Cerebellar functional connectivity relates to lower urinary tract function: A 7 Tesla study.

OBJECTIVES: The objective of this study is to explore the functional connectivity (FC) of the cerebellum during the storage phase of micturition, through detecting spontaneous blood-oxygen-level dependent signal between the cerebellum and different brain regions using a high-resolution 7 Tesla magnetic resonance imaging (MRI) scanner. MATERIALS AND METHODS: We recruited healthy individuals with no reported history of neurological disease or lower urinary tract (LUT) symptoms. Participants were asked to drink 500 mL of water and then empty their bladders before entering the MRI scanner. They underwent a T1-weighted anatomical scan, followed by an initial (8 min) empty bladder resting state functional MRI (rs-fMRI) acquisition. Once subjects felt the desire to void, a second rs-fMRI scan was obtained, this time with a full bladder state. We established a priori cerebellar regions of interest from the literature to perform seed-to-voxel analysis using nonparametric statistics based on the Threshold Free Cluster Enhancement method and utilized a voxel threshold of p < 0.05. RESULTS: Twenty individuals (10 male and 10 female) with a median age of 25 years (IQR [3.5]) participated in the study. We placed 31 different 4-mm spherical seeds throughout the cerebellum and assessed their FC with the remainder of the brain. Three of these (left cerebellar tonsil, right posterolateral lobe, right posterior lobe) showed significant differences in connectivity when comparing scans conducted with a full bladder to those with an empty bladder. Additionally, we observed sex differences in FC, with connectivity being higher in women during the empty bladder condition. CONCLUSION: Our initial findings reveal, for the first time, that the connectivity of the cerebellar network is modulated by bladder filling and is associated with LUT function. Unraveling the cerebellum's role in bladder function lays the foundation for a more comprehensive understanding of urinary pathologies affecting this area.

Relationships between balance performance and connectivity of motor cortex with primary somatosensory cortex and cerebellum in middle aged and older adults.

Connectivity of somatosensory cortex (S1) and cerebellum with the motor cortex (M1) is critical for balance control. While both S1-M1 and cerebellar-M1 connections are affected with aging, the implications of altered connectivity for balance control are not known. We investigated the relationship between S1-M1 and cerebellar-M1 connectivity and standing balance in middle-aged and older adults. Our secondary objective was to investigate how cognition affected the relationship between connectivity and balance. Our results show that greater S1-M1 and cerebellar-M1 connectivity was related to greater postural sway during standing. This may be indicative of an increase in functional recruitment of additional brain networks to maintain upright balance despite differences in network connectivity. Also, cognition moderated the relationship between S1-M1 connectivity and balance, such that those with lower cognition had a stronger relationship between connectivity and balance performance. It may be that individuals with poor cognition need increased recruitment of brain regions (compensation for cognitive declines) and in turn, higher wiring costs, which would be associated with increased functional connectivity.

Non-invasive neuromodulation of cerebello-hippocampal volume-behavior relationships.

The study here explores the link between transcranial direct current stimulation (tDCS) and brain-behavior relationships. We propose that tDCS may indirectly influence the complex relationships between brain volume and behavior. We focused on the dynamics between the hippocampus (HPC) and cerebellum (CB) in cognitive processes, a relationship with significant implications for understanding memory and motor skills. Seventy-four young adults (mean age: 22±0.42 years, mean education: 14.7±0.25 years) were randomly assigned to receive either anodal, cathodal, or sham stimulation. Following stimulation, participants completed computerized tasks assessing working memory and sequence learning in a magnetic resonance imaging (MRI) environment. We investigated the statistical interaction between CB and HPC volumes. Our findings showed that individuals with larger cerebellar volumes had shorter reaction times (RT) on a high-load working memory task in the sham stimulation group. In contrast, the anodal stimulation group exhibited faster RTs during the low-load working memory condition. These RT differences were associated with the cortical volumetric interaction between CB-HPC. Literature suggests that anodal stimulation down-regulates the CB and here, those with larger volumes perform more quickly, suggesting the potential need for additional cognitive resources to compensate for cerebellar downregulation. This new insight suggests that tDCS can aid in revealing structure-function relationships, due to greater performance variability, especially in young adults. It may also reveal new targets of interest in the study of aging or in diseases where there is also greater behavioral variability.

