The association of regional cerebral blood flow and glucose metabolism in normative ageing and insulin resistance.

Rising rates of insulin resistance and an ageing population are set to exact an increasing toll on individuals and society. Here we examine the contribution of age and insulin resistance to the association of cerebral blood flow and glucose metabolism; both critical process in the supply of energy for the brain. Thirty-four younger (20-42 years) and 41 older (66-86 years) healthy adults underwent a simultaneous resting state MR/PET scan, including arterial spin labelling. Rates of cerebral blood flow and glucose metabolism were derived using a functional atlas of 100 brain regions. Older adults had lower cerebral blood flow than younger adults in 95 regions, reducing to 36 regions after controlling for cortical atrophy and blood pressure. Lower cerebral blood flow was also associated with worse working memory and slower reaction time in tasks requiring cognitive flexibility and response inhibition. Younger and older insulin sensitive adults showed small, negative correlations between relatively high rates of regional cerebral blood flow and glucose metabolism. This pattern was inverted in insulin resistant older adults, who showed hypoperfusion and hypometabolism across the cortex, and a positive correlation. In insulin resistant younger adults, the association showed inversion to positive correlations, although not to the extent seen in older adults. Our findings suggest that the normal course of ageing and insulin resistance alter the rates of and associations between cerebral blood flow and glucose metabolism. They underscore the criticality of insulin sensitivity to brain health across the adult lifespan.

Protective role of parenthood on age-related brain function in mid- to late-life.

The experience of parenthood can profoundly alter one's body, mind, and environment, yet we know little about the long-term associations between parenthood and brain function and aging in adulthood. Here, we investigate the link between number of children parented (parity) and age on brain function in 19,964 females and 17,607 males from the UK Biobank. In both females and males, increased parity was positively associated with functional connectivity, particularly within the somato/motor network. Critically, the spatial topography of parity-linked effects was inversely correlated with the impact of age on functional connectivity across the brain for both females and males, suggesting that a higher number of children is associated with patterns of brain function in the opposite direction to age-related alterations. These results indicate that the changes accompanying parenthood may confer benefits to brain health across the lifespan, highlighting the importance of future work to understand the associated mechanisms.

Integrating multimodal and multiscale connectivity blueprints of the human cerebral cortex in health and disease.

The brain is composed of disparate neural populations that communicate and interact with one another. Although fiber bundles, similarities in molecular architecture, and synchronized neural activity all reflect how brain regions potentially interact with one another, a comprehensive study of how all these interregional relationships jointly reflect brain structure and function remains missing. Here, we systematically integrate 7 multimodal, multiscale types of interregional similarity ("connectivity modes") derived from gene expression, neurotransmitter receptor density, cellular morphology, glucose metabolism, haemodynamic activity, and electrophysiology in humans. We first show that for all connectivity modes, feature similarity decreases with distance and increases when regions are structurally connected. Next, we show that connectivity modes exhibit unique and diverse connection patterns, hub profiles, spatial gradients, and modular organization. Throughout, we observe a consistent primacy of molecular connectivity modes-namely correlated gene expression and receptor similarity-that map onto multiple phenomena, including the rich club and patterns of abnormal cortical thickness across 13 neurological, psychiatric, and neurodevelopmental disorders. Finally, to construct a single multimodal wiring map of the human cortex, we fuse all 7 connectivity modes and show that the fused network maps onto major organizational features of the cortex including structural connectivity, intrinsic functional networks, and cytoarchitectonic classes. Altogether, this work contributes to the integrative study of interregional relationships in the human cerebral cortex.

The maternal brain is more flexible and responsive at rest: effective connectivity of the parental caregiving network in postpartum mothers.

