Disrupted limbic-prefrontal effective connectivity in response to fearful faces in lifetime depression.

BACKGROUND: Multiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically N<50). It remains unclear if any alterations are a characteristic of current depression or of past experience of depression, and whether there are MDD-related changes in effective connectivity between the two brain regions. METHODS: Activations and effective connectivity between the amygdala and dorsolateral prefrontal cortex (DLPFC) in response to fearful face stimuli were studied in a large population-based sample from Generation Scotland. Participants either had no history of MDD (N=664 in activation analyses, N=474 in connectivity analyses) or had a diagnosis of MDD during their lifetime (LMDD, N=290 in activation analyses, N=214 in connectivity analyses). The within-scanner task involved implicit facial emotion processing of neutral and fearful faces. RESULTS: Compared to controls, LMDD was associated with increased activations in left amygdala (PFWE=0.031,kE=4) and left DLPFC (PFWE=0.002,kE=33), increased mean bilateral amygdala activation (ß=0.0715,P=0.0314), and increased inhibition from left amygdala to left DLPFC, all in response to fearful faces contrasted to baseline. Results did not appear to be attributable to depressive illness severity or antidepressant medication status at scan time. LIMITATIONS: Most studied participants had past rather than current depression, average severity of ongoing depression symptoms was low, and a substantial proportion of participants were receiving medication. The study was not longitudinal and the participants were only assessed a single time. CONCLUSIONS: LMDD is associated with hyperactivity of the amygdala and DLPFC, and with stronger amygdala to DLPFC inhibitory connectivity, all in response to fearful faces, unrelated to depression severity at scan time. These results help reduce inconsistency in past literature and suggest disruption of 'bottom-up' limbic-prefrontal effective connectivity in depression.

Characterizing the Neurobiological Mechanisms of Action of Exercise and Cognitive-Behavioral Interventions for Rheumatoid Arthritis Fatigue: A Magnetic Resonance Imaging Brain Study.

OBJECTIVE: Chronic fatigue is a major clinical unmet need among patients with rheumatoid arthritis (RA). Current therapies are limited to nonpharmacological interventions, such as personalized exercise programs (PEPs) and cognitive-behavioral approaches (CBAs); however, most patients still continue to report severe fatigue. To inform more effective therapies, we conducted a magnetic resonance imaging (MRI) brain study of PEPs and CBAs, nested within a randomized controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. METHODS: A subgroup of patients with RA (n = 90), participating in an RCT of PEPs and CBAs for fatigue, undertook a multimodal MRI brain scan following randomization to either usual care (UC) alone or in addition to PEPs and CBAs and again after the intervention (six months). Brain regional volumetric, functional, and structural connectivity indices were curated and then computed employing a causal analysis framework. The primary outcome was fatigue improvement (Chalder fatigue scale). RESULTS: Several structural and functional connections were identified as mediators of fatigue improvement in both PEPs and CBAs compared to UC. PEPs had a more pronounced effect on functional connectivity than CBAs; however, structural connectivity between the left isthmus cingulate cortex (L-ICC) and left paracentral lobule (L-PCL) was shared, and the size of mediation effect ranked highly for both PEPs and CBAs (ßAverage = -0.46, SD 0.61; ßAverage = -0.32, SD 0.47, respectively). CONCLUSION: The structural connection between the L-ICC and L-PCL appears to be a dominant mechanism for how both PEPs and CBAs reduce fatigue among patients with RA. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting.

The cerebellum plays more than one role in the dysregulation of appetite: Review of structural evidence from typical and eating disorder populations.

