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The UK Biobank (UKB) has the largest adult brain imaging dataset, which encompasses over 40,000 participants. A significant number of Mendelian randomization (MR) studies based on UKB neuroimaging data have been published to validate potential causal relationships identified in observational studies. Relevant articles published before December 2023 were identified following the PRISMA protocol. Included studies (n = 34) revealed that there were causal relationships between various lifestyles, diseases, biomarkers, and brain image-derived phenotypes (BIDPs). In terms of lifestyle habits and environmental factors, there were causal relationships between alcohol consumption, tea intake, coffee consumption, smoking, educational attainment, and certain BIDPs. Additionally, some BIDPs could serve as mediators between leisure/physical inactivity and major depressive disorder. Regarding diseases, BIDPs have been found to have causal relationships not only with Alzheimer's disease, stroke, psychiatric disorders, and migraine, but also with cardiovascular diseases, diabetes, poor oral health, osteoporosis, and ankle sprain. In addition, there were causal relationships between certain biological markers and BIDPs, such as blood pressure, LDL-C, IL-6, telomere length, and more. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) interacts with psychopathology in a complex way; however, little is known about the underlying brain, biochemical, and genetic mechanisms. To clarify the phenotypic and genetic associations between IBS and brain health, we performed a comprehensive retrospective cohort study on a large population. Our study included 171,104 participants from the UK Biobank who underwent a thorough assessment of IBS, with the majority also providing neuroimaging, behavioral, biochemical, and genetic information. Multistage linked analyses were conducted, including phenome-wide association analysis, polygenic risk score calculation, and 2-sample Mendelian randomization analysis. The phenome-wide association analysis showed that IBS was linked to brain health problems, including anxiety and depression, and poor cognitive performance. Significantly lower brain volumes associated with more severe IBS were found in key areas related to emotional regulation and higher-order cognition, including the medial orbitofrontal cortex/ventromedial prefrontal cortex, anterior insula, anterior and mid-cingulate cortices, dorsolateral prefrontal cortex, and hippocampus. Higher triglycerides, lower high-intensity lipoprotein, and lower platelets were also related (p < 1 × 10−10) to more severe IBS. Finally, Mendelian randomization analyses demonstrated potential causal relationships between IBS and brain health and indicated possible mediating effects of dyslipidemia and inflammation. For the first time, this study provides a comprehensive understanding of the relationship between IBS and brain health phenotypes, integrating perspectives from neuroimaging, behavioral performance, biochemical factors, and genetics, which is of great significance for clinical applications to potentially address brain health impairments in patients with IBS. [ABSTRACT FROM AUTHOR]

Chronic pain affects nearly 20% of the U.S. population. It is a leading cause of disability globally and is associated with a heightened risk for suicide. The role of the central nervous system in the perception and maintenance of chronic pain has recently been accepted, but specific brain circuitries involved have yet to be mapped across pain types in a large-scale study. We used data from the UK Biobank (N = 21,968) to investigate brain structural alterations in individuals reporting chronic pain compared with pain-free control participants and their mediating effect on history of suicide attempt. Chronic pain and, more notably, chronic multisite pain was associated with, on average, lower surface area throughout the cortex after adjusting for demographic, clinical, and neuropsychiatric confounds. Only participants with abdominal pain showed lower subcortical volumes, including the amygdala and brainstem, and lower cerebellum volumes. Participants with chronic headaches showed a widespread thicker cortex compared with control participants. Mediation analyses revealed that precuneus thickness mediated the relationship of chronic multisite pain and history of suicide attempt. Mediating effects were also identified specific to localized pain, with the strongest effect being amygdala volume in individuals with chronic abdominal pain. Results support a widespread effect of chronic pain on brain structure and distinct brain structures underlying chronic musculoskeletal pain, visceral pain, and headaches. Mediation effects of regions in the extended ventromedial prefrontal cortex subsystem suggest that exacerbated negative internal states, negative self-referencing, and impairments in future planning may underlie suicidal behaviors in individuals with chronic pain. [ABSTRACT FROM AUTHOR]

Global prevalence of Alzheimer's Disease has a strong sex bias, with women representing approximately two‐thirds of the patients. Yet, the role of sex‐specific risk factors during midlife, including hormone replacement therapy (HRT) and their interaction with other major risk factors for Alzheimer's Disease, such as apolipoprotein E (APOE)‐e4 genotype and age, on brain health remains unclear. We investigated the relationship between HRT (i.e., use, age of initiation and duration of use) and brain health (i.e., cognition and regional brain volumes). We then consider the multiplicative effects of HRT and APOE status (i.e., e2/e2, e2/e3, e3/e3, e3/e4 and e4/e4) via a two‐way interaction and subsequently age of participants via a three‐way interaction. Women from the UK Biobank with no self‐reported neurological conditions were included (N = 207,595 women, mean age = 56.25 years, standard deviation = 8.01 years). Generalised linear regression models were computed to quantify the cross‐sectional association between HRT and brain health, while controlling for APOE status, age, time since attending centre for completing brain health measure, surgical menopause status, smoking history, body mass index, education, physical activity, alcohol use, ethnicity, socioeconomic status, vascular/heart problems and diabetes diagnosed by doctor. Analyses of structural brain regions further controlled for scanner site. All brain volumes were normalised for head size. Two‐way interactions between HRT and APOE status were modelled, in addition to three‐way interactions including age. Results showed that women with the e4/e4 genotype who have used HRT had 1.82% lower hippocampal, 2.4% lower parahippocampal and 1.24% lower thalamus volumes than those with the e3/e3 genotype who had never used HRT. However, this interaction was not detected for measures of cognition. No clinically meaningful three‐way interaction between APOE, HRT and age was detected when interpreted relative to the scales of the cognitive measures used and normative models of ageing for brain volumes in this sample. Differences in hippocampal volume between women with the e4/e4 genotype who have used HRT and those with the e3/e3 genotype who had never used HRT are equivalent to approximately 1–2 years of hippocampal atrophy observed in typical health ageing trajectories in midlife (i.e., 0.98%–1.41% per year). Effect sizes were consistent within APOE e4/e4 group post hoc sensitivity analyses, suggesting observed effects were not solely driven by APOE status and may, in part, be attributed to HRT use. Although, the design of this study means we cannot exclude the possibility that women who have used HRT may have a predisposition for poorer brain health. [ABSTRACT FROM AUTHOR]

In the realm of cognitive science, the phenomenon of "successful cognitive aging" stands as a hallmark of individuals who exhibit cognitive abilities surpassing those of their age-matched counterparts. However, it is paramount to underscore a significant gap in the current research, which is marked by a paucity of comprehensive inquiries that deploy substantial sample sizes to methodically investigate the cerebral biomarkers and contributory elements underpinning this cognitive success. It is within this context that our present study emerges, harnessing data derived from the UK Biobank. In this study, a highly selective cohort of 1060 individuals aged 65 and above was meticulously curated from a larger pool of 17,072 subjects. The selection process was guided by their striking cognitive resilience, ascertained via rigorous evaluation encompassing both generic and specific cognitive assessments, compared to their peers within the same age stratum. Notably, the cognitive abilities of the chosen participants closely aligned with the cognitive acumen commonly observed in middle-aged individuals. Our study leveraged a comprehensive array of neuroimaging-derived metrics, obtained from three Tesla MRI scans (T1-weighted images, dMRI, and resting-state fMRI). The metrics included image-derived phenotypes (IDPs) that addressed grey matter morphology, the strength of brain network connectivity, and the microstructural attributes of white matter. Statistical analyses were performed employing ANOVA, Mann–Whitney U tests, and chi-square tests to evaluate the distinctive aspects of IDPs pertinent to the domain of successful cognitive aging. Furthermore, these analyses aimed to elucidate lifestyle practices that potentially underpin the maintenance of cognitive acumen throughout the aging process. Our findings unveiled a robust and compelling association between heightened cognitive aptitude and the integrity of white matter structures within the brain. Furthermore, individuals who exhibited successful cognitive aging demonstrated markedly enhanced activity in the cerebral regions responsible for auditory perception, voluntary motor control, memory retention, and emotional regulation. These advantageous cognitive attributes were mirrored in the health-related lifestyle choices of the surveyed cohort, characterized by elevated educational attainment, a lower incidence of smoking, and a penchant for moderate alcohol consumption. Moreover, they displayed superior grip strength and enhanced walking speeds. Collectively, these findings furnish valuable insights into the multifaceted determinants of successful cognitive aging, encompassing both neurobiological constituents and lifestyle practices. Such comprehensive comprehension significantly contributes to the broader discourse on aging, thereby establishing a solid foundation for the formulation of targeted interventions aimed at fostering cognitive well-being among aging populations. [ABSTRACT FROM AUTHOR]