The field of neuroscience has largely overlooked the impact of motherhood on brain function outside the context of responses to infant stimuli. Here, we apply spectral dynamic causal modelling (spDCM) to resting-state fMRI data to investigate differences in brain function between a group of 40 first-time mothers at 1-year postpartum and 39 age- and education-matched women who have never been pregnant. Using spDCM, we investigate the directionality (top-down vs. bottom-up) and valence (inhibition vs excitation) of functional connections between six key left hemisphere brain regions implicated in motherhood: the dorsomedial prefrontal cortex, ventromedial prefrontal cortex, posterior cingulate cortex, parahippocampal gyrus, amygdala, and nucleus accumbens. We show a selective modulation of inhibitory pathways related to differences between (1) mothers and non-mothers, (2) the interactions between group and cognitive performance and (3) group and social cognition, and (4) differences related to maternal caregiving behaviour. Across analyses, we show consistent disinhibition between cognitive and affective regions suggesting more efficient, flexible, and responsive behaviour, subserving cognitive performance, social cognition, and maternal caregiving. Together our results support the interpretation of these key regions as constituting a parental caregiving network. The nucleus accumbens and the parahippocampal gyrus emerging as 'hub' regions of this network, highlighting the global importance of the affective limbic network for maternal caregiving, social cognition, and cognitive performance in the postpartum period.

Matrescence: lifetime impact of motherhood on cognition and the brain.

Profound environmental, hormonal, and neurobiological changes mark the transition to motherhood as a major biosocial life event. Despite the ubiquity of motherhood, the enduring impact of caregiving on cognition and the brain across the lifespan is not well characterized and represents a unique window of opportunity to investigate human neural and cognitive development. By integrating insights from the human and animal maternal brain literatures with theories of cognitive ageing, we outline a framework for understanding maternal neural and cognitive changes across the lifespan. We suggest that the increased cognitive load of motherhood provides an initial challenge during the peripartum period, requiring continuous adaptation; yet when these demands are sustained across the lifespan, they result in increased late-life cognitive reserve.

Brain connectomics: time for a molecular imaging perspective?

In the past two decades brain connectomics has evolved into a major concept in neuroscience. However, the current perspective on brain connectivity and how it underpins brain function relies mainly on the hemodynamic signal of functional magnetic resonance imaging (MRI). Molecular imaging provides unique information inaccessible to MRI-based and electrophysiological techniques. Thus, positron emission tomography (PET) has been successfully applied to measure neural activity, neurotransmission, and proteinopathies in normal and pathological cognition. Here, we position molecular imaging within the brain connectivity framework from the perspective of timeliness, validity, reproducibility, and resolution. We encourage the neuroscientific community to take an integrative approach whereby MRI-based, electrophysiological techniques, and molecular imaging contribute to our understanding of the brain connectome.

Metabolic and functional connectivity provide unique and complementary insights into cognition-connectome relationships.

A major challenge in current cognitive neuroscience is how functional brain connectivity gives rise to human cognition. Functional magnetic resonance imaging (fMRI) describes brain connectivity based on cerebral oxygenation dynamics (hemodynamic connectivity), whereas [18F]-fluorodeoxyglucose functional positron emission tomography (FDG-fPET) describes brain connectivity based on cerebral glucose uptake (metabolic connectivity), each providing a unique characterization of the human brain. How these 2 modalities differ in their contribution to cognition and behavior is unclear. We used simultaneous resting-state FDG-fPET/fMRI to investigate how hemodynamic connectivity and metabolic connectivity relate to cognitive function by applying partial least squares analyses. Results revealed that although for both modalities the frontoparietal anatomical subdivisions related the strongest to cognition, using hemodynamic measures this network expressed executive functioning, episodic memory, and depression, whereas for metabolic measures this network exclusively expressed executive functioning. These findings demonstrate the unique advantages that simultaneous FDG-PET/fMRI has to provide a comprehensive understanding of the neural mechanisms that underpin cognition and highlights the importance of multimodality imaging in cognitive neuroscience research.

Cognition-oriented treatments and physical exercise on cognitive function in Huntington's disease: a systematic review.

