Nuclei-specific hypothalamus networks predict a dimensional marker of stress in humans.

The hypothalamus is part of the hypothalamic-pituitary-adrenal axis which activates stress responses through release of cortisol. It is a small but heterogeneous structure comprising multiple nuclei. In vivo human neuroimaging has rarely succeeded in recording signals from individual hypothalamus nuclei. Here we use human resting-state fMRI (n = 498) with high spatial resolution to examine relationships between the functional connectivity of specific hypothalamic nuclei and a dimensional marker of prolonged stress. First, we demonstrate that we can parcellate the human hypothalamus into seven nuclei in vivo. Using the functional connectivity between these nuclei and other subcortical structures including the amygdala, we significantly predict stress scores out-of-sample. Predictions use 0.0015% of all possible brain edges, are specific to stress, and improve when using nucleus-specific compared to whole-hypothalamus connectivity. Thus, stress relates to connectivity changes in precise and functionally meaningful subcortical networks, which may be exploited in future studies using interventions in stress disorders.

Individual differences in brain aging: heterogeneity in cortico-hippocampal but not caudate atrophy rates.

It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.

Relationship between nuclei-specific amygdala connectivity and mental health dimensions in humans.

There has been increasing interest in using neuroimaging measures to predict psychiatric disorders. However, predictions usually rely on large brain networks and large disorder heterogeneity. Thus, they lack both anatomical and behavioural specificity, preventing the advancement of targeted interventions. Here we address both challenges. First, using resting-state functional magnetic resonance imaging, we parcellated the amygdala, a region implicated in mood disorders, into seven nuclei. Next, a questionnaire factor analysis provided subclinical mental health dimensions frequently altered in anxious-depressive individuals, such as negative emotions and sleep problems. Finally, for each behavioural dimension, we identified the most predictive resting-state functional connectivity between individual amygdala nuclei and highly specific regions of interest, such as the dorsal raphe nucleus in the brainstem or medial frontal cortical regions. Connectivity in circumscribed amygdala networks predicted behaviours in an independent dataset. Our results reveal specific relations between mental health dimensions and connectivity in precise subcortical networks.

Associations of dietary markers with brain volume and connectivity: A systematic review of MRI studies.

The high prevalence of unhealthy dietary patterns and related brain disorders, such as dementia, emphasizes the importance of research that examines the effect of dietary factors on brain health. Identifying markers of brain health, such as volume and connectivity, that relate to diet is an important first step towards understanding the lifestyle determinants of healthy brain ageing. We conducted a systematic review of 52 studies (total n = 21,221 healthy participants aged 26-80 years, 55 % female) that assessed with a range of MRI measurements, which brain areas, connections, and cerebrovascular factors were associated with dietary markers. We report associations between regional brain measures and dietary health. Collectively, lower diet quality was related to reduced brain volume and connectivity, especially in white and grey matter of the frontal, temporal and parietal lobe, cingulate, entorhinal cortex and the hippocampus. Associations were also observed in connecting fibre pathways and in particular the default-mode, sensorimotor and attention networks. However, there were also some inconsistencies in research methods and findings. We recommend that future research use more comprehensive and consistent dietary measures, more representative samples, and examine the role of key subcortical regions previously highlighted in relevant animal work.

Study Protocol: The Heart and Brain Study.