OBJECTIVE: Dysregulated appetite control is characteristic of anorexia nervosa (AN), bulimia nervosa (BN), and obesity (OB). Studies using a broad range of methods suggest the cerebellum plays an important role in aspects of weight and appetite control, and is implicated in both AN and OB by reports of aberrant gray matter volume (GMV) compared to nonclinical populations. As functions of the cerebellum are anatomically segregated, specific localization of aberrant anatomy may indicate the mechanisms of its relationship with weight and appetite in different states. We sought to determine if there were consistencies in regions of cerebellar GMV changes in AN/BN and OB, as well as across normative (NOR) variation. METHOD: Systematic review and meta-analysis using GingerALE. RESULTS: Twenty-six publications were identified as either case-control studies (nOB  = 277; nAN/BN  = 510) or regressed weight from NOR data against brain volume (total n = 3830). AN/BN and OB analyses both showed consistently decreased GMV within Crus I and Lobule VI, but volume reduction was bilateral for AN/BN and unilateral for OB. Analysis of the NOR data set identified a cluster in right posterior lobe that overlapped with AN/BN cerebellar reduction. Sensitivity analyses indicated robust repeatability for NOR and AN/BN cohorts, but found OB-specific heterogeneity. DISCUSSION: Findings suggest that more than one area of the cerebellum is involved in control of eating behavior and may be differentially affected in normal variation and pathological conditions. Specifically, we hypothesize an association with sensorimotor and emotional learning via Lobule VI in AN/BN, and executive function via Crus I in OB.

Structural and Functional Brain Changes in Acute Takotsubo Syndrome.

BACKGROUND: Takotsubo syndrome mimics an acute myocardial infarction, typically in the aftermath of mental or physical stress. OBJECTIVES: The mechanism by which emotional processing in the context of stress leads to significant cardiac injury is poorly understood, so a full exploration of brain structure and function in takotsubo syndrome patients merits investigation. METHODS: Twenty-five acute (<5 days) takotsubo patients and 25 control subjects were recruited into this observational cross-sectional study. Surface-based morphometry was carried out on magnetic resonance imaging (MRI) brain scans to extract cortical morphology based on volume, thickness, and surface area with the use of Freesurfer. Cortical morphology general linear models were corrected for age, sex, photoperiod, and total brain volume. Resting-state functional MRI and diffusion tensor tractography images were preprocessed and analyzed with the use of the Functional Magnetic Resonance Imaging of the Brain Diffusion Toolbox and Functional Connectivity Toolbox. RESULTS: There was significantly smaller total white matter and subcortical gray matter volumes in takotsubo (P < 0.001), with smaller total brain surface area but increased total cortical thickness (both P < 0.001). Individual gray matter regions (hippocampus and others) were significantly smaller in takotsubo (P < 0.001); only thalamus and insula were larger (P < 0.001). There was significant hyperfunctional and hypofunctional connectivity in multiple areas, including thalamus-amygdala-insula and basal ganglia (P < 0.05). All structural tractography connections were increased in takotsubo (P < 0.05). CONCLUSIONS: The authors showed smaller gray and white matter volumes driven by smaller cortical surface area, but increased cortical thickness and structural tractography connections with bidirectional changes in functional connectivity linked to emotion, language, reasoning, perception, and autonomic control. These are interventional targets in takotsubo patients' rehabilitation.

Associations of negative affective biases and depressive symptoms in a community-based sample.

BACKGROUND: Major depressive disorder (MDD) was previously associated with negative affective biases. Evidence from larger population-based studies, however, is lacking, including whether biases normalise with remission. We investigated associations between affective bias measures and depressive symptom severity across a large community-based sample, followed by examining differences between remitted individuals and controls. METHODS: Participants from Generation Scotland (N = 1109) completed the: (i) Bristol Emotion Recognition Task (BERT), (ii) Face Affective Go/No-go (FAGN), and (iii) Cambridge Gambling Task (CGT). Individuals were classified as MDD-current (n = 43), MDD-remitted (n = 282), or controls (n = 784). Analyses included using affective bias summary measures (primary analyses), followed by detailed emotion/condition analyses of BERT and FAGN (secondary analyses). RESULTS: For summary measures, the only significant finding was an association between greater symptoms and lower risk adjustment for CGT across the sample (individuals with greater symptoms were less likely to bet more, despite increasingly favourable conditions). This was no longer significant when controlling for non-affective cognition. No differences were found for remitted-MDD v. controls. Detailed analysis of BERT and FAGN indicated subtle negative biases across multiple measures of affective cognition with increasing symptom severity, that were independent of non-effective cognition [e.g. greater tendency to rate faces as angry (BERT), and lower accuracy for happy/neutral conditions (FAGN)]. Results for remitted-MDD were inconsistent. CONCLUSIONS: This suggests the presence of subtle negative affective biases at the level of emotion/condition in association with depressive symptoms across the sample, over and above those accounted for by non-affective cognition, with no evidence for affective biases in remitted individuals.

