doing so, we focused on the functional connectivity patterns of this part of the cortex with other brain areas in a context characterized with language engagement and disengagement that recruits the neural mechanisms of cognitive control. We found that in switching to L2, which was cognitively less demanding, the right rostral IPC had positive functional connectivity with the anterior division of the cingulate gyrus and the precentral gyrus. However, in switching to L1, which was cognitively more demanding, the right IPC rostral cluster had negative functional coupling with the postcentral gyrus and the precuneus cortex and positive connectivity with the posterior lobe of the cerebellum. In this condition, the left IPC rostral cluster had negative functional coupling with the superior frontal gyrus and the precuneus cortex. Thus, the connectivity patterns of the rostral IPC was influenced by the cognitive demand in an asymmetrical and lateral manner during cognitive control of language.
Connectivity Profile of Middle Inferior Parietal Cortex Confirms the Hypothesis About Modulating Cortical Areas.
According to the correlated transmitter-receptor based structure of the inferior parietal cortex (IPC), this brain area is divided into three clusters, namely, the caudal, the middle and the rostral. Nevertheless, in associating different cognitive functions to the IPC, previous studies considered this part of the cortex as a whole and thus inconsistent results have been reported. Using multiband echo planar imaging (EPI), we investigated the connectivity profile of the middle IPC while forty-five participants performed a task requiring cognitive control. The middle IPC demonstrated functional associations which do not have similarities to a contributing part in the frontoparietal network, in processing cognitive control. At the same time, this cortical area showed negative functional connectivity with both the precuneus cortex, which is resting- state related, and brain areas related to general cognitive functions. That is, the functions of the middle IPC are not accommodated by the traditional categorization of different brain areas i.e. resting state-related or task-related networks and this advanced our hypothesis about modulating cortical areas. Such brain areas are characterized by their negative functional connectivity with parts of the cortex involved in task performance, proportional to the difficulty of the task; yet, their functional associations are inconsistent with the resting state-related cortical areas.
Dual Function of Primary Somatosensory Cortex in Cognitive Control of Language: Evidence from Resting State fMRI.
Resting state functional connectivity can be leveraged to investigate bilingual individual differences in cognitive control of language; however, thus far no report is provided on how the connectivity profiles of brain functional networks at rest point to different language control behavior in bilinguals. In order to address this gap in state-of-the-art research we did a functional connectivity analysis on the resting state data acquired via multiband EPI to investigate three resting state networks of interest namely, the frontoparietal network (FPN), the salience network (SN), and the default mode network (DMN), which are related to cognitive control, between two groups of Dutch-English bilinguals based on how they performed in a language switching task. Results demonstrated that there is the increased coupling of the left primary somatosensory cortex with the dorsolateral prefrontal cortex in the group with better performance in cognitive control of language and the increased coupling of the right primary somatosensory cortex with the inferior parietal cortex in the group with poorer performance in this executive function. As regards these results, we claim that the primary somatosensory cortex has a dual function in coupling with the dorsolateral prefrontal cortex and the inferior parietal cortex in the FPN, and in fact, in what characterizes bilingual individual differences in cognitive control of language in healthy participants. The results of this study provide a model for future research in cognitive control of language and may serve as a reference in clinical neuroscience when bilinguals are diagnosed with dysfunction in cognitive control.
Mapping caudal inferior parietal cortex supports the hypothesis about a modulating cortical area.
The cytoarchitectonically tripartite organization of the inferior parietal cortex (IPC) into the rostral, the middle and the caudal clusters has been generally ignored when associating different functions to this part of the cortex, resulting in inconsistencies about how IPC is understood. In this study, we investigated the patterns of functional connectivity of the caudal IPC in a task requiring cognitive control, using multiband EPI. This part of the cortex demonstrated functional connectivity patterns dissimilar to a cognitive control area and at the same time the caudal IPC showed negative functional associations with both task-related brain areas and the precuneus cortex, which is active during resting state. We found evidence suggesting that the traditional categorization of different brain areas into either task-related or resting state-related networks cannot accommodate the functions of the caudal IPC. This underlies the hypothesis about a new brain functional category as a modulating cortical area proposing that its involvement in task performance, in a modulating manner, is marked by deactivation in the patterns of functional associations with parts of the brain that are recognized to be involved in doing a task, proportionate to task difficulty; however, its patterns of functional connectivity in some other respects do not correspond to the resting state-related parts of the cortex.