BACKGROUND: It is well-established that what is good for the heart is good for the brain. Vascular factors such as hypertension, diabetes, and high cholesterol, and genetic factors such as the apolipoprotein E4 allele increase the risk of developing both cardiovascular disease and dementia. However, the mechanisms underlying the heart-brain association remain unclear. Recent evidence suggests that impairments in vascular phenotypes and cerebrovascular reactivity (CVR) may play an important role in cognitive decline. The Heart and Brain Study combines state-of-the-art vascular ultrasound, cerebrovascular magnetic resonance imaging (MRI) and cognitive testing in participants of the long-running Whitehall II Imaging cohort to examine these processes together. This paper describes the study protocol, data pre-processing and overarching objectives. METHODS AND DESIGN: The 775 participants of the Whitehall II Imaging cohort, aged 65 years or older in 2019, have received clinical and vascular risk assessments at 5-year-intervals since 1985, as well as a 3T brain MRI scan and neuropsychological tests between 2012 and 2016 (Whitehall II Wave MRI-1). Approximately 25% of this cohort are selected for the Heart and Brain Study, which involves a single testing session at the University of Oxford (Wave MRI-2). Between 2019 and 2023, participants will undergo ultrasound scans of the ascending aorta and common carotid arteries, measures of central and peripheral blood pressure, and 3T MRI scans to measure CVR in response to 5% carbon dioxide in air, vessel-selective cerebral blood flow (CBF), and cerebrovascular lesions. The structural and diffusion MRI scans and neuropsychological battery conducted at Wave MRI-1 will also be repeated. Using this extensive life-course data, the Heart and Brain Study will examine how 30-year trajectories of vascular risk throughout midlife (40-70 years) affect vascular phenotypes, cerebrovascular health, longitudinal brain atrophy and cognitive decline at older ages. DISCUSSION: The study will generate one of the most comprehensive datasets to examine the longitudinal determinants of the heart-brain association. It will evaluate novel physiological processes in order to describe the optimal window for managing vascular risk in order to delay cognitive decline. Ultimately, the Heart and Brain Study will inform strategies to identify at-risk individuals for targeted interventions to prevent or delay dementia.

Multimodal brain-age prediction and cardiovascular risk: The Whitehall II MRI sub-study.

Brain age is becoming a widely applied imaging-based biomarker of neural aging and potential proxy for brain integrity and health. We estimated multimodal and modality-specific brain age in the Whitehall II (WHII) MRI cohort using machine learning and imaging-derived measures of gray matter (GM) morphology, white matter microstructure (WM), and resting state functional connectivity (FC). The results showed that the prediction accuracy improved when multiple imaging modalities were included in the model (R2 = 0.30, 95% CI [0.24, 0.36]). The modality-specific GM and WM models showed similar performance (R2 = 0.22 [0.16, 0.27] and R2 = 0.24 [0.18, 0.30], respectively), while the FC model showed the lowest prediction accuracy (R2 = 0.002 [-0.005, 0.008]), indicating that the FC features were less related to chronological age compared to structural measures. Follow-up analyses showed that FC predictions were similarly low in a matched sub-sample from UK Biobank, and although FC predictions were consistently lower than GM predictions, the accuracy improved with increasing sample size and age range. Cardiovascular risk factors, including high blood pressure, alcohol intake, and stroke risk score, were each associated with brain aging in the WHII cohort. Blood pressure showed a stronger association with white matter compared to gray matter, while no differences in the associations of alcohol intake and stroke risk with these modalities were observed. In conclusion, machine-learning based brain age prediction can reduce the dimensionality of neuroimaging data to provide meaningful biomarkers of individual brain aging. However, model performance depends on study-specific characteristics including sample size and age range, which may cause discrepancies in findings across studies.

Multiple associative structures created by reinforcement and incidental statistical learning mechanisms.

Learning the structure of the world can be driven by reinforcement but also occurs incidentally through experience. Reinforcement learning theory has provided insight into how prediction errors drive updates in beliefs but less attention has been paid to the knowledge resulting from such learning. Here we contrast associative structures formed through reinforcement and experience of task statistics. BOLD neuroimaging in human volunteers demonstrates rigid representations of rewarded sequences in temporal pole and posterior orbito-frontal cortex, which are constructed backwards from reward. By contrast, medial prefrontal cortex and a hippocampal-amygdala border region carry reward-related knowledge but also flexible statistical knowledge of the currently relevant task model. Intriguingly, ventral striatum encodes prediction error responses but not the full RL- or statistically derived task knowledge. In summary, representations of task knowledge are derived via multiple learning processes operating at different time scales that are associated with partially overlapping and partially specialized anatomical regions.