The corpus callosum (CC) is the main structure transferring information between the cerebral hemispheres. Although previous large-scale genome-wide association study (GWAS) has illustrated the genetic architecture of white matter integrity of CC, CC volume is less stressed. Using MRI data from 33,861 individuals in UK Biobank, we conducted univariate and multivariate GWAS for CC fractional anisotropy (FA) and volume with PLINK 2.0 and MOSTest. All discovered SNPs in the multivariate framework were functionally annotated in FUMA v1.3.8. In the meanwhile, a series of gene property analyses was conducted simultaneously. In addition, we estimated genetic relationship between CC metrics and other neuropsychiatric traits and diseases. We identified a total of 36 and 82 significant genomic loci for CC FA and volume (P < 5 × 10−8). And 53 and 27 genes were respectively mapped by four mapping strategies. For CC volume, gene-set analysis revealed pathways mainly relating to cell migration; cell-type analysis found the top enrichment in neuroglia while for CC FA in GABAergic neurons. Furthermore, we found a lot of genetic overlap and shared loci between CC FA and volume and common neuropsychiatric diseases. Collectively, this study helps to better understand the genetic architecture of whole CC and CC subregions. However, the way to divide CC FA and volume in our study restricts the interpretations of our results. Future work will be needed to pay attention to the genetic structure of white matter volume, and an appropriate division of CC may help to better understand CC structure. • The genetic architecture of microstructure and macrostructure of corpus callosum (CC). • Genetic correlations between CC metrics and other brain measures derived from MRI. • Genetic overlap between CC metrics and common neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

Purpose: To examine the association between dietary magnesium (Mg) intake and brain volumes and white matter lesions (WMLs) in middle to early old age. Methods: Participants (aged 40–73 years) from UK Biobank (n = 6001) were included and stratified by sex. Dietary Mg was measured using an online computerised 24 h recall questionnaire to estimate daily Mg intake. Latent class analysis and hierarchical linear regression models were performed to investigate the association between baseline dietary Mg, Mg trajectories, and brain volumes and WMLs. Associations between baseline Mg, and baseline blood pressure (BP) measures, and baseline Mg, Mg trajectories and BP changes (between baseline and wave 2) were also investigated to assess whether BP mediates the link between Mg intake and brain health. All analyses controlled for health and socio-demographic covariates. Possible interactions between menopausal status and Mg trajectories in predicting brain volumes and WMLs were also investigated. Results: On average, higher baseline dietary Mg intake was associated with larger brain volumes (gray matter [GM]: 0.001% [SE = 0.0003]; left hippocampus [LHC]: 0.0013% [SE = 0.0006]; and right hippocampus [RHC]: 0.0023% [SE = 0.0006]) in both men and women. Latent class analysis of Mg intake revealed three classes: "high-decreasing" (men = 3.2%, women = 1.9%), "low-increasing" (men = 1.09%, women = 1.62%), and "stable normal" (men = 95.71%, women = 96.51%). In women, only the "high-decreasing" trajectory was significantly associated with larger brain volumes (GM: 1.17%, [SE = 0.58]; and RHC: 2.79% [SE = 1.11]) compared to the "normal-stable", the "low-increasing" trajectory was associated with smaller brain volumes (GM: − 1.67%, [SE = 0.30]; white matter [WM]: − 0.85% [SE = 0.42]; LHC: − 2.43% [SE = 0.59]; and RHC: − 1.50% [SE = 0.57]) and larger WMLs (1.6% [SE = 0.53]). Associations between Mg and BP measures were mostly non-significant. Furthermore, the observed neuroprotective effect of higher dietary Mg intake in the "high-decreasing" trajectory appears to be greater in post-menopausal than pre-menopausal women. Conclusions: Higher dietary Mg intake is related to better brain health in the general population, and particularly in women. [ABSTRACT FROM AUTHOR]

Communities across the globe are faced with a rapidly aging society, where age is the main risk factor for cognitive decline and development of Alzheimer's and related diseases. Despite extensive research, there have been no successful treatments yet. A rare group of individuals called "super-agers" have been noted to thrive with their exceptional ability to maintain a healthy brain and normal cognitive function even in old age. Studying their traits, lifestyles, and environments may provide valuable insight. This study used a data-driven approach to identify potential super-agers among 7121 UK Biobank participants and found that these individuals have the highest total brain volume, best cognitive performance, and lowest functional connectivity. The researchers suggest a novel hypothesis that these super-agers possess enhanced neural processing efficiency that increases with age and introduce a definition of the "neural efficiency index." Furthermore, several other types of aging were identified and significant structural–functional differences were observed between them, highlighting the benefit of research efforts in personalized medicine and precision nutrition. [ABSTRACT FROM AUTHOR]

Background: Seizures can occur unpredictably in patients with acute encephalitis syndrome (AES), and many suffer from poor long-term neurological sequelae. Establishing factors associated with acute seizures risk and poor outcomes could support clinical care. We aimed to conduct regional and volumetric analysis of cerebral oedema on magnetic resonance imaging (MRI) in patients with AES. We assessed the relationship of brain oedema with acute seizure activity and long-term neurological outcome. Methods: In a multi-centre cohort study, adults and children presenting with an AES were recruited in the UK. The clinical and brain MRI data were retrospectively reviewed. The outcomes variables were inpatient acute seizure activity and neurological disability at six-months post-discharge. A poor outcome was defined as a Glasgow outcome score (GOS) of 1–3. We quantified regional brain oedema on MRI through stereological examination of T2-weighted images using established methodology by independent and blinded assessors. Clinical and neuroimaging variables were analysed by multivariate logistic regression to assess for correlation with acute seizure activity and outcome. Results: The study cohort comprised 69 patients (mean age 31.8 years; 53.6% female), of whom 41 (59.4%) had acute seizures as inpatients. A higher Glasgow coma scale (GCS) score on admission was a negative predictor of seizures (OR 0.61 [0.46–0.83], p = 0.001). Even correcting for GCS on admission, the presence of cortical oedema was a significant risk factor for acute seizure activity (OR 5.48 [1.62–18.51], p = 0.006) and greater volume of cerebral oedema in these cortical structures increased the risk of acute seizures (OR 1.90 [1.12–3.21], p = 0.017). At six-month post-discharge, 21 (30.4%) had a poor neurological outcome. Herpes simplex virus encephalitis was associated with higher risk of poor outcomes in univariate analysis (OR 3.92 [1.08–14.20], p = 0.038). When controlling for aetiology, increased volume of cerebral oedema was an independent risk factor for adverse neurological outcome at 6 months (OR 1.73 [1.06–2.83], p = 0.027). Conclusions: Both the presence and degree of cerebral oedema on MRIs of patients with AES may help identify patients at risk of acute seizure activity and subsequent long-term morbidity. [ABSTRACT FROM AUTHOR]

Alcohol misuse is a major global public health issue. The disorder is characterized by aberrant neural networks interacting with environment and genetics. Dissecting the neural substrates and functional networks that relate to longitudinal changes in alcohol use from those that relate to alcohol misuse cross-sectionally is important to elucidate therapeutic approaches. To assess how neuroimaging data, including T1, resting-state functional magnetic resonance imaging, and diffusion-weighted imaging, relate to alcohol misuse cross-sectionally and longitudinally in the UK Biobank, this study analyzed range of alcohol misuse in a population-based normative sample of 24,784 participants, ages 45 to 81 years old, in a cross-sectional analysis and a sample of 3070 participants in a longitudinal analysis 2 years later. Cross-sectional analysis showed that alcohol use is associated with a reduction in dorsal anterior cingulate cortex and dorsomedial prefrontal cortex gray matter concentration and functional resting-state connectivity (nodal degree: t 24,422 = −12.99, p < 1 × 10−17). Reduced dorsal anterior cingulate cortex/dorsomedial prefrontal cortex functional connections to the ventrolateral prefrontal cortex, amygdala, and striatum relate to greater alcohol use. In a longitudinal analysis, higher resting-state nodal degree (t 3036 = −3.27, p =.0011) and T1 gray matter concentration in the ventromedial prefrontal cortex relate to reduced alcohol intake frequency 2 years later. Higher ventromedial prefrontal cortex and frontoparietal executive network functional connectivity is associated with lower subsequent drinking longitudinally. Dorsal versus ventromedial prefrontal regions are differentially related to alcohol misuse cross-sectionally or longitudinally in a large UK Biobank normative dataset. Our study provides a comprehensive understanding of the neurobiological substrates of alcohol use as a state or prospectively, thereby providing potential targets for clinical treatment. [ABSTRACT FROM AUTHOR]