In Vivo Amygdala Nuclei Volumes in Schizophrenia and Bipolar Disorders.
Abnormalities in amygdala volume are well-established in schizophrenia and commonly reported in bipolar disorders. However, the specificity of volumetric differences in individual amygdala nuclei is largely unknown. Patients with schizophrenia disorders (SCZ, N = 452, mean age 30.7 ± 9.2 [SD] years, females 44.4%), bipolar disorders (BP, N = 316, 33.7 ± 11.4, 58.5%), and healthy controls (N = 753, 34.1 ± 9.1, 40.9%) underwent T1-weighted magnetic resonance imaging. Total amygdala, nuclei, and intracranial volume (ICV) were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple linear regression models, adjusting for age, age2, ICV, and sex, were fitted to examine diagnostic group and subgroup differences in volume, respectively. Bilateral total amygdala and all nuclei volumes, except the medial and central nuclei, were significantly smaller in patients relative to controls. The largest effect sizes were found for the basal nucleus, accessory basal nucleus, and cortico-amygdaloid transition area (partial η2 > 0.02). The diagnostic subgroup analysis showed that reductions in amygdala nuclei volume were most widespread in schizophrenia, with the lateral, cortical, paralaminar, and central nuclei being solely reduced in this disorder. The right accessory basal nucleus was marginally smaller in SCZ relative to BP (t = 2.32, P = .05). Our study is the first to demonstrate distinct patterns of amygdala nuclei volume reductions in a well-powered sample of patients with schizophrenia and bipolar disorders. Volume differences in the basolateral complex (lateral, basal, and accessory basal nuclei), an integral part of the threat processing circuitry, were most prominent in schizophrenia.
Oxytocin-pathway polygenic scores for severe mental disorders and metabolic phenotypes in the UK Biobank.
Oxytocin is a neuromodulator and hormone that is typically associated with social cognition and behavior. In light of its purported effects on social cognition and behavior, research has investigated its potential as a treatment for psychiatric illnesses characterized by social dysfunction, such as schizophrenia and bipolar disorder. While the results of these trials have been mixed, more recent evidence suggests that the oxytocin system is also linked with cardiometabolic conditions for which individuals with severe mental disorders are at a higher risk for developing. To investigate whether the oxytocin system has a pleiotropic effect on the etiology of severe mental illness and cardiometabolic conditions, we explored oxytocin's role in the shared genetic liability of schizophrenia, bipolar disorder, type-2 diabetes, and several phenotypes linked with cardiovascular disease and type 2 diabetes risk using a polygenic pathway-specific approach. Analysis of a large sample with about 480,000 individuals (UK Biobank) revealed statistically significant associations across the range of phenotypes analyzed. By comparing these effects to those of polygenic scores calculated from 100 random gene sets, we also demonstrated the specificity of many of these significant results. Altogether, our results suggest that the shared effect of oxytocin-system dysfunction could help partially explain the co-occurrence of social and cardiometabolic dysfunction in severe mental illnesses.
Apolipoprotein ɛ4 Status and Brain Structure 12 Months after Mild Traumatic Injury: Brain Age Prediction Using Brain Morphometry and Diffusion Tensor Imaging.