Brain mapping inflammatory-arthritis-related fatigue in the pursuit of novel therapeutics.

Despite developments in pharmacological treatments, chronic fatigue is an unresolved issue for most people with inflammatory arthritis that severely disrupts their personal and working lives. Fatigue in these patients is not strongly linked with peripheral disease activity but is associated with CNS-derived symptoms such as chronic pain, sleep disturbance, and depression. Therefore, a neurobiological basis should be considered when pursuing novel fatigue-specific therapeutics. In this Review, we focus on clinical imaging biomarkers that map candidate brain regions and are crucial in fatigue pathophysiology. We then evaluate neuromodulation techniques that could affect these candidate brain regions and are potential treatment strategies for fatigue in patients with inflammatory arthritis. We delineate work that is still required for neuroimaging and neuromodulation to eventually become part of a clinical pathway to treat and manage fatigue.

Age-associated sex and asymmetry differentiation in hemispheric and lobar cortical ribbon complexity across adulthood: A UK Biobank imaging study.

Cortical morphology changes with ageing and age-related neurodegenerative diseases. Previous studies suggest that the age effect is more pronounced in the frontal lobe. However, our knowledge of structural complexity changes in male and female brains is still limited. We measured cortical ribbon complexity through fractal dimension (FD) analysis at the hemisphere and lobe level in 7010 individuals from the UK Biobank imaging cohort to study age-related sex differences (3332 males, age ranged 45-79 years). FD decreases significantly with age and sexual dimorphism exists. With correction for brain size, females showed higher complexity in the left hemisphere and left and right parietal lobes whereas males showed higher complexity in the right temporal and left and right occipital lobes. A nonlinear age effect was observed in the left and right frontal, and right temporal lobes. Differential patterns of age effects were observed in both sexes with relatively more age-affected regions in males. Significantly higher rightward asymmetries at hemisphere, frontal, parietal, and occipital lobe level and higher leftward asymmetry in temporal lobe were observed. There was no age-by-sex-by asymmetry interaction in any region. When controlling for brain size, the leftward hemispheric, and temporal lobe asymmetry decreased with age. Males had significantly lower asymmetry between hemispheres and higher asymmetry in the parietal and occipital lobes than females. This work provides distinct patterns of age-related sex and asymmetry differences that can aid in the future development of sex-specific models of the normal brain to ascribe cognitive functional significance of these patterns in ageing.

Cognition and brain iron deposition in whole grey matter regions and hippocampal subfields.

Regional brain iron accumulation is observed in many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, and is associated with cognitive decline. We explored associations between age, cognition and iron content in grey matter regions and hippocampal subfields in 380 participants of the Aberdeen children of the 1950s cohort and their first-generation relatives (aged 26-72 years). Participants underwent cognitive assessment at the time of MRI scanning. Quantitative susceptibility mapping of these MRI data was used to assess iron content in grey matter regions and in hippocampal subfields. Principle component analysis was performed on cognitive test scores to create a general cognition score. Spline analysis was used with the Akaike information criterion to determine if order 1, 2 or 3 natural splines were optimal for assessing non-linear relationships between regional iron and age. Multivariate linear models were used to assess associations between regional iron and cognition. Higher iron correlated with older age in the left putamen across all ages and in the right putamen of only participants over 58. Whereas a decrease in iron with older age was observed in the right thalamus and left pallidum across all ages. Right amygdala iron levels were associated with poorer general cognition scores and poorer immediate recall scores. Iron was not associated with any measures of cognitive performance in other regions of interest. Our results suggest that, whilst iron in some regions was associated with cognitive performance, there is an overall lack of association between regional iron content and cognitive ability in cognitively healthy individuals.