Obese adults are often reported to have smaller brain volumes than their non-obese peers. Whether this represents evidence of accelerations in obesity-driven atrophy or is instead a legacy of developmental differences established earlier in the lifespan remains unclear. This study investigated whether early-life differences in adiposity explain differences in numerous adult brain traits commonly attributed to mid-life obesity. We used a two-sample life course Mendelian randomization study in 37 501 adults recruited to UK Biobank (UKB) imaging centres from 2014, with secondary analyses in 6996 children assessed in the Adolescent Brain Cognitive Development Study (ABCD) recruited from 2018. Exposures were genetic variants for childhood (266 variants) and adult (470 variants) adiposity derived from a genome-wide association study (GWAS) of 407 741 UKB participants. Primary outcomes were: adult total brain volume; grey matter volume, thickness and surface area; white matter volume and hyperintensities; and hippocampus, amygdala and thalamus volumes at mean age 55 in the UKB. Secondary outcomes were equivalent childhood measures collected at mean age 10 in ABCD. In the UKB, individuals who were genetically predicted to have had higher levels of adiposity in childhood were found to have multiple smaller adult brain volumes relative to intracranial volume [e.g. z-score difference in normalized brain volume per category increase in adiposity-95% confidence interval (CI) = -0.20 (-0.28, -0.12); P = 4 × 10-6]. These effect sizes remained essentially unchanged after accounting for birthweight or current adult obesity in multivariable models, whereas most observed adult effects attenuated towards null [e.g. adult z-score (95% CI) for total volume = 0.06 (-0.05, 0.17); P = 0.3]. Observational analyses in ABCD showed a similar pattern of changes already present in those with a high body mass index by age 10 [z-score (95% CI) = -0.10 (-0.13, -0.07); P = 8 × 10-13], with follow-up genetic risk score analyses providing some evidence for a causal effect already at this early age. Sensitivity analyses revealed that many of these effects were likely due to the persistence of larger head sizes established in those who gained excess weight in childhood [childhood z-score (95% CI) for intracranial volume = 0.14 (0.05, 0.23); P = 0.002], rather than smaller brain sizes per se. Our data suggest that the persistence of early-life developmental differences across the life course may underlie numerous neuroimaging traits commonly attributed to obesity-related atrophy in later life., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Alterations in brain size and organization represent some of the most distinctive changes in the emergence of our species. Yet, there is limited understanding of how genetic factors contributed to altered neuroanatomy during human evolution. Here, we analyze neuroimaging and genetic data from up to 30,000 people in the UK Biobank and integrate with genomic annotations for different aspects of human evolution, including those based on ancient DNA and comparative genomics. We show that previously reported signals of recent polygenic selection for cortical anatomy are not replicable in a more ancestrally homogeneous sample. We then investigate relationships between evolutionary annotations and common genetic variants shaping cortical surface area and white-matter connectivity for each hemisphere. Our analyses identify single-nucleotide polymorphism heritability enrichment in human-gained regulatory elements that are active in early brain development, affecting surface areas of several parts of the cortex, including left-hemispheric speech-associated regions. We also detect heritability depletion in genomic regions with Neanderthal ancestry for connectivity of the uncinate fasciculus; this is a white-matter tract involved in memory, language, and socioemotional processing with relevance to neuropsychiatric disorders. Finally, we show that common genetic loci associated with left-hemispheric pars triangularis surface area overlap with a human-gained enhancer and affect regulation of ZIC4, a gene implicated in neurogenesis. This work demonstrates how genomic investigations of present-day neuroanatomical variation can help shed light on the complexities of our evolutionary past. [ABSTRACT FROM AUTHOR]

Background: To quantify the association between blood pressure (BP) across its full range, brain volumes and white matter lesions (WMLs) while investigating the effects of age, sex, body mass index (BMI), and antihypertensive medication. Methods: UK Biobank participants (n = 36,260) aged (40–70) years were included and stratified by sex and four age groups (age ≤ 45, 46–55, 56–65 and > 65 years). Multi-level regression analyses were used to assess the association between mean arterial pressure (MAP), systolic BP (SBP), diastolic BP (DBP), and brain volumes segmented using the FreeSufer software (gray matter volume [GMV], white matter volume [WMV], left [LHCV] and right hippocampal volume [RHCV]) and WMLs. Interaction effects between body mass index (BMI), antihypertensive medication and BP in predicting brain volumes and WMLs were also investigated. Results: Every 10 mmHg higher DBP was associated with lower brain volumes (GMV: −0.19%–−0.40%) [SE = 47.7–62.4]; WMV: −0.20–−0.23% [SE = 34.66–53.03]; LHCV: −0.40–−0.59% [SE = 0.44–0.57]; RHCV: −0.17–−0.57% [SE = 0.32–0.95]) across all age groups. A similar pattern was detected in both sexes, although it was weaker in men. Every 10 mmHg higher MAP was associated with larger WMLs across all age groups but peaked >65 years (1.19–1.23% [SE = 0.002]). Both lower BMI and anti-hypertensive medication appeared to afford a protective effect. Conclusion: Higher BP is associated with worse cerebral health across the full BP range from middle adulthood and into old age. [ABSTRACT FROM AUTHOR]

Few studies have investigated brain responses to different art media. Investigations into brain processes during art making have highlighted important structures. Neuroimaging tools have been used to investigate activation of brain areas whilst artmaking, but not in a therapeutic setting. This review highlights recent advancements in this area and encourages researchers to be the first to apply this in the UK. To understand how the principles of neuroscience are currently informing the literature to explain the effects of art media in art therapy practice. Review of published peer-reviewed research between years 2000 and 2020 on neuroscience and art therapy. Findings were summarised into categories discussing psychological/neurobiological issues, art media, neuroimaging technology, and models posited. Forty-six studies were found; majority discussed the structure and function of the brain to explain art therapy processes. The Expressive Therapies Continuum (ETC) model theorised that media properties stimulate different levels of visual and cognitive processing. The novel Mobile Brain/Body Imaging (MoBI) neuroimaging technology may be used as a means of quantifying data. Significant progress has been made in attempting to explain brain responses during the art therapy process. However empirical data is needed to prove theoretical models. The use of neuroimaging has started this process to lead research into evidence-based practice. Evidencing the ground-breaking ETC model, using neuroimaging and MoBI technology is needed through close collaboration between transdisciplinary departments. Art therapists should be encouraged to use the ETC to inform art therapy assessment, planning and treatment. Neuroscience is the study of the brain and its processes, and recently technology has been available to researchers to examine brain processes in detail. This systematic narrative review explores recent literature that uses the principles of neuroscience to investigate the effects of art therapy, with a specific interest in art media. A systematic narrative review is when the findings of the study rely on the use of words to summarise the data. Art media is an important part of art therapy, as it is through artistic expressions that the client communicates their inner troubles. Different art media has been shown to elicit different feelings and behavioural responses in clients. However, research showing brain responses to different art media is limited. This study highlights ways in which further research in this field can take place. Results show that significant advancements have already been made that identify important structures and functions of the brain accessed during art therapy. Important models which incorporate neuroscience principles and theorise the art therapy process are highlighted. A significant model is the Expressive Therapies Continuum. This model explains how the brain processes information when different art media is used. However empirical data is needed to substantiate the theory behind this model. The use of neuroimaging technology is one way to achieve this. Therefore, this paper encourages transdisciplinary research to further investigate the effects different art media has on the brain during the art therapy process. [ABSTRACT FROM AUTHOR]

Background and Objectives: Cerebral small vessel disease (cSVD) is the most common pathology underlying vascular cognitive impairment. Although other clinical features of cSVD are increasingly recognized, it is likely that certain symptoms are being overlooked. A comprehensive description of cSVD associations with clinical phenotypes at scale is lacking. The objective of this study was to conduct a large-scale, hypothesis-free study of associations between cSVD and clinical phenotypes in UK Biobank (UKB)., Methods: We included participants from the UKB imaging study who had available information on total volume of white matter hyperintensities (WMHs), the most common cSVD neuroimaging feature. We included various UKB variables describing clinical phenotypes, defined as observable signs and symptoms of individuals with concurrent neuroimaging evidence of cSVD. We conducted a phenome scan using the open-source PHESANT software package. Total volume of WMHs was introduced as the independent variable and clinical phenotypes as the dependent variables in the regression model. The association of each phenotype with total volume of WMHs was tested using one of several regression analyses (all age at recruitment and sex-adjusted). All associations were corrected for multiple comparisons using the false discovery rate (FDR) correction method., Results: We included 45,013 participants in the analysis (mean age = 54.97 years, SD = 7.55). We confirm previously reported associations with depression (odds ratio [OR] = 1.07 [95% CI 1.05-1.10]), apathy (OR = 1.11 [95% CI 1.08-1.14]), falls (OR = 1.11 [95% CI 1.09-1.13]), respiratory problems (OR = 1.14 [95% CI 1.04-1.25]), and sleep disturbance (OR = 1.07 [95% CI 1.04-1.09], all FDR-adjusted p < 0.001). We further identified associations with all-cause dental issues (OR = 0.94 [95% CI 0.96-0.92]), hearing problems (OR = 1.06 [95% CI 1.03-1.08]), and eye problems (OR = 0.93 [95% CI 0.91-0.95], all FDR-adjusted p < 0.001)., Discussion: Our findings suggest that presence of cSVD associates with concurrent clinical phenotypes across several body systems. We have corroborated established associations of cSVD and present novel ones. While our results do not provide causality or direction of association because of the cross-sectional nature of our study, they support the need for a more holistic view of cSVD in research, practice, and policy.