Cognitive impairment is prevalent in Huntington's disease (HD), with no treatments currently available. While cognition-oriented treatments and physical exercise have shown efficacy in improving cognition in other populations, they have not been systematically reviewed in HD. This systematic review aims to examine the effects of cognitive and exercise interventions on cognition in HD, along with effects on psychosocial function, functional independence, and neuroimaging outcomes. Seventeen studies (three cognitive, seven exercise, seven combining cognitive and physical exercise) were included. While there was generally low certainty of evidence, interventions that included cognitive training appeared to have larger effect sizes on cognition, while physical exercise (alone or combined with cognitive rehabilitation or stimulation) showed negligible effect sizes. On the other hand, combined interventions had larger effects on psychosocial function. Finally, effects on functional independence appeared negligible following exercise and combined interventions, and effects on neuroimaging outcomes were inconclusive. Larger studies should seek to confirm the benefits of cognitive and physical interventions, and further explore changes in functional independence and neural outcomes.

Lower brain glucose metabolism in normal ageing is predominantly frontal and temporal: A systematic review and pooled effect size and activation likelihood estimates meta-analyses.

This review provides a qualitative and quantitative analysis of cerebral glucose metabolism in ageing. We undertook a systematic literature review followed by pooled effect size and activation likelihood estimates (ALE) meta-analyses. Studies were retrieved from PubMed following the PRISMA guidelines. After reviewing 635 records, 21 studies with 22 independent samples (n = 911 participants) were included in the pooled effect size analyses. Eight studies with eleven separate samples (n = 713 participants) were included in the ALE analyses. Pooled effect sizes showed significantly lower cerebral metabolic rates of glucose for older versus younger adults for the whole brain, as well as for the frontal, temporal, parietal, and occipital lobes. Among the sub-cortical structures, the caudate showed a lower metabolic rate among older adults. In sub-group analyses controlling for changes in brain volume or partial volume effects, the lower glucose metabolism among older adults in the frontal lobe remained significant, whereas confidence intervals crossed zero for the other lobes and structures. The ALE identified nine clusters of lower glucose metabolism among older adults, ranging from 200 to 2640 mm3 . The two largest clusters were in the left and right inferior frontal and superior temporal gyri and the insula. Clusters were also found in the inferior temporal junction, the anterior cingulate and caudate. Taken together, the results are consistent with research showing less efficient glucose metabolism in the ageing brain. The findings are discussed in the context of theories of cognitive ageing and are compared to those found in neurodegenerative disease.

The older adult brain is less modular, more integrated, and less efficient at rest: A systematic review of large-scale resting-state functional brain networks in aging.

The literature on large-scale resting-state functional brain networks across the adult lifespan was systematically reviewed. Studies published between 1986 and July 2021 were retrieved from PubMed. After reviewing 2938 records, 144 studies were included. Results on 11 network measures were summarized and assessed for certainty of the evidence using a modified GRADE method. The evidence provides high certainty that older adults display reduced within-network and increased between-network functional connectivity. Older adults also show lower segregation, modularity, efficiency and hub function, and decreased lateralization and a posterior to anterior shift at rest. Higher-order functional networks reliably showed age differences, whereas primary sensory and motor networks showed more variable results. The inflection point for network changes is often the third or fourth decade of life. Age effects were found with moderate certainty for within- and between-network altered patterns and speed of dynamic connectivity. Research on within-subject bold variability and connectivity using glucose uptake provides low certainty of age differences but warrants further study. Taken together, these age-related changes may contribute to the cognitive decline often seen in older adults.

Evidence of Subjective, But Not Objective, Cognitive Deficit in New Mothers at 1-Year Postpartum.

Background: The experience and even existence of cognitive deficits in the postpartum period is uncertain, with only a few scientific studies, reporting inconsistent results. Methods: In this study, we investigate cognition in 86 women (43 first-time mothers 1 year postpartum and 43 non-mothers). Results: Mothers and non-mothers showed no significant differences on measures of objective cognition (verbal memory, working memory, and processing speed or theory of mind). Despite the absence of objective differences, mothers self-reported significantly worse subjective memory than non-mothers. To interpret the difference between objective and subjective measures of memory, we investigated relationships between subjective memory, objective memory, and wellbeing. Mothers, but not non-mothers, showed a positive correlation between subjective and objective measures of memory, indicating mothers are "in-tune" with their memory performance. Mothers also demonstrated a positive relationship between subjective memory and wellbeing (sleep, anxiety, and depression), where better wellbeing correlated with higher subjective memory. This relationship was not apparent in non-mothers. The results suggest that poorer sleep, higher anxiety, and higher depression are related to reports of poorer self-reported memory in mothers. Conclusion: Our results add to our growing understanding of maternal cognition at 1 year postpartum, with no evidence of cognitive differences between mothers and non-mothers.