BACKGROUND: Apolipoprotein E (APOE) ɛ4 is associated with poor outcome following moderate to severe traumatic brain injury (TBI). There is a lack of studies investigating the influence of APOE ɛ4 on intracranial pathology following mild traumatic brain injury (MTBI). This study explores the association between APOE ɛ4 and MRI measures of brain age prediction, brain morphometry, and diffusion tensor imaging (DTI). METHODS: Patients aged 16 to 65 with acute MTBI admitted to the trauma center were included. Multimodal MRI was performed 12 months after injury and associated with APOE ɛ4 status. Corrections for multiple comparisons were done using false discovery rate (FDR). RESULTS: Of included patients, 123 patients had available APOE, volumetric, and DTI data of sufficient quality. There were no differences between APOE ɛ4 carriers (39%) and non-carriers in demographic and clinical data. Age prediction revealed high accuracy both for the DTI-based and the brain morphometry based model. Group comparisons revealed no significant differences in brain-age gap between ɛ4 carriers and non-carriers, and no significant differences in conventional measures of brain morphometry and volumes. Compared to non-carriers, APOE ɛ4 carriers showed lower fractional anisotropy (FA) in the hippocampal part of the cingulum bundle, which did not remain significant after FDR adjustment. CONCLUSION: APOE ɛ4 carriers might be vulnerable to reduced neuronal integrity in the cingulum. Larger cohort studies are warranted to replicate this finding.
Brain age prediction using fMRI network coupling in youths and associations with psychiatric symptoms.
OBJECTIVE: Magnetic resonance imaging (MRI) has shown that estimated brain age is deviant from chronological age in various common brain disorders. Brain age estimation could be useful for investigating patterns of brain maturation and integrity, aiding to elucidate brain mechanisms underlying these heterogeneous conditions. Here, we examined functional brain age in two large samples of children and adolescents and its relation to mental health. METHODS: We used resting-state fMRI data from the Philadelphia Neurodevelopmental Cohort (PNC; n = 1126, age range 8-22 years) to estimate functional connectivity between brain networks, and utilized these as features for brain age prediction. We applied the prediction model to 1387 individuals (age range 8-22 years) in the Healthy Brain Network sample (HBN). In addition, we estimated brain age in PNC using a cross-validation framework. Next, we tested for associations between brain age gap and various aspects of psychopathology and cognitive performance. RESULTS: Our model was able to predict age in the independent test samples, with a model performance of r = 0.54 for the HBN test set, supporting consistency in functional connectivity patterns between samples and scanners. Linear models revealed a significant association between brain age gap and psychopathology in PNC, where individuals with a lower estimated brain age, had a higher overall symptom burden. These associations were not replicated in HBN. DISCUSSION: Our findings support the use of brain age prediction from fMRI-based connectivity. While requiring further extensions and validations, the approach may be instrumental for detecting brain phenotypes related to intrinsic connectivity and could assist in characterizing risk in non-typically developing populations.
Adipose tissue distribution from body MRI is associated with cross-sectional and longitudinal brain age in adults.
There is an intimate body-brain connection in ageing, and obesity is a key risk factor for poor cardiometabolic health and neurodegenerative conditions. Although research has demonstrated deleterious effects of obesity on brain structure and function, the majority of studies have used conventional measures such as waist-to-hip ratio, waist circumference, and body mass index. While sensitive to gross features of body composition, such global anthropometric features fail to describe regional differences in body fat distribution and composition. The sample consisted of baseline brain magnetic resonance imaging (MRI) acquired from 790 healthy participants aged 18-94 years (mean ± standard deviation (SD) at baseline: 46.8 ± 16.3), and follow-up brain MRI collected from 272 of those individuals (two time-points with 19.7 months interval, on average (min = 9.8, max = 35.6). Of the 790 included participants, cross-sectional body MRI data was available from a subgroup of 286 participants, with age range 19-86 (mean = 57.6, SD = 15.6). Adopting a mixed cross-sectional and longitudinal design, we investigated cross-sectional body magnetic resonance imaging measures of adipose tissue distribution in relation to longitudinal brain structure using MRI-based morphometry (T1) and diffusion tensor imaging (DTI). We estimated tissue-specific brain age at two time points and performed Bayesian multilevel modelling to investigate the associations between adipose measures at follow-up and brain age gap (BAG) - the difference between actual age and the prediction of the brain's biological age - at baseline and follow-up. We also tested for interactions between BAG and both time and age on each adipose measure. The results showed credible associations between T1-based BAG and liver fat, muscle fat infiltration (MFI), and weight-to-muscle ratio (WMR), indicating older-appearing brains in people with higher measures of adipose tissue. Longitudinal evidence supported interaction effects between time and MFI and WMR on T1-based BAG, indicating accelerated ageing over the course of the study period in people with higher measures of adipose tissue. The results show that specific measures of fat distribution are associated with brain ageing and that different compartments of adipose tissue may be differentially linked with increased brain ageing, with potential to identify key processes involved in age-related transdiagnostic disease processes.