Structural brain aging has demonstrated strong inter-individual heterogeneity and mirroring patterns with brain development. However, due to the lack of large-scale longitudinal neuroimaging studies, most of the existing research focused on the cross-sectional changes of brain aging. In this investigation, we present a data-driven approach that incorporate both cross-sectional changes and longitudinal trajectories of structural brain aging and identified two brain aging patterns among 37,013 healthy participants from UK Biobank. Participants with accelerated brain aging also demonstrated accelerated biological aging, cognitive decline and increased genetic susceptibilities to major neuropsychiatric disorders. Further, by integrating longitudinal neuroimaging studies from a multi-center adolescent cohort, we validated the 'last in, first out' mirroring hypothesis and identified brain regions with manifested mirroring patterns between brain aging and brain development. Genomic analyses revealed risk loci and genes contributing to accelerated brain aging and delayed brain development, providing molecular basis for elucidating the biological mechanisms underlying brain aging and related disorders., Competing Interests: HD, RS, JK, AB, SD, HF, AG, HG, PG, AH, RB, JM, MM, EA, FN, DP, SH, NN, JF, MS, NV, HW, RW, GS, XL, JF No competing interests declared, TB Dr Banaschewski served in an advisory or consultancy role for eye level, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche, and Takeda. He received conference support or speaker's fee by Janssen, Medice and Takeda. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the presentwork is unrelated to these relationships, CB Reviewing editor, eLife, LP Dr Poustka served in an advisory or consultancy role for Roche and Viforpharm and received speaker's fee by Shire. She received royalties from Hogrefe, Kohlhammer and Schattauer. The present work is unrelated to the above grants and relationships, (© 2024, Duan et al.)

There is a scarcity of prospective longitudinal research targeted at early postnatal life which maps developmental pathways of early-stage processing and brain specialisation in the context of early adversity. Follow up from infancy into the one-five year age range is key, as it constitutes a critical gap between infant and early childhood studies. Availability of portable neuroimaging (functional near infrared spectroscopy (fNIRS) and electroencephalography (EEG)) has enabled access to rural settings increasing the diversity of our sampling and broadening developmental research to include previously underrepresented ethnic-racial and geographical groups in low- and middle- income countries (LMICs). The primary objective of the Brain Imaging for Global Health (BRIGHT) project was to establish brain function - using longitudinal data from mother - for-age reference curves infant dyads living in the UK and rural Gambia and investigate the association between context-associated moderators and developmental trajectories across the first two years of life in The Gambia. In total, 265 participating families were seen during pregnancy, at 7-14 days, 1-, 5-, 8-, 12-, 18- and 24-months post-partum. An additional visit is now underway at 3-5 years to assess pre-school outcomes. The majority of our Gambian cohort live in poverty, but while resource-poor in many factors they commonly experience a rich and beneficial family and caregiving context with multigenerational care and a close-knit supportive community. Understanding the impact of different factors at play in such an environment ( i.e. , detrimental undernutrition versus beneficial multigenerational family support) will (i) improve the representativeness of models of general cognitive developmental pathways from birth, (ii) identify causal pathways of altered trajectories associated with early adversity at both individual and group level, and (iii) identify the context-associated moderators ( i.e. social context) that protect development despite the presence of poverty-associated challenges. This will in turn contribute to the development of targeted interventions., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Lloyd-Fox S et al.)

Purpose: Post-operative MRI is used to assess extent of resection, monitor treatment response and detect progression in high-grade glioma. However, compliance with accepted guidelines for follow-up MRI, and impact on management/outcomes is unclear., Methods: Multi-center, retrospective observational cohort study of patients with confirmed WHO grade 4 glioma (August 2018-February 2019) receiving oncological treatment., Primary Objective: investigate follow-up MRI surveillance practice and compliance with recommendations from NICE (Post-operative scan < 72h, MRI every 3-6 months) and EANO (Post-operative scan < 48h, MRI every 3 months)., Results: There were 754 patients from 26 neuro-oncology centers with a median age of 63 years (IQR 54-70), yielding 10,100 (median, 12.5/person, IQR 5.2-19.4) person-months of follow-up. Of patients receiving debulking surgery, most patients had post-operative MRI within 72 h of surgery (78.0%, N = 407/522), and within 48 h of surgery (64.2%, N = 335/522). The median number of subsequent follow-up MRI scans was 1 (IQR 0-4). Compliance with NICE and EANO recommendations for follow-up MRI was 52.8% (N = 398/754) and 24.9% (N = 188/754), respectively. On multivariable Cox regression analysis, increased time spent in recommended follow-up according to NICE guidelines was associated with longer OS (HR 0.56, 95% CI 0.46-0.66, P < 0.001), but not PFS (HR 0.93, 95% CI 0.79-1.10, P = 0.349). Increased time spent in recommended follow-up according to EANO guidelines was associated with longer OS (HR 0.54, 95% CI 0.45-0.63, P < 0.001) but not PFS (HR 0.99, 95% CI 0.84-1.16, P = 0.874)., Conclusion: Regular surveillance follow-up for glioblastoma is associated with longer OS. Prospective trials are needed to determine whether regular or symptom-directed MRI influences outcomes., (© 2024. The Author(s).)

Objectives: We aimed to investigate the association of regular opioid use, compared with non-opioid analgesics, with incident dementia and neuroimaging outcomes among chronic pain patients., Design: The primary design is a prospective cohort study. To triangulate evidence, we also conducted a nested case-control study analyzing opioid prescriptions and a cross-sectional study analyzing neuroimaging outcomes., Setting and Participants: Dementia-free UK Biobank participants with chronic pain and regular analgesic use., Measurements: Chronic pain status and regular analgesic use were captured using self-reported questionnaires and verbal interviews. Opioid prescription data were obtained from primary care records. Dementia cases were ascertained using primary care, hospital, and death registry records. Propensity score-matched Cox proportional hazards analysis, conditional logistic regression, and linear regression were applied to the data in the prospective cohort, nested case-control, and cross-sectional studies, respectively., Results: Prospective analyses revealed that regular opioid use, compared with non-opioid analgesics, was associated with an increased dementia risk over the 15-year follow-up (Hazard ratio [HR], 1.18 [95% confidence interval (CI): 1.08-1.30]; Absolute rate difference [ARD], 0.44 [95% CI: 0.19-0.71] per 1000 person-years; Wald χ 2 = 3.65; df = 1; p <0.001). The nested case-control study suggested that a higher number of opioid prescriptions was associated with an increased risk of dementia (1 to 5 prescriptions: OR = 1.21, 95% CI: 1.07-1.37, Wald χ 2 = 3.02, df = 1, p = 0.003; 6 to 20: OR = 1.27, 95% CI: 1.08-1.50, Wald χ 2 = 2.93, df = 1, p = 0.003; more than 20: OR = 1.43, 95% CI: 1.23-1.67, Wald χ 2 = 4.57, df = 1, p < 0.001). Finally, neuroimaging analyses revealed that regular opioid use was associated with lower total grey matter and hippocampal volumes, and higher white matter hyperintensities volumes., Conclusion: Regular opioid use in chronic pain patients was associated with an increased risk of dementia and poorer brain health when compared to non-opioid analgesic use. These findings imply a need for re-evaluation of opioid prescription practices for chronic pain patients and, if further evidence supports causality, provide insights into strategies to mitigate the burden of dementia., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sex is a biological variable that contributes to individual variability in brain structure and behavior. Neuroimaging studies of population‐based samples have identified normative differences in brain structure between males and females, many of which are exacerbated in psychiatric and neurological conditions. Still, sex differences in MRI outcomes are understudied, particularly in clinical samples with known sex differences in disease risk, prevalence, and expression of clinical symptoms. Here we review the existing literature on sex differences in adult brain structure in normative samples and in 14 distinct psychiatric and neurological disorders. We discuss commonalities and sources of variance in study designs, analysis procedures, disease subtype effects, and the impact of these factors on MRI interpretation. Lastly, we identify key problems in the neuroimaging literature on sex differences and offer potential recommendations to address current barriers and optimize rigor and reproducibility. In particular, we emphasize the importance of large‐scale neuroimaging initiatives such as the Enhancing NeuroImaging Genetics through Meta‐Analyses consortium, the UK Biobank, Human Connectome Project, and others to provide unprecedented power to evaluate sex‐specific phenotypes in major brain diseases. [ABSTRACT FROM AUTHOR]