Cerebello-Hippocampal Interactions in the Human Brain: A New Pathway for Insights Into Aging.

The cerebellum is recognized as being important for optimal behavioral performance across task domains, including motor function, cognition, and affect. Decades of work have highlighted cerebello-thalamo-cortical circuits, from both structural and functional perspectives. However, these circuits of interest have been primarily (though not exclusively) focused on targets in the cerebral cortex. In addition to these cortical connections, the circuit linking the cerebellum and hippocampus is of particular interest. Recently, there has been an increased interest in this circuit, thanks in large part to novel findings in the animal literature demonstrating that neuronal firing in the cerebellum impacts that in the hippocampus. Work in the human brain has provided evidence for interactions between the cerebellum and hippocampus, though primarily this has been in the context of spatial navigation. Given the role of both regions in cognition and aging, and emerging evidence indicating that the cerebellum is impacted in age-related neurodegenerative disease such as Alzheimer's, I propose that further attention to this circuit is warranted. Here, I provide an overview of cerebello-hippocampal interactions in animal models and from human imaging and outline the possible utility of further investigations to improve our understanding of aging and age-related cognitive decline.

Functional Connectivity Differences in Distinct Dentato-Cortical Networks in Alzheimer's Disease and Mild Cognitive Impairment.

Recent research has implicated the cerebellum in Alzheimer's disease (AD), and cerebrocerebellar network connectivity is emerging as a possible contributor to symptom severity. The cerebellar dentate nucleus (DN) has parallel motor and non-motor sub-regions that project to motor and frontal regions of the cerebral cortex, respectively. These distinct dentato-cortical networks have been delineated in the non-human primate and human brain. Importantly, cerebellar regions prone to atrophy in AD are functionally connected to atrophied regions of the cerebral cortex, suggesting that dysfunction perhaps occurs at a network level. Investigating functional connectivity (FC) alterations of the DN is a crucial step in understanding the cerebellum in AD and in mild cognitive impairment (MCI). Inclusion of this latter group stands to provide insights into cerebellar contributions prior to diagnosis of AD. The present study investigated FC differences in dorsal (dDN) and ventral (vDN) DN networks in MCI and AD relative to cognitively normal participants (CN) and relationships between FC and behavior. Our results showed patterns indicating both higher and lower functional connectivity in both dDN and vDN in AD compared to CN. However, connectivity in the AD group was lower when compared to MCI. We argue that these findings suggest that the patterns of higher FC in AD may act as a compensatory mechanism. Additionally, we found associations between the individual networks and behavior. There were significant interactions between dDN connectivity and motor symptoms. However, both DN seeds were associated with cognitive task performance. Together, these results indicate that cerebellar DN networks are impacted in AD, and this may impact behavior. In concert with the growing body of literature implicating the cerebellum in AD, our work further underscores the importance of investigations of this region. We speculate that much like in psychiatric diseases such as schizophrenia, cerebellar dysfunction results in negative impacts on thought and the organization therein. Further, this is consistent with recent arguments that the cerebellum provides crucial scaffolding for cognitive function in aging. Together, our findings stand to inform future clinical work in the diagnosis and understanding of this disease.

Consensus Paper: Cerebellum and Ageing.

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

Bacillus Calmette-Guérin vaccination as defense against SARS-CoV-2 (BADAS): a randomized controlled trial to protect healthcare workers in the USA by enhanced trained immune responses.