Local CpG density affects the trajectory and variance of age-associated DNA methylation changes.

BACKGROUND: DNA methylation is an epigenetic mark associated with the repression of gene promoters. Its pattern in the genome is disrupted with age and these changes can be used to statistically predict age with epigenetic clocks. Altered rates of aging inferred from these clocks are observed in human disease. However, the molecular mechanisms underpinning age-associated DNA methylation changes remain unknown. Local DNA sequence can program steady-state DNA methylation levels, but how it influences age-associated methylation changes is unknown. RESULTS: We analyze longitudinal human DNA methylation trajectories at 345,895 CpGs from 600 individuals aged between 67 and 80 to understand the factors responsible for age-associated epigenetic changes at individual CpGs. We show that changes in methylation with age occur at 182,760 loci largely independently of variation in cell type proportions. These changes are especially apparent at 8322 low CpG density loci. Using SNP data from the same individuals, we demonstrate that methylation trajectories are affected by local sequence polymorphisms at 1487 low CpG density loci. More generally, we find that low CpG density regions are particularly prone to change and do so variably between individuals in people aged over 65. This differs from the behavior of these regions in younger individuals where they predominantly lose methylation. CONCLUSIONS: Our results, which we reproduce in two independent groups of individuals, demonstrate that local DNA sequence influences age-associated DNA methylation changes in humans in vivo. We suggest that this occurs because interactions between CpGs reinforce maintenance of methylation patterns in CpG dense regions.

Sexual dimorphism in the relationship between brain complexity, volume and general intelligence (g): a cross-cohort study.

Changes in brain morphology have been reported during development, ageing and in relation to different pathologies. Brain morphology described by the shape complexity of gyri and sulci can be captured and quantified using fractal dimension (FD). This measure of brain structural complexity, as well as brain volume, are associated with intelligence, but less is known about the sexual dimorphism of these relationships. In this paper, sex differences in the relationship between brain structural complexity and general intelligence (g) in two diverse geographic and cultural populations (UK and Indian) are investigated. 3D T1-weighted magnetic resonance imaging (MRI) data and a battery of cognitive tests were acquired from participants belonging to three different cohorts: Mysore Parthenon Cohort (MPC); Aberdeen Children of the 1950s (ACONF) and UK Biobank. We computed MRI derived structural brain complexity and g estimated from a battery of cognitive tests for each group. Brain complexity and volume were both positively corelated with intelligence, with the correlations being significant in women but not always in men. This relationship is seen across populations of differing ages and geographical locations and improves understanding of neurobiological sex-differences.

Brain predictors of fatigue in rheumatoid arthritis: A machine learning study.