Open data initiatives such as the UK Biobank and Human Connectome Project provide researchers with access to neuroimaging, genetic, and other data for large samples of left-and right-handed participants, allowing for more robust investigations of handedness than ever before. Handedness inventories are universal tools for assessing participant handedness in these large-scale neuroimaging contexts. These self-report measures are typically used to screen and recruit subjects, but they are also widely used as variables in statistical analyses of fMRI and other data. Recent investigations into the validity of handedness inventories, however, suggest that self-report data from these inventories might not reflect hand preference/performance as faithfully as previously thought. Using data from the Human Connectome Project, we assessed correspondence between three handedness measures – the Edinburgh Handedness Inventory (EHI), the Rolyan 9-hole pegboard, and grip strength – in 1179 healthy subjects. We show poor association between the different handedness measures, with roughly 10% of the sample having at least one behavioural measure which indicates hand-performance bias opposite to the EHI score, and over 65% of left-handers having one or more mismatched handedness scores. We discuss implications for future work, urging researchers to critically consider direction, degree, and consistency of handedness in their data. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and depression are debilitating brain disorders that are often comorbid. Shared brain mechanisms have been implicated, yet findings are inconsistent, reflecting the complexity of the underlying pathophysiology. As both disorders are (partly) heritable, characterising their genetic overlap may provide aetiological clues. While previous studies have indicated negligible genetic correlations, this study aims to expose the genetic overlap that may remain hidden due to mixed directions of effects. Methods: We applied Gaussian mixture modelling, through MiXeR, and conjunctional false discovery rate (cFDR) analysis, through pleioFDR, to genome-wide association study (GWAS) summary statistics of AD (n = 79,145) and depression (n = 450,619). The effects of identified overlapping loci on AD and depression were tested in 403,029 participants of the UK Biobank (UKB) (mean age 57.21, 52.0% female), and mapped onto brain morphology in 30,699 individuals with brain MRI data. Results: MiXer estimated 98 causal genetic variants overlapping between the 2 disorders, with 0.44 concordant directions of effects. Through pleioFDR, we identified a SNP in the TMEM106B gene, which was significantly associated with AD (B = −0.002, p = 9.1 × 10–4) and depression (B = 0.007, p = 3.2 × 10–9) in the UKB. This SNP was also associated with several regions of the corpus callosum volume anterior (B > 0.024, p < 8.6 × 10–4), third ventricle volume ventricle (B = −0.025, p = 5.0 × 10–6), and inferior temporal gyrus surface area (B = 0.017, p = 5.3 × 10–4). Discussion: Our results indicate there is substantial genetic overlap, with mixed directions of effects, between AD and depression. These findings illustrate the value of biostatistical tools that capture such overlap, providing insight into the genetic architectures of these disorders. [ABSTRACT FROM AUTHOR]

Objectives: MRI remains the preferred imaging investigation for glioblastoma. Appropriate and timely neuroimaging in the follow-up period is considered to be important in making management decisions. There is a paucity of evidence-based information in current UK, European and international guidelines regarding the optimal timing and type of neuroimaging following initial neurosurgical treatment. This study assessed the current imaging practices amongst UK neuro-oncology centres, thus providing baseline data and informing future practice. Methods: The lead neuro-oncologist, neuroradiologist and neurosurgeon from every UK neuro-oncology centre were invited to complete an online survey. Participants were asked about current and ideal imaging practices following initial treatment. Results: Ninety-two participants from all 31 neuro-oncology centres completed the survey (100% response rate). Most centres routinely performed an early post-operative MRI (87%, 27/31), whereas only a third performed a pre-radiotherapy MRI (32%, 10/31). The number and timing of scans routinely performed during adjuvant TMZ treatment varied widely between centres. At the end of the adjuvant period, most centres performed an MRI (71%, 22/31), followed by monitoring scans at 3 monthly intervals (81%, 25/31). Additional short-interval imaging was carried out in cases of possible pseudoprogression in most centres (71%, 22/31). Routine use of advanced imaging was infrequent; however, the addition of advanced sequences was the most popular suggestion for ideal imaging practice, followed by changes in the timing of EPMRI. Conclusion: Variations in neuroimaging practices exist after initial glioblastoma treatment within the UK. Multicentre, longitudinal, prospective trials are needed to define the optimal imaging schedule for assessment. Key Points: • Variations in imaging practices exist in the frequency, timing and type of interval neuroimaging after initial treatment of glioblastoma within the UK. • Large, multicentre, longitudinal, prospective trials are needed to define the optimal imaging schedule for assessment. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the associations of recreational screen time with risks of brain-related disorders (dementia, stroke, and Parkinson's disease) and neuroimaging features., Design: Prospective cohort study., Setting and Participants: A total of 407,792 participants from the UK Biobank who were free of dementia, stroke, or Parkinson's disease at enrollment (2006-2010)., Methods: TV viewing and time spent using the computer were self-reported at baseline. Among a subsample of 40,692 participants, neuroimaging features were measured by magnetic resonance imaging in 2014. Data were analyzed using Cox proportional hazard models, restricted cubic spline models, and general linear regression models., Results: During a median follow-up of 12.6 years, 5227 incident dementia, 6822 stroke, and 2308 Parkinson's disease cases were identified. Compared with TV viewing >0-1 h/day, watching TV ≥5 h/day was associated with higher risks of dementia [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.28-1.62], stroke (HR, 1.12; 95% CI, 1.01-1.25), and Parkinson's disease (HR, 1.28; 95% CI, 1.06-1.54). Moreover, we observed inverse associations between TV viewing time and both gray matter volume and hippocampus volume (P trend <.001). However, we did not observe the significant associations between discretional computer use and brain-related disorders or neuroimaging features., Conclusions and Implications: Our findings suggest that high TV viewing time is associated with increased risk of various brain-related disorders, highlighting recreational TV viewing could have an important impact on brain-related health., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Adolescents exhibit remarkable heterogeneity in the structural architecture of brain development. However, due to limited large-scale longitudinal neuroimaging studies, existing research has largely focused on population averages, and the neurobiological basis underlying individual heterogeneity remains poorly understood. Here we identify, using the IMAGEN adolescent cohort followed up over 9 years (14-23 y), three groups of adolescents characterized by distinct developmental patterns of whole-brain gray matter volume (GMV). Group 1 show continuously decreasing GMV associated with higher neurocognitive performances than the other two groups during adolescence. Group 2 exhibit a slower rate of GMV decrease and lower neurocognitive performances compared with Group 1, which was associated with epigenetic differences and greater environmental burden. Group 3 show increasing GMV and lower baseline neurocognitive performances due to a genetic variation. Using the UK Biobank, we show these differences may be attenuated in mid-to-late adulthood. Our study reveals clusters of adolescent neurodevelopment based on GMV and the potential long-term impact., (© 2024. The Author(s).)