Blood pressure variability and structural brain changes: a systematic review.

BACKGROUND: Blood pressure variability (BPV) has been linked with cognitive impairment and dementia. However, the pathophysiological mechanisms by which BPV affects cognition are unclear. This systematic review aims to assess the links between different BPV measures and white and grey matter structures. METHODS AND RESULTS: The following databases were searched from inception through to January 2021; EMBASE, MEDLINE, EMCARE and SCOPUS. Studies that reported on the relationship between within-individual BPV (short, medium or long-term variability) or a circadian blood pressure (BP) measurement and MRI assessed brain structures were included. Overall, 20 studies met the criteria and were included, of which 11 studies looked at short-term BPV, eight articles investigated visit-to-visit BPV and one study looked at a compositional BPV measurement. Due to heterogeneity in study samples, meta-analysis was not possible. Across the included studies, associations between MRI indices and BP dipping patterns were mixed; higher long-term BPV and higher sleep systolic BPV was found to be associated with lower whole brain volume and hippocampal volume. CONCLUSION: Increased BPV, in particular systolic long-term and systolic night-time BPV, appears to be associated with lower brain volume and hippocampal volume. This highlights the adverse effect that increased BPV has upon the brain, potentially contributing to cognitive decline, including dementia, in late-life.

Monash DaCRA fPET-fMRI: A dataset for comparison of radiotracer administration for high temporal resolution functional FDG-PET.

BACKGROUND: "Functional" [18F]-fluorodeoxyglucose positron emission tomography (FDG-fPET) is a new approach for measuring glucose uptake in the human brain. The goal of FDG-fPET is to maintain a constant plasma supply of radioactive FDG in order to track, with high temporal resolution, the dynamic uptake of glucose during neuronal activity that occurs in response to a task or at rest. FDG-fPET has most often been applied in simultaneous BOLD-fMRI/FDG-fPET (blood oxygenation level-dependent functional MRI fluorodeoxyglucose functional positron emission tomography) imaging. BOLD-fMRI/FDG-fPET provides the capability to image the 2 primary sources of energetic dynamics in the brain, the cerebrovascular haemodynamic response and cerebral glucose uptake. FINDINGS: In this Data Note, we describe an open access dataset, Monash DaCRA fPET-fMRI, which contrasts 3 radiotracer administration protocols for FDG-fPET: bolus, constant infusion, and hybrid bolus/infusion. Participants (n = 5 in each group) were randomly assigned to each radiotracer administration protocol and underwent simultaneous BOLD-fMRI/FDG-fPET scanning while viewing a flickering checkerboard. The bolus group received the full FDG dose in a standard bolus administration, the infusion group received the full FDG dose as a slow infusion over the duration of the scan, and the bolus-infusion group received 50% of the FDG dose as bolus and 50% as constant infusion. We validate the dataset by contrasting plasma radioactivity, grey matter mean uptake, and task-related activity in the visual cortex. CONCLUSIONS: The Monash DaCRA fPET-fMRI dataset provides significant reuse value for researchers interested in the comparison of signal dynamics in fPET, and its relationship with fMRI task-evoked activity.

Brain-predicted age difference is associated with cognitive processing in later-life.

Brain age is a neuroimaging-based biomarker of aging. This study examined whether the difference between brain age and chronological age (brain-PAD) is associated with cognitive function at baseline and longitudinally. Participants were relatively healthy, predominantly white community-dwelling older adults (n = 531, aged ≥70 years), with high educational attainment (61% ≥12 years) and socioeconomic status (59% ≥75th percentile). Brain age was estimated from T1-weighted magnetic resonance images using an algorithm by Cole et al., 2018. After controlling for age, gender, education, depression and body mass index, brain-PAD was negatively associated with psychomotor speed (Symbol Digit Modalities Test) at baseline (Bonferroni p < 0.006), but was not associated with baseline verbal fluency (Controlled Oral Word Association Test), delayed recall (Hopkins Learning Test Revised), or general cognitive status (Mini-Mental State Examination). Baseline brain-PAD was not associated with 3-year change in cognition (Bonferroni p > 0.006). These findings indicate that even in relatively healthy older people, accelerated brain aging is associated with worse psychomotor speed, but future longitudinal research into changes in brain-PAD is needed.