BACKGROUND: Fatigue is a common and burdensome symptom in Rheumatoid Arthritis (RA), yet is poorly understood. Currently, clinicians rely solely on fatigue questionnaires, which are inherently subjective measures. For the effective development of future therapies and stratification, it is of vital importance to identify biomarkers of fatigue. In this study, we identify brain differences between RA patients who improved and did not improve their levels of fatigue based on Chalder Fatigue Scale variation (ΔCFS≥ 2), and we compared the performance of different classifiers to distinguish between these samples at baseline. METHODS: Fifty-four fatigued RA patients underwent a magnetic resonance (MR) scan at baseline and 6 months later. At 6 months we identified those whose fatigue levels improved and those for whom it did not. More than 900 brain features across three data sets were assessed as potential predictors of fatigue improvement. These data sets included clinical, structural MRI (sMRI) and diffusion tensor imaging (DTI) data. A genetic algorithm was used for feature selection. Three classifiers were employed in the discrimination of improvers and non-improvers of fatigue: a Least Square Linear Discriminant (LSLD), a linear Support Vector Machine (SVM) and a SVM with Radial Basis Function kernel. RESULTS: The highest accuracy (67.9%) was achieved with the sMRI set, followed by the DTI set (63.8%), whereas classification performance using clinical features was at the chance level. The mean curvature of the left superior temporal sulcus was most strongly selected during the feature selection step, followed by the surface are of the right frontal pole and the surface area of the left banks of the superior temporal sulcus. CONCLUSIONS: The results presented evidence a superiority of brain metrics over clinical metrics in predicting fatigue changes. Further exploration of these methods may support clinicians to triage patients towards the most appropriate fatigue alleviating therapies.

Blunted neuroeconomic loss aversion in schizophrenia.

BACKGROUND: Abnormal social decision-making is prominent in schizophrenia. Antipsychotic medication often improves interpersonal functioning but this action is poorly understood. Neuroeconomic paradigms are an effective method of investigating social decision-making in psychiatric disorders that can be adapted for use with neuroimaging. Using a neuroeconomic approach, it has been shown that healthy humans reproducibly alter their behavior in different contexts, including exhibiting loss aversion: a higher sensitivity to loss outcomes compared to gains of the same magnitude. METHODS: Here, using a novel loss aversion task and fMRI, we tested three hypotheses: controls exhibiting normal behavioral loss aversion show changes in brain activity consistent with previous studies on healthy subjects; behavioral loss aversion is significantly reduced in schizophrenia and associated with abnormal activity in the same brain regions activated in controls during loss aversion behavior; and for the patient group alone, there is a significant correlation between increased psychotic symptoms, blunted loss aversion and abnormal brain activity. These hypotheses were tested in patients with schizophrenia and healthy controls using a loss aversion paradigm and fMRI. RESULTS: The results support the hypotheses, with patients exhibiting significantly blunted behavioral loss aversion compared to controls. Controls showed a robust loss aversion brain activation pattern in the medial temporal lobe, insula and dopaminergic-linked areas, which was blunted in schizophrenia. CONCLUSIONS: Our results are consistent with blunted loss aversion being a reproducible feature of schizophrenia, likely due to abnormal dopaminergic and medial temporal lobe function, suggesting a route by which antipsychotics could influence interpersonal behavior.

A meta-analytic investigation of grey matter differences in anorexia nervosa and autism spectrum disorder.

Recent research reports Anorexia Nervosa (AN) to be highly dependent upon neurobiological function. Some behaviours, particularly concerning food selectivity are found in populations with both Autism Spectrum Disorder (ASD) and AN, and there is a proportionally elevated number of anorexic patients exhibiting symptoms of ASD. We performed a systematic review of structural MRI literature with the aim of identifying common structural neural correlates common to both AN and ASD. Across 46 ASD publications, a meta-analysis of volumetric differences between ASD and healthy controls revealed no consistently affected brain regions. Meta-analysis of 23 AN publications revealed increased volume within the orbitofrontal cortex and medial temporal lobe, and adult-only AN literature revealed differences within the genu of the anterior cingulate cortex. The changes are consistent with alterations in flexible reward-related learning and episodic memory reported in neuropsychological studies. There was no structural overlap between ASD and AN. Findings suggest no consistent neuroanatomical abnormality associated with ASD, and evidence is lacking to suggest that reported behavioural similarities between those with AN and ASD are due to neuroanatomical structural similarities.

Investigation of the Inter- and Intrascanner Reproducibility and Repeatability of Radiomics Features in T1-Weighted Brain MRI.