Genome-wide association studies of brain imaging phenotypes are mainly performed in European populations, but other populations are severely under-represented. Here, we conducted Chinese-alone and cross-ancestry genome-wide association studies of 3,414 brain imaging phenotypes in 7,058 Chinese Han and 33,224 white British participants. We identified 38 new associations in Chinese-alone analyses and 486 additional new associations in cross-ancestry meta-analyses at P < 1.46 × 10 -11 for discovery and P < 0.05 for replication. We pooled significant autosomal associations identified by single- or cross-ancestry analyses into 6,443 independent associations, which showed uneven distribution in the genome and the phenotype subgroups. We further divided them into 44 associations with different effect sizes and 3,557 associations with similar effect sizes between ancestries. Loci of these associations were shared with 15 brain-related non-imaging traits including cognition and neuropsychiatric disorders. Our results provide a valuable catalog of genetic associations for brain imaging phenotypes in more diverse populations., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5–15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI. [ABSTRACT FROM AUTHOR]

Sex hormones such as estrogen fluctuate across the female lifespan, with high levels during reproductive years and natural decline during the transition to menopause. Women's exposure to estrogen may influence their heightened risk of Alzheimer's disease (AD) relative to men, but little is known about how it affects normal brain aging. Recent findings from the UK Biobank demonstrate less apparent brain aging in women with a history of multiple childbirths, highlighting a potential link between sex‐hormone exposure and brain aging. We investigated endogenous and exogenous sex‐hormone exposure, genetic risk for AD, and neuroimaging‐derived biomarkers for brain aging in 16,854 middle to older‐aged women. The results showed that as opposed to parity, higher cumulative sex‐hormone exposure was associated with more evident brain aging, indicating that i) high levels of cumulative exposure to sex‐hormones may have adverse effects on the brain, and ii) beneficial effects of pregnancies on the female brain are not solely attributable to modulations in sex‐hormone exposure. In addition, for women using hormonal replacement therapy (HRT), starting treatment earlier was associated with less evident brain aging, but only in women with a genetic risk for AD. Genetic factors may thus contribute to how timing of HRT initiation influences women's brain aging trajectories. [ABSTRACT FROM AUTHOR]

A few studies report that parental longevity is associated with preserved cognition and physical function and lower risk of Alzheimer's disease. However, data on structural neuroimaging correlates of parental longevity and its spatial distribution are limited. This study aims to examine relationships of parental longevity with regional brain structure and to explore sex differences. We identified 12,970 UK Biobank participants (mean age = 64.4, 51.5%women) with data on parental longevity, regional gray matter volumes, and white matter microstructure. Participants were categorized based on whether at least one parent lived to age 85 or older or neither parent survived to age 85. Associations of parental longevity, maternal, and paternal longevity with each neuroimaging marker of interest were examined using linear regression, adjusted for demographics, APOE e4 status, lifestyle, and cardiometabolic conditions. Compared to participants whose both parents died before 85 (43%), those with at least one parent surviving to 85 (57%) had greater volumes in hippocampus, parahippocampal gyrus, middle temporal lobe, and primary sensorimotor cortex and had lower mean diffusivity in posterior thalamic radiation and uncinate fasciculus. Associations were prominent with maternal longevity. Adjustment for cardiometabolic conditions did not affect observed associations except mean diffusivity in posterior thalamic radiation. There were no structural differences in other areas. Parental longevity is associated with preserved brain structure localized in primary sensorimotor cortex and temporal areas including hippocampus. These relationships are prominent with maternal longevity. Longitudinal studies are needed to determine whether changes in these brain structures account for the association between parental longevity and dementia. [ABSTRACT FROM AUTHOR]

The brain-age paradigm is proving increasingly useful for exploring aging-related disease and can predict important future health outcomes. Most brain-age research uses structural neuroimaging to index brain volume. However, aging affects multiple aspects of brain structure and function, which can be examined using multimodality neuroimaging. Using UK Biobank, brain-age was modeled in n = 2205 healthy people with T1-weighted MRI, T2-FLAIR, T2∗, diffusion-MRI, task fMRI, and resting-state fMRI. In a held-out healthy validation set (n = 520), chronological age was accurately predicted (r = 0.78, mean absolute error = 3.55 years) using LASSO regression, higher than using any modality separately. Thirty-four neuroimaging phenotypes were deemed informative by the regression (after bootstrapping); predominantly gray-matter volume and white-matter microstructure measures. When applied to new individuals from UK Biobank (n = 14,701), significant associations with multimodality brain-predicted age difference (brain-PAD) were found for stroke history, diabetes diagnosis, smoking, alcohol intake and some, but not all, cognitive measures (corrected p < 0.05). Multimodality neuroimaging can improve brain-age prediction, and derived brain-PAD values are sensitive to biomedical and lifestyle factors that negatively impact brain and cognitive health. • Brain-age was predicted from 6 different neuroimaging modalities. • Combined multi-modality brain-age was more accurate than any single modality. • Thirty-four neuroimaging measures were informative for brain-age prediction. • Informative measures generally reflect brain volume and white-matter microstructure. • Brain-age was associated with stroke, diabetes, smoking, alcohol and cognition. [ABSTRACT FROM AUTHOR]

Objective: To understand the changes in functional connectivity between brain areas of potential importance in migraine during different phases of the attack. Background: Migraine is a symptomatically heterogeneous disorder. Understanding the possible changes in brain function and, therefore, neurobiology during different phases of the migraine attack is important in developing disease biomarkers and advancing therapeutics. Design: Randomized, double‐blind, placebo‐controlled, multi‐visit experimental study. Methods: Subjects aged 18‐50 years with migraine with and without aura (≤22 headache days per month) were recruited from across the UK using advertising, from both population and hospital clinic samples (n = 53). Consented subjects were randomized to a 0.5 µg/kg/min nitroglycerin infusion or to placebo over 20 minutes across different study visits, during the period February 2015‐July 2017.* All subjects were exposed to a nitroglycerin infusion at least on 1 occasion at screening.** For those subjects who consented to participate in imaging visits (n = 25), structural T1, T2 and FLAIR sequences and resting state blood oxygen level dependant contrast (rsBOLD) time series, using a multiecho EPI sequence, were conducted over 30‐40 minutes at baseline and rsBOLD during premonitory symptoms and migraine headache on a 3T General Electric MR750 MRI scanner. For the placebo visit, the imaging was conducted at the same times following infusion in the absence of symptoms. Results: Montreal Neurological Institute (MNI) coordinates were used to characterize identified brain areas of connectivity change. Using repeated measures ANOVA models with time (visit number) and trigger substance (nitroglycerin/placebo) as factors, significant positive functional coupling was found between the thalami bilaterally and the right precuneus and cuneus regions during the nitroglycerin‐triggered premonitory phase (T = 3.23, peak connectivity change at [−6, −68, 40] for left thalamus, P = 0.012 and [−4, −68, 40] for right thalamus, P = 0.019). The nitroglycerin‐triggered premonitory phase was associated with a change in the direction of connectivity from positive to negative between the pons and the limbic lobe (T = 3.47, peak connectivity change at [2, 8, 50], P < 0.001). The headache phase of the nitroglycerin‐triggered migraine attack was associated with ongoing negative functional coupling between the pons and the cingulate and frontal cortices, and positive functional coupling between the pons and the cerebellar tonsils and medulla (T = 3.47, peak connectivity change at [−8, −52, −58], P = 0.007). Conclusions: Understanding the functional reorganization between subcortical and cortical brain areas in different phases of the migraine attack provides novel insights into the abnormal sensory processing and integration during migraine, as well as functional correlation with clinical symptoms displayed during each phase. [*Correction added on July 22, 2020 after first online publication: This sentence was revised from, "Consented subjects had a 0.5 μg/kg/min nitroglycerin infusion...".] [**Correction added on July 22, 2020 after first online publication: This sentence was revised from, "... at least on 1 occasion at screening."] [ABSTRACT FROM AUTHOR]

Alcohol consumption and genetic risk for Alzheimer disease (AD) are among many factors known to be associated with brain structure in cognitively healthy adults. It is unclear, however, whether the effect of alcohol consumption on brain structure varies depending on a person's level of genetic risk for AD. We hypothesized that there is an interaction effect of alcohol consumption and a 33-SNP AD polygenic risk score (PRS) on the cortical thickness of brain regions known to be affected early in the course of AD. Studying 6,213 cognitively healthy subjects from the UK Biobank, we found a significant interaction effect of the 33-SNP AD PRS and alcohol consumption on this AD Cortical Thickness Signature. Stratified, among those who consume 12-24 g/day of alcohol, the 33-SNP AD PRS had a significant, positive association with AD Cortical Thickness Signature, with high-risk subjects having the greatest AD Cortical Thickness Signature. There were no significant associations of the 33-SNP AD PRS with AD Cortical Thickness Signature among the nondrinker or <1, 1-6, 6-12, 24-48, or >48 g/day groups. It is unclear whether this interaction is due to a detrimental or beneficial effect of moderate alcohol consumption in those with the highest genetic risk for AD. [ABSTRACT FROM AUTHOR]