BACKGROUND: A large epidemic, such as that observed with SARS-CoV-2, seriously challenges available hospital capacity, and this would be augmented by infection of healthcare workers (HCW). Bacillus Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in vitro and in vivo. Preliminary analyses suggest that regions of the world with existing BCG vaccination programs have lower incidence and mortality from COVID-19. We hypothesize that BCG vaccination can reduce SARS-CoV-2 infection and disease severity. METHODS: This will be a placebo-controlled adaptive multi-center randomized controlled trial. A total of 1800 individuals considered to be at high risk, including those with comorbidities (hypertension, diabetes, obesity, reactive airway disease, smokers), racial and ethnic minorities, elderly, teachers, police, restaurant wait-staff, delivery personnel, health care workers who are defined as personnel working in a healthcare setting, at a hospital, medical center or clinic (veterinary, dental, ophthalmology), and first responders (paramedics, firefighters, or law enforcement), will be randomly assigned to two treatment groups. The treatment groups will receive intradermal administration of BCG vaccine or placebo (saline) with groups at a 1:1 ratio. Individuals will be tracked for evidence of SARS-CoV-2 infection and severity as well as obtaining whole blood to track immunological markers, and a sub-study will include cognitive function and brain imaging. The majority of individuals will be followed for 6 months, with an option to extend for another 6 months, and the cognitive sub-study duration is 2 years. We will plot Kaplan-Meier curves that will be plotted comparing groups and hazard ratios and p-values reported using Cox proportional hazard models. DISCUSSION: It is expected this trial will allow evaluation of the effects of BCG vaccination at a population level in high-risk healthcare individuals through a mitigated clinical course of SARS-CoV-2 infection and inform policy making during the ongoing epidemic. TRIAL REGISTRATION: ClinicalTrials.gov NCT04348370. Registered on April 16, 2020.

Time dependent effects of cerebellar tDCS on cerebello-cortical connectivity networks in young adults.

The cerebellum is involved in non-motor processing, supported by topographically distinct cerebellar activations and closed loop circuits between the cerebellum and the cortex. Disruptions to cerebellar function and network connectivity in aging or disease may negatively impact prefrontal function and processing. Cerebellar resources may be important for offloading cortical processing, providing crucial scaffolding for normative performance and function. Here, we used transcranial direct current stimulation (tDCS) to temporarily alter cerebellar function and subsequently investigated resting state network connectivity. This allows us to investigate network changes that may parallel what is seen in aging and clinical populations, providing additional insights into these key circuits. Critically, what happens to these circuits if the cerebellum is not functioning optimally remains relatively unknown. We employed a between-subjects design applying anodal (n=25), cathodal (n=25), or sham (n=24) stimulation to the cerebellum to examine the effect of stimulation on cerebello-cortical resting state connectivity in young adults. We predicted increased functional connectivity following cathodal stimulation and decreased functional connectivity following anodal stimulation. We found, anodal stimulation resulted in increased connectivity in both ipsilateral and contralateral regions of the cortex, perhaps indicative of a compensatory response to degraded cerebellar output. Additionally, a sliding window analysis also demonstrated a time dependent nature to the impacts of cerebellar tDCS on connectivity, particularly in cognitive region in the cortex. Assuming the difference in connectivity and network-behavior relationships here parallels what occurs in aging or disease, this may provide a mechanism whereby offloading of function to the cerebellum is negatively impacted, resulting in subsequent differences in prefrontal cortical activation patterns and performance deficits. These results might inform and update existing compensatory models of function to include the cerebellum as a vital structure needed for scaffolding.

Network segregation in aging females and evaluation of the impact of sex steroid hormones.