BACKGROUND: Radiomics is the high throughput analysis of medical images using computer algorithms, which specifically assess textural features. It has increasingly been proposed as a tool for the development of imaging biomarkers. However, an important acknowledged limitation of radiomics is the lack of reproducibility of features produced. PURPOSE: To assess reproducibility and repeatability of radiomics variables in brain MRI through a multivisit, multicenter study. STUDY TYPE: Retrospective. POPULATION: Fourteen individuals visiting three institutions twice, 10 males with the mean age of 36.3 years and age range 25-51. FIELD STRENGTH: 3D T1W inversion recovery on three 1.5-T General Electric scanners. ASSESSMENT: Radiomics analysis by a consultant radiologist performed on the T1W images of the whole brain on all visits. All possible radiomics features were generated. STATISTICAL TEST: Concordance correlation coefficient (CCC) and dynamic range (DR) for all variables were calculated to assess the test-retest repeatability. Intraclass correlation coefficients (ICCs) were calculated to investigate the reproducibility of features across centers. RESULTS: Of 1596 features generated, 57 from center 1, 15 from center 2, and 22 from center 3 had a CCC > 0.9 and DR > 0.9. Eight variables had CCC > 0.9 and DR > 0.9 in all centers. Forty-one variables had an ICC of >0.9. No variables had CCC > 0.9, DR > 0.9, and ICC > 0.9. DATA CONCLUSION: Repeatability and reproducibility of variables is a significant limitation of radiomics analysis in 3DT1W brain MRI. Careful selection of radiomic features is required. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Amygdala and subregion volumes are associated with photoperiod and seasonal depressive symptoms: A cross-sectional study in the UK Biobank cohort.

Although seasonal changes in amygdala volume have been demonstrated in animals, seasonal differences in human amygdala subregion volumes have yet to be investigated. Amygdala volume has also been linked to depressed mood. Therefore, we hypothesised that differences in photoperiod would predict differences in amygdala or subregion volumes and that this association would be linked to depressed mood. 10,033 participants ranging in age from 45 to 79 years were scanned by MRI in a single location. Amygdala subregion volumes were obtained using automated processing and segmentation algorithms. A mediation analysis tested whether amygdala volume mediated the relationship between photoperiod and mood. Photoperiod was positively associated with total amygdala volume (p < .001). Multivariate (GLM) analyses revealed significant effects of photoperiod across all amygdala subregion volumes for both hemispheres (p < .001). Post hoc univariate regression analyses revealed significant associations of photoperiod with each amygdala subregion volume (p < .001). PLS showed the highest loadings of amygdala subregions in lateral nucleus, ABN, basal nucleus, CAT, PLN, AAA, central nucleus, cortical nucleus and medial nucleus for left hemisphere and ABN, lateral nucleus, CAT, PLN, cortical nucleus, AAA, central nucleus and medial nucleus for right hemisphere. There were no significant associations between photoperiod and mood nor between mood scores and amygdala volumes, and due to the lack of these associations, the mediation hypothesis was not supported. This study is the first to demonstrate an association between photoperiod and amygdala volume. These findings add to the evidence supporting the role of photoperiod on brain structural plasticity.

Even a little sleepiness influences neural activation and clinical reasoning in novices.

BACKGROUND AND AIMS: Sleepiness influences alertness and cognitive functioning and impacts many aspects of medical care, including clinical reasoning. However, dual processing theory suggests that sleepiness will impact clinical reasoning differently in different individual, depending on their level of experience with the given condition. Our aim, therefore, was to examine the association between clinical reasoning, neuroanatomical activation, and sleepiness in senior medical students. METHODS: Our methodology replicated an earlier study but with novices rather than board-certified physicians. Eighteen final-year medical students answered validated multiple-choice questions (MCQs) during an fMRI scan. Each MCQ was projected in three phases: reading, answering, and reflection (modified think aloud). Echo-planar imaging (EPI) scans gave a time series that reflected blood oxygenation level dependent (BOLD) signal in each location (voxel) within the brain. Sleep data were collected via self-report (Epworth Sleepiness Scale) and actigraphy. These data were correlated with answer accuracy using Pearson correlation. RESULTS: Analysis revealed an increased BOLD signal in the right dorsomedial prefrontal cortex (P < .05) during reflection (Phase 3) associated with increased self-reported sleepiness (ESS) immediately before scanning. Covariate analysis also revealed that increased BOLD signal in the right supramarginal gyrus (P < .05) when reflecting (Phase 3) was associated with increased correct answer response time. Both patterns indicate effortful analytic (System 2) reasoning. CONCLUSION: Our findings that novices use System 2 thinking for clinical reasoning and even a little (perceived) sleepiness influences their clinical reasoning ability to suggest that the parameters for safe working may be different for novices (eg, junior doctors) and experienced physicians.