Task-evoked simultaneous FDG-PET and fMRI data for measurement of neural metabolism in the human visual cortex.

Understanding how the living human brain functions requires sophisticated in vivo neuroimaging technologies to characterise the complexity of neuroanatomy, neural function, and brain metabolism. Fluorodeoxyglucose positron emission tomography (FDG-PET) studies of human brain function have historically been limited in their capacity to measure dynamic neural activity. Simultaneous [18 F]-FDG-PET and functional magnetic resonance imaging (fMRI) with FDG infusion protocols enable examination of dynamic changes in cerebral glucose metabolism simultaneously with dynamic changes in blood oxygenation. The Monash vis-fPET-fMRI dataset is a simultaneously acquired FDG-fPET/BOLD-fMRI dataset acquired from n = 10 healthy adults (18-49 yrs) whilst they viewed a flickering checkerboard task. The dataset contains both raw (unprocessed) images and source data organized according to the BIDS specification. The source data includes PET listmode, normalization, sinogram and physiology data. Here, the technical feasibility of using opensource frameworks to reconstruct the PET listmode data is demonstrated. The dataset has significant re-use value for the development of new processing pipelines, signal optimisation methods, and to formulate new hypotheses concerning the relationship between neuronal glucose uptake and cerebral haemodynamics.

Interactive effects of the APOE and BDNF polymorphisms on functional brain connectivity: the Tasmanian Healthy Brain Project.

Resting-state functional magnetic resonance imaging measures pathological alterations in neurodegenerative diseases, including Alzheimer's disease. Disruption in functional connectivity may be a potential biomarker of ageing and early brain changes associated with AD-related genes, such as APOE and BDNF. The objective of this study was to identify group differences in resting-state networks between individuals with BDNF Val66Met and APOE polymorphisms in cognitively healthy older persons. Dual regression following Independent Components Analysis were performed to examine differences associated with these polymorphisms. APOE ε3 homozygotes showed stronger functional connectivity than APOE ε4 carriers. Males showed stronger functional connectivity between the Default Mode Network (DMN) and grey matter premotor cortex, while females showed stronger functional connectivity between the executive network and lateral occipital cortex and parahippocampal gyrus. Additionally, we found that with increasing cognitive reserve, functional connectivity increased within the Dorsal Attention Network (DAN), but decreased within the DMN. Interaction effects indicated stronger functional connectivity in Met/ε3 carriers than in Met/ε4 and Val/ε4 within both the DMN and DAN. APOE/BDNF interactions may therefore influence the integrity of functional brain connections in older adults, and may underlie a vulnerable phenotype for subsequent Alzheimer's-type dementia.

Afraid of the dark: Light acutely suppresses activity in the human amygdala.

Light improves mood. The amygdala plays a critical role in regulating emotion, including fear-related responses. In rodents the amygdala receives direct light input from the retina, and light may play a role in fear-related learning. A direct effect of light on the amygdala represents a plausible mechanism of action for light's mood-elevating effects in humans. However, the effect of light on activity in the amygdala in humans is not well understood. We examined the effect of passive dim-to-moderate white light exposure on activation of the amygdala in healthy young adults using the BOLD fMRI response (3T Siemens scanner; n = 23). Participants were exposed to alternating 30s blocks of light (10 lux or 100 lux) and dark (<1 lux), with each light intensity being presented separately. Light, compared with dark, suppressed activity in the amygdala. Moderate light exposure resulted in greater suppression of amygdala activity than dim light. Furthermore, functional connectivity between the amygdala and ventro-medial prefrontal cortex was enhanced during light relative to dark. These effects may contribute to light's mood-elevating effects, via a reduction in negative, fear-related affect and enhanced processing of negative emotion.