• Individuals remain poorly predictable from population-level analyses of the brain. • The fidelity limits data scale, compute, and model flexibility impose are unknown. • We quantify these limits in multimodal, multitarget analyses across 23810 people. • We show a radical change in modelling regimes is needed for individual prediction. Our knowledge of the organisation of the human brain at the population-level is yet to translate into power to predict functional differences at the individual-level, limiting clinical applications and casting doubt on the generalisability of inferred mechanisms. It remains unknown whether the difficulty arises from the absence of individuating biological patterns within the brain, or from limited power to access them with the models and compute at our disposal. Here we comprehensively investigate the resolvability of such patterns with data and compute at unprecedented scale. Across 23 810 unique participants from UK Biobank, we systematically evaluate the predictability of 25 individual biological characteristics, from all available combinations of structural and functional neuroimaging data. Over 4526 GPU*hours of computation, we train, optimize, and evaluate out-of-sample 700 individual predictive models, including fully-connected feed-forward neural networks of demographic, psychological, serological, chronic disease, and functional connectivity characteristics, and both uni- and multi-modal 3D convolutional neural network models of macro- and micro-structural brain imaging. We find a marked discrepancy between the high predictability of sex (balanced accuracy 99.7%), age (mean absolute error 2.048 years, R2 0.859), and weight (mean absolute error 2.609Kg, R2 0.625), for which we set new state-of-the-art performance, and the surprisingly low predictability of other characteristics. Neither structural nor functional imaging predicted an individual's psychology better than the coincidence of common chronic disease (p < 0.05). Serology predicted chronic disease (p < 0.05) and was best predicted by it (p < 0.001), followed by structural neuroimaging (p < 0.05). Our findings suggest either more informative imaging or more powerful models will be needed to decipher individual level characteristics from the human brain. We make our models and code openly available. [ABSTRACT FROM AUTHOR]

Environmental exposures during the perinatal period are known to have a long-term effect on adult physical and mental health. One such influential environmental exposure is the time of year of birth which affects the amount of daylight, nutrients, and viral load that an individual is exposed to within this key developmental period. Here, we investigate associations between season of birth (seasonality), four mental health traits (n = 137,588) and multi-modal neuroimaging measures (n = 33,212) within the UK Biobank. Summer births were associated with probable recurrent Major Depressive Disorder (β = 0.026, pcorr = 0.028) and greater mean cortical thickness in temporal and occipital lobes (β = 0.013 to 0.014, pcorr<0.05). Winter births were associated with greater white matter integrity globally, in the association fibers, thalamic radiations, and six individual tracts (β = -0.013 to -0.022, pcorr<0.05). Results of sensitivity analyses adjusting for birth weight were similar, with an additional association between winter birth and white matter microstructure in the forceps minor and between summer births, greater cingulate thickness and amygdala volume. Further analyses revealed associations between probable depressive phenotypes and a range of neuroimaging measures but a paucity of interactions with seasonality. Our results suggest that seasonality of birth may affect later-life brain structure and play a role in lifetime recurrent Major Depressive Disorder. Due to the small effect sizes observed, and the lack of associations with other mental health traits, further research is required to validate birth season effects in the context of different latitudes, and by co-examining genetic and epigenetic measures to reveal informative biological pathways., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2024 Viejo-Romero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies., Methods: We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (N main  = 2632; N APOE-interaction  = 1810)., Results: Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (β = -3.89 mL [-5.81, -1.97], P adjusted  < 0.05); these were largely attenuated in fully adjusted models (β = -1.59 mL [-3.55, 0.36], P = 0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed., Discussion: We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Studies of white matter microstructure in depression typically show alterations in individuals with depression, but they are frequently limited by small sample sizes and the absence of longitudinal measures of depressive symptoms. Depressive symptoms are dynamic, however, and understanding the neurobiology of different trajectories could have important clinical implications. We examined associations between current and longitudinal measures of depressive symptoms and white matter microstructure (fractional anisotropy and mean diffusivity [MD]) in the UK Biobank Imaging Study. Depressive symptoms were assessed on two to four occasions over 5.9 to 10.7 years (n = 18,959 individuals on at least two occasions, n = 4444 on four occasions), from which we derived four measures of depressive symptomatology: cross-sectional measure at the time of scan and three longitudinal measures, namely trajectory and mean and intrasubject variance over time. Decreased white matter microstructure in the anterior thalamic radiation demonstrated significant associations across all four measures of depressive symptoms (MD: βs =.020–.029, p corr <.030). The greatest effect sizes were seen between white matter microstructure and longitudinal progression (MD: βs =.030–.040, p corr <.049). Cross-sectional symptom severity was particularly associated with decreased white matter integrity in association fibers and thalamic radiations (MD: βs =.015–.039, p corr <.041). Greater mean and within-subject variance were mainly associated with decreased white matter microstructure within projection fibers (MD: βs =.019–.029, p corr <.044). These findings indicate shared and differential neurobiological associations with severity, course, and intrasubject variability of depressive symptoms. This enriches our understanding of the neurobiology underlying dynamic features of the disorder. [ABSTRACT FROM AUTHOR]

Tobacco use and major depression are both leading contributors to the global burden of disease and are also highly comorbid. Previous research indicates bi-directional causality between tobacco use and depression, but the mechanisms that underlie this causality are unclear, especially for the causality from tobacco use to depression. Here we narratively review the available evidence for a potential causal role of gray matter volume in the association. We summarize the findings of large existing neuroimaging meta-analyses, studies in UK Biobank, and the Enhancing NeuroImaging Genetics through MetaAnalysis (ENIGMA) consortium and assess the overlap in implicated brain areas. In addition, we review two types of methods that allow us more insight into the causal nature of associations between brain volume and depression/smoking: longitudinal studies and Mendelian Randomization studies. While the available evidence suggests overlap in the alterations in brain volumes implicated in tobacco use and depression, there is a lack of research examining the underlying pathophysiology. We conclude with recommendations on (genetically-informed) causal inference methods useful for studying these associations. • The mechanisms underlying the causality between smoking and depression are unclear. • We review gray volume meta- and mega-analyses for smoking and depression. • There is overlap in the alterations in brain volumes implicated. • There is research gap on the potential role of brain volume in this association. • We end with recommendations on how to fill this research gap. [ABSTRACT FROM AUTHOR]

Background: Resting heart rate (RHR), has been related to increased risk of dementia, but the relationship between RHR and brain age is unclear., Objective: We aimed to investigate the association of RHR with brain age and brain age gap (BAG, the difference between predicted brain age and chronological age) assessed by multimodal Magnetic Resonance Imaging (MRI) in mid- and old-aged adults., Design: A longitudinal study from the UK Biobank neuroimaging project where participants underwent brain MRI scans 9+ years after baseline., Setting: A population-based study., Participants: A total of 33,381 individuals (mean age 54.74 ± 7.49 years; 53.44% female)., Measurements: Baseline RHR was assessed by blood pressure monitor and categorized as <60, 60-69 (reference), 70-79, or ≥80 beats per minute (bpm). Brain age was predicted using LASSO through 1,079 phenotypes in six MRI modalities (including T1-weighted MRI, T2-FLAIR, T2*, diffusion-MRI, task fMRI, and resting-state fMRI). Data were analyzed using linear regression models., Results: As a continuous variable, higher RHR was associated with older brain age (β for per 1-SD increase: 0.331, 95% [95% confidence interval, CI]: 0.265, 0.398) and larger BAG (β: 0.263, 95% CI: 0.202, 0.324). As a categorical variable, RHR 70-79 bpm and RHR ≥80 bpm were associated with older brain age (β [95% CI]: 0.361 [0.196, 0.526] / 0.737 [0.517, 0.957]) and larger BAG (0.256 [0.105, 0.407] / 0.638 [0.436, 0.839]), but RHR< 60 bpm with younger brain age (-0.324 [-0.500, -0.147]) and smaller BAG (-0.230 [-0.392, -0.067]), compared to the reference group. These associations between elevated RHR and brain age were similar in both middle-aged (<60) and older (≥60) adults, whereas the association of RHR< 60 bpm with younger brain age and larger BAG was only significant among middle-aged adults. In stratification analysis, the association between RHR ≥80 bpm and older brain age was present in people with and without CVDs, while the relation of RHR 70-79 bpm to brain age present only in people with CVD., Conclusion: Higher RHR (>80 bpm) is associated with older brain age, even among middle-aged adults, but RHR< 60 bpm is associated with younger brain age. Greater RHR could be an indicator for accelerated brain aging., Competing Interests: The authors declare that they have no competing interests.