Males and females show differential patterns in connectivity in resting-state networks (RSNs) during normal aging, from early adulthood to late middle age. Age-related differences in network integration (effectiveness of specialized communication at the global network level) and segregation (functional specialization at the local level of specific brain regions) may also differ by sex. These differences may be due at least in part to endogenous hormonal fluctuation, such as that which occurs in females during midlife with the transition to menopause when levels of estrogens and progesterone drop markedly. A limited number of studies that have investigated sex differences in the action of steroid hormones in brain networks. Here we investigated how sex steroid hormones relate to age-network relationships in both males and females, with a focus on network segregation. Females displayed a significant quadratic relationship between age and network segregation for the cerebellar-basal ganglia and salience networks. In both cases, segregation was still increasing through adulthood, highest in midlife, and with a downturn thereafter. However, there were no significant relationships between sex steroid hormone levels and network segregation levels in females, and they did not exhibit significant associations between progesterone or 17ß-estradiol and network segregation. Patterns of connectivity between the cerebellum and basal ganglia have been associated with cognitive performance and self-reported balance confidence in older adults. Together, these findings suggest that network segregation patterns with age in females vary by network, and that sex steroid hormones are not associated with this measure of connectivity in this cross-sectional analysis. Though this is a null effect, it remains critical for understanding the extent to which hormones relate to brain network architecture.

Hormone-sleep interactions predict cerebellar connectivity and behavior in aging females.

Sex hormones fluctuate over the course of the female lifespan and are associated with brain health and cognition. Thus, hormonal changes throughout female adulthood, and with menopause in particular, may contribute to sex differences in brain function and behavior. Further, sex hormones have been correlated with sleep patterns, which also exhibit sex-specific impacts on the brain and behavior. As such, the interplay between hormones and sleep may contribute to late-life brain and behavioral outcomes in females. Here, in a sample of healthy adult females (n = 79, ages 35-86), we evaluated the effect of hormone-sleep interactions on cognitive and motor performance as well as cerebellar-frontal network connectivity. Salivary samples were used to measure 17ß-estradiol, progesterone, and testosterone levels while overnight actigraphy was used to quantify sleep patterns. Cognitive behavior was quantified using the composite average of standardized scores on memory, processing speed, and attentional tasks, and motor behavior was indexed with sequence learning, balance, and dexterity tasks. We analyzed resting-state connectivity correlations for two specific cerebellar-frontal networks: a Crus I to dorsolateral prefrontal cortex network and a Lobule V to primary motor cortex network. In sum, results indicate that sex hormones and sleep patterns interact to predict cerebellar-frontal connectivity and behavior in aging females. Together, the current findings further highlight the potential consequences of endocrine aging in females and suggest that the link between sex hormones and sleep patterns may contribute, in part, to divergent outcomes between sexes in advanced age.

Cerebello-basal Ganglia Networks and Cortical Network Global Efficiency.

The cerebellum (CB) and basal ganglia (BG) each have topographically distinct functional subregions that are functionally and anatomically interconnected with cortical regions through discrete thalamic loops and with each other via disynaptic connections, with previous work detailing high levels of functional connectivity between these phylogenetically ancient regions. It was posited that this CB-BG network provides support for cortical systems processing, spanning cognitive, emotional, and motor domains, implying that subcortical network measures are strongly related to cortical network measures (Bostan & Strick, 2018); however, it is currently unknown how network measures within distinct CB-BG networks relate to cortical network measures. Here, 122 regions of interest comprising cognitive and motor CB-BG networks and 7 canonical cortical resting-state were used to investigate whether the integration (quantified using global efficiency, GE) of cognitive CB-BG network (CCBN) nodes and their segregation from motor CB-BG network (MCBN) nodes is related to cortical network GE and segregation in 233 non-related, right-handed participants (Human Connectome Project-1200). CCBN GE positively correlated with GE in the default mode, motor, and auditory networks and MCBN GE positively correlated with GE in all networks, except the default mode and emotional. MCBN segregation was related to motor network segregation. These findings highlight the CB-BG network's potential role in cortical networks associated with executive function, task switching, and verbal working memory. This work has implications for understanding cortical network organization and cortical-subcortical interactions in healthy adults and may help in determining biomarkers and deciphering subcortical differences seen in disease states.

Age-related differences in functional network segregation in the context of sex and reproductive stage.