Hair glucocorticoids are associated with childhood adversity, depressive symptoms and reduced global and lobar grey matter in Generation Scotland.

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (ßrange = -0.057 to -0.104, all PFDR < 0.05). Increased levels of hair cortisone were significantly associated with MDD (lifetime-MDD status, current symptoms, and severity; ßrange = 0.071 to 0.115, all PFDR = < 0.05), with early-life adversity (ß = 0.083, P = 0.017), and with reduced global and regional brain volumes (global: ß = -0.059, P = 0.043; nucleus accumbens: ß = -0.075, PFDR = 0.044). Associations with total glucocorticoids followed a similar pattern to the cortisol findings. In this large community-based sample, elevated glucocorticoids were significantly associated with MDD, with early, but not later-life stress, and with reduced global and regional brain phenotypes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD.

Early life predictors of late life cerebral small vessel disease in four prospective cohort studies.

Development of cerebral small vessel disease, a major cause of stroke and dementia, may be influenced by early life factors. It is unclear whether these relationships are independent of each other, of adult socio-economic status or of vascular risk factor exposures. We examined associations between factors from birth (ponderal index, birth weight), childhood (IQ, education, socio-economic status), adult small vessel disease, and brain volumes, using data from four prospective cohort studies: STratifying Resilience And Depression Longitudinally (STRADL) (n = 1080; mean age = 59 years); the Dutch Famine Birth Cohort (n = 118; mean age = 68 years); the Lothian Birth Cohort 1936 (LBC1936; n = 617; mean age = 73 years), and the Simpson's cohort (n = 110; mean age = 78 years). We analysed each small vessel disease feature individually and summed to give a total small vessel disease score (range 1-4) in each cohort separately, then in meta-analysis, adjusted for vascular risk factors and adult socio-economic status. Higher birth weight was associated with fewer lacunes [odds ratio (OR) per 100 g = 0.93, 95% confidence interval (CI) = 0.88 to 0.99], fewer infarcts (OR = 0.94, 95% CI = 0.89 to 0.99), and fewer perivascular spaces (OR = 0.95, 95% CI = 0.91 to 0.99). Higher childhood IQ was associated with lower white matter hyperintensity burden (OR per IQ point = 0.99, 95% CI 0.98 to 0.998), fewer infarcts (OR = 0.98, 95% CI = 0.97 to 0.998), fewer lacunes (OR = 0.98, 95% CI = 0.97 to 0.999), and lower total small vessel disease burden (OR = 0.98, 95% CI = 0.96 to 0.999). Low education was associated with more microbleeds (OR = 1.90, 95% CI = 1.33 to 2.72) and lower total brain volume (mean difference = -178.86 cm3, 95% CI = -325.07 to -32.66). Low childhood socio-economic status was associated with fewer lacunes (OR = 0.62, 95% CI = 0.40 to 0.95). Early life factors are associated with worse small vessel disease in later life, independent of each other, vascular risk factors and adult socio-economic status. Risk for small vessel disease may originate in early life and provide a mechanistic link between early life factors and risk of stroke and dementia. Policies investing in early child development may improve lifelong brain health and contribute to the prevention of dementia and stroke in older age.