Cardiometabolic risk factors associated with brain age and accelerate brain ageing.
The structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs) are associated with dementia and other brain disorders. In this mixed cross-sectional and longitudinal study (interval mean = 19.7 months), including 790 healthy individuals (mean age = 46.7 years, 53% women), we investigated CMRs and health indicators including anthropometric measures, lifestyle factors, and blood biomarkers in relation to brain structure using MRI-based morphometry and diffusion tensor imaging (DTI). We performed tissue specific brain age prediction using machine learning and performed Bayesian multilevel modeling to assess changes in each CMR over time, their respective association with brain age gap (BAG), and their interaction effects with time and age on the tissue-specific BAGs. The results showed credible associations between DTI-based BAG and blood levels of phosphate and mean cell volume (MCV), and between T1-based BAG and systolic blood pressure, smoking, pulse, and C-reactive protein (CRP), indicating older-appearing brains in people with higher cardiometabolic risk (smoking, higher blood pressure and pulse, low-grade inflammation). Longitudinal evidence supported interactions between both BAGs and waist-to-hip ratio (WHR), and between DTI-based BAG and systolic blood pressure and smoking, indicating accelerated ageing in people with higher cardiometabolic risk (smoking, higher blood pressure, and WHR). The results demonstrate that cardiometabolic risk factors are associated with brain ageing. While randomized controlled trials are needed to establish causality, our results indicate that public health initiatives and treatment strategies targeting modifiable cardiometabolic risk factors may also improve risk trajectories and delay brain ageing.
White matter integrity as a marker for cognitive plasticity in aging.
Age-related differences in white matter (WM) integrity are substantial, but it is unknown whether between-subject variability in WM integrity influences the capacity for cognitive improvement. We investigated the effects of memory training related to active and passive control conditions in older adults and tested whether WM integrity at baseline was predictive of training benefits. We hypothesized that (1) memory improvement would be restricted to the training group, (2) widespread areas would show greater mean diffusivity (MD) and lower fractional anisotropy in older adults relative to young adults, and (3) within these areas, variability in WM microstructure in the older group would be predictive of training gains. The results showed that only the group receiving training improved their memory. Significant age differences in MD and fractional anisotropy were found in widespread areas. Within these areas, voxelwise analyses showed a negative relationship between MD and memory improvement in 3 clusters, indicating that WM integrity could serve as a marker for the ability to adapt in response to cognitive challenges in aging.
Multimodal brain-age prediction and cardiovascular risk: The Whitehall II MRI sub-study.