A recent (2016) Office for National Statistics report stated that dementia is now “the leading cause of death” in England and Wales. Ever fixated with the syndrome (an unfailingly newsworthy topic), the British press was quick to respond to the bulletin, consistently headlining that dementia was the nation’s “biggest killer,” while (re)formulating other aspects of the report in distorting and emotive metaphorical terms. In this paper we examine how the media, through use of a recurring set of linguistic and visual semiotic tropes, portrayed dementia as an agentive entity, a “killer,” which remorselessly attacks its “victims.” Such a broadly loaded and sensationalist representation, we argue, not only construed dementia as a direful and pernicious disease, but also, crucially, obscured the personal and social contexts in which the syndrome is understood and experienced (not least by people with dementia themselves). This intensely lurid type of representation not only fails to address the ageist misinformation and common misunderstandings that all too commonly surround dementia, but is also likely to exacerbate the stress and depression frequently experienced by people with dementia and their families. [ABSTRACT FROM AUTHOR]

• Performed a GWAS of FA and MD in 25,415 UKB individuals free of stroke, dementia, and other major disorders of the central nervous system (CNS) and replicated in Adolescent Brain Cognitive Development (ABCD) study. • Identified 11 genetic loci (P < 8.3 × 10−9) and 86 genes associated with cerebellar white matter microstructure. • Functional enrichment analysis implicated the involvement of GABAergic neurons and cholinergic pathways. • Report the overall genetic correlation and specific loci shared between cerebellar white matter microstructural integrity and brain-related traits. The cerebellum is recognized as being involved in neurocognitive and motor functions with communication with extra-cerebellar regions relying on the white matter integrity of the cerebellar peduncles. However, the genetic determinants of cerebellar white matter integrity remain largely unknown. We conducted a genome-wide association analysis of cerebellar white matter microstructure using diffusion tensor imaging data from 25,415 individuals from UK Biobank. The integrity of cerebellar white matter microstructure was measured as fractional anisotropy (FA) and mean diffusivity (MD). Identification of independent genomic loci, functional annotation, and tissue and cell-type analysis were conducted with FUMA. The linkage disequilibrium score regression (LDSC) was used to calculate genetic correlations between cerebellar white matter microstructure and regional brain volumes and brain-related traits. Furthermore, the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was employed to identify the shared genetic basis between cerebellar white matter microstructure and common brain disorders. We identified 11 genetic loci (P < 8.3 × 10−9) and 86 genes associated with cerebellar white matter microstructure. Further functional enrichment analysis implicated the involvement of GABAergic neurons and cholinergic pathways. Significant polygenetic overlap between cerebellar white matter tracts and their anatomically connected or adjacent brain regions was detected. In addition, we report the overall genetic correlation and specific loci shared between cerebellar white matter microstructural integrity and brain-related traits, including movement, cognitive, psychiatric, and cerebrovascular categories. Collectively, this study represents a step forward in understanding the genetics of cerebellar white matter microstructure and its shared genetic etiology with common brain disorders. [ABSTRACT FROM AUTHOR]

Purpose: To describe an approach to the use of optical coherence tomography (OCT) imaging in large, population-based studies, including methods for OCT image acquisition, storage, and the remote, rapid, automated analysis of retinal thickness. Methods: In UK Biobank, OCT images were acquired between 2009 and 2010 using a commercially available “spectral domain” OCT device (3D OCT-1000, Topcon). Images were obtained using a raster scan protocol, 6 mm x 6 mm in area, and consisting of 128 B-scans. OCT image sets were stored on UK Biobank servers in a central repository, adjacent to high performance computers. Rapid, automated analysis of retinal thickness was performed using custom image segmentation software developed by the Topcon Advanced Biomedical Imaging Laboratory (TABIL). This software employs dual-scale gradient information to allow for automated segmentation of nine intraretinal boundaries in a rapid fashion. Results: 67,321 participants (134,642 eyes) in UK Biobank underwent OCT imaging of both eyes as part of the ocular module. 134,611 images were successfully processed with 31 images failing segmentation analysis due to corrupted OCT files or withdrawal of subject consent for UKBB study participation. Average time taken to call up an image from the database and complete segmentation analysis was approximately 120 seconds per data set per login, and analysis of the entire dataset was completed in approximately 28 days. Conclusions: We report an approach to the rapid, automated measurement of retinal thickness from nearly 140,000 OCT image sets from the UK Biobank. In the near future, these measurements will be publically available for utilization by researchers around the world, and thus for correlation with the wealth of other data collected in UK Biobank. The automated analysis approaches we describe may be of utility for future large population-based epidemiological studies, clinical trials, and screening programs that employ OCT imaging. [ABSTRACT FROM AUTHOR]

In this article, I discuss areas where scientists can have impact and that I feel are important for the future of innovative research and societal impacts. Initially, I summarise my research career. I then move on to problem solving, using techniques such as functional neuroimaging and psychopharmacology, and new developments, such as the application of the computerised neuropsychological tests CANTAB, which I co-invented. CANTAB was inspired by the need for early detection, pharmacological treatment and neuropsychological understanding of cognitive deficits in neurodegenerative and neuropsychiatric disorders. Finally, I address neuroethical and societal concerns through books, articles and the media and affected UK government policy through the Foresight Project. In future, young scientists hopefully will contribute more time to these important areas of policy development and public engagement. [ABSTRACT FROM AUTHOR]

• Integration of evolutionary signatures with neuroimaging and genetic data from the UK biobank. • Contributions of genomic annotations spanning 30 million years to human sulcal morphology. • Genetic variations within human gained enhancers explained more trait heritability than expected for the left and right calloso-marginal posterior fissures and the right central sulcus. The expansion of the cerebral cortex is one of the most distinctive changes in the evolution of the human brain. Cortical expansion and related increases in cortical folding may have contributed to emergence of our capacities for high-order cognitive abilities. Molecular analysis of humans, archaic hominins, and non-human primates has allowed identification of chromosomal regions showing evolutionary changes at different points of our phylogenetic history. In this study, we assessed the contributions of genomic annotations spanning 30 million years to human sulcal morphology measured via MRI in more than 18,000 participants from the UK Biobank. We found that variation within brain-expressed human gained enhancers, regulatory genetic elements that emerged since our last common ancestor with Old World monkeys, explained more trait heritability than expected for the left and right calloso-marginal posterior fissures and the right central sulcus. Intriguingly, these are sulci that have been previously linked to the evolution of locomotion in primates and later on bipedalism in our hominin ancestors. [ABSTRACT FROM AUTHOR]

Introduction: We hypothesized that liver fibrosis is associated with worse cognitive performance and corresponding brain imaging changes., Methods: We examined the association of liver fibrosis with cognition and brain imaging parameters in the UK Biobank study. Liver fibrosis was assessed using the Fibrosis-4 (FIB-4) score. The primary cognitive outcome was the digit symbol substitution test (DSST); secondary outcomes were additional executive function/processing speed and memory tests. Imaging outcomes were hippocampal, total brain, and white matter hyperintensity (WMH) volumes., Results: We included 105,313 participants with cognitive test data, and 41,982 with magnetic resonance imaging (MRI). In adjusted models, liver fibrosis was associated with worse performance on the DSST and tests of executive function but not memory. Liver fibrosis was associated with lower hippocampal and total brain volumes, without compelling association with WMH volume., Discussion: Liver fibrosis is associated with worse performance on select cognitive tests and lower hippocampal and total brain volumes., Highlights: It is increasingly recognized that chronic liver conditions impact brain health. We performed an analysis of data from the UK Biobank prospective cohort study. Liver fibrosis was associated with worse performance on executive function tests. Liver fibrosis was not associated with memory impairment. Liver fibrosis was associated with lower hippocampal and total brain volumes., (© 2022 the Alzheimer's Association.)

Telomeres form protective caps at the ends of chromosomes, and their attrition is a marker of biological aging. Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. The mechanism underlying this risk is unclear, and may involve brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized. Here we show that leucocyte telomere length (LTL) is associated with multi-modal MRI phenotypes in 31,661 UK Biobank participants. Longer LTL is associated with: i) larger global and subcortical grey matter volumes including the hippocampus, ii) lower T1-weighted grey-white tissue contrast in sensory cortices, iii) white-matter microstructure measures in corpus callosum and association fibres, iv) lower volume of white matter hyperintensities, and v) lower basal ganglia iron. Longer LTL was protective against certain related clinical manifestations, namely all-cause dementia (HR 0.93, 95% CI: 0.91-0.96), but not stroke or Parkinson's disease. LTL is associated with multiple MRI endophenotypes of neurodegenerative disease, suggesting a pathway by which longer LTL may confer protective against dementia., Competing Interests: TN “Paid statistical consultancy, Perspectum”. The other authors declare no competing financial interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Topiwala et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)