Age is accompanied by differences in the organization of functional brain networks, which impact behavior in adulthood. Functional networks become less segregated and more integrated with age. However, sex differences in network segregation declines with age are not well-understood. Further, network segregation in the context of female reproductive stage is relatively understudied, though unmasking such relationships would be informative for elucidating biological mechanisms that contribute to sex-specific differences in aging. In the current work, we used data from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) repository to evaluate differences in resting-state network segregation as a product of sex and reproductive stage. Reproductive stage was categorized using the Stages of Reproductive Aging Workshop (STRAW+10) criteria. Replicating prior work, we investigated the following functional networks: auditory, cerebellar-basal ganglia, cingulo-opercular task control, default mode, dorsal attention, fronto-parietal task control, salience, sensory somatomotor mouth, sensory somatomotor hand, ventral attention, and visual. First, our results mirror findings from previous work indicating that network segregation is lower with increasing age. Second, when analyzing associations between network segregation and age within each sex separately, we find qualitative differences between females and males. Finally, we report significant effects of reproductive stage on network segregation, though these findings are likely driven by age. Broadly, our results suggest that impacts of sex may be important to evaluate when investigating network segregation differences across adulthood, though further work is needed to determine the unique role of menopause and sex hormones on the organization of functional brain networks within aging females.

Anodal cerebellar stimulation increases cortical activation: Evidence for cerebellar scaffolding of cortical processing.

While the cerebellum contributes to nonmotor task performance, the specific contributions of the structure remain unknown. One possibility is that the cerebellum allows for the offloading of cortical processing, providing support during task performance, using internal models. Here we used transcranial direct current stimulation to modulate cerebellar function and investigate the impact on cortical activation patterns. Participants (n = 74; 22.03 ± 3.44 years) received either cathodal, anodal, or sham stimulation over the right cerebellum before a functional magnetic resonance imaging scan during which they completed a sequence learning and a working memory task. We predicted that cathodal stimulation would improve, and anodal stimulation would hinder task performance and cortical activation. Behaviorally, anodal stimulation negatively impacted behavior during late-phase sequence learning. Functionally, we found that anodal cerebellar stimulation resulted in increased bilateral cortical activation, particularly in parietal and frontal regions known to be involved in cognitive processing. This suggests that if the cerebellum is not functioning optimally, there is a greater need for cortical resources.

Test-retest reliability of a finger-tapping fMRI task in a healthy population.

Measuring brain activity during functional MRI (fMRI) tasks is one of the main tools to identify brain biomarkers of disease or neural substrates associated with specific symptoms. However, identifying correct biomarkers relies on reliable measures. Recently, poor reliability was reported for task-based fMRI measures. The present study aimed to demonstrate the reliability of a finger-tapping fMRI task across two sessions in healthy participants. Thirty-one right-handed healthy participants aged 18-60 years took part in two MRI sessions 3 weeks apart during which we acquired finger-tapping task-fMRI. We examined the overlap of activations between sessions using Dice similarity coefficients, assessing their location and extent. Then, we compared amplitudes calculating intraclass correlation coefficients (ICCs) in three sets of regions of interest (ROIs) in the motor network: literature-based ROIs (10-mm-radius spheres centred on peaks of an activation likelihood estimation), anatomical ROIs (regions as defined in an atlas) and ROIs based on conjunction analyses (superthreshold voxels in both sessions). Finger tapping consistently activated expected regions, for example, left primary sensorimotor cortices, premotor area and right cerebellum. We found good-to-excellent overlap of activations for most contrasts (Dice coefficients: .54-.82). Across time, ICCs showed large variability in all ROI sets (.04-.91). However, ICCs in most ROIs indicated fair-to-good reliability (mean = .52). The least specific contrast consistently yielded the best reliability. Overall, the finger-tapping task showed good spatial overlap and fair reliability of amplitudes on group level. Although caution is warranted in interpreting correlations of activations with other variables, identification of activated regions in response to a task and their between-group comparisons are still valid and important modes of analysis in neuroimaging to find population tendencies and differences.

New Frontiers for the Understanding of Aging: The Power and Possibilities of Studying the Cerebellum.

Understanding behavior in aging has benefited greatly from cognitive neuroscience. Our foundational understanding of the brain in advanced age is based on what now amounts to several decades of work demonstrating differences