Brain age is becoming a widely applied imaging-based biomarker of neural aging and potential proxy for brain integrity and health. We estimated multimodal and modality-specific brain age in the Whitehall II (WHII) MRI cohort using machine learning and imaging-derived measures of gray matter (GM) morphology, white matter microstructure (WM), and resting state functional connectivity (FC). The results showed that the prediction accuracy improved when multiple imaging modalities were included in the model (R2 = 0.30, 95% CI [0.24, 0.36]). The modality-specific GM and WM models showed similar performance (R2 = 0.22 [0.16, 0.27] and R2 = 0.24 [0.18, 0.30], respectively), while the FC model showed the lowest prediction accuracy (R2 = 0.002 [-0.005, 0.008]), indicating that the FC features were less related to chronological age compared to structural measures. Follow-up analyses showed that FC predictions were similarly low in a matched sub-sample from UK Biobank, and although FC predictions were consistently lower than GM predictions, the accuracy improved with increasing sample size and age range. Cardiovascular risk factors, including high blood pressure, alcohol intake, and stroke risk score, were each associated with brain aging in the WHII cohort. Blood pressure showed a stronger association with white matter compared to gray matter, while no differences in the associations of alcohol intake and stroke risk with these modalities were observed. In conclusion, machine-learning based brain age prediction can reduce the dimensionality of neuroimaging data to provide meaningful biomarkers of individual brain aging. However, model performance depends on study-specific characteristics including sample size and age range, which may cause discrepancies in findings across studies.
Prominent health problems, socioeconomic deprivation, and higher brain age in lonely and isolated individuals: A population-based study.
Loneliness is linked to increased risk for Alzheimer's disease, but little is known about factors potentially contributing to adverse brain health in lonely individuals. In this study, we used data from 24,867 UK Biobank participants to investigate risk factors related to loneliness and estimated brain age based on neuroimaging data. The results showed that on average, individuals who self-reported loneliness on a single yes/no item scored higher on neuroticism, depression, social isolation, and socioeconomic deprivation, performed less physical activity, and had higher BMI compared to individuals who did not report loneliness. In line with studies pointing to a genetic overlap of loneliness with neuroticism and depression, permutation feature importance ranked these factors as the most important for classifying lonely vs. not lonely individuals (ROC AUC = 0.83). While strongly linked to loneliness, neuroticism and depression were not associated with brain age estimates. Conversely, objective social isolation showed a main effect on brain age, and individuals reporting both loneliness and social isolation showed higher brain age relative to controls - as part of a prominent risk profile with elevated scores on socioeconomic deprivation and unhealthy lifestyle behaviours, in addition to neuroticism and depression. While longitudinal studies are required to determine causality, this finding may indicate that the combination of social isolation and a genetic predisposition for loneliness involves a risk for adverse brain health. Importantly, the results underline the complexity in associations between loneliness and adverse health outcomes, where observed risks likely depend on a combination of interlinked variables including genetic as well as social, behavioural, physical, and socioeconomic factors.
Dissecting unique and common variance across body and brain health indicators using age prediction.
Ageing is a heterogeneous multisystem process involving different rates of decline in physiological integrity across biological systems. The current study dissects the unique and common variance across body and brain health indicators and parses inter-individual heterogeneity in the multisystem ageing process. Using machine-learning regression models on the UK Biobank data set (N = 32,593, age range 44.6-82.3, mean age 64.1 years), we first estimated tissue-specific brain age for white and gray matter based on diffusion and T1-weighted magnetic resonance imaging (MRI) data, respectively. Next, bodily health traits, including cardiometabolic, anthropometric, and body composition measures of adipose and muscle tissue from bioimpedance and body MRI, were combined to predict 'body age'. The results showed that the body age model demonstrated comparable age prediction accuracy to models trained solely on brain MRI data. The correlation between body age and brain age predictions was 0.62 for the T1 and 0.64 for the diffusion-based model, indicating a degree of unique variance in brain and bodily ageing processes. Bayesian multilevel modelling carried out to quantify the associations between health traits and predicted age discrepancies showed that higher systolic blood pressure and higher muscle-fat infiltration were related to older-appearing body age compared to brain age. Conversely, higher hand-grip strength and muscle volume were related to a younger-appearing body age. Our findings corroborate the common notion of a close connection between somatic and brain health. However, they also suggest that health traits may differentially influence age predictions beyond what is captured by the brain imaging data, potentially contributing to heterogeneous ageing rates across biological systems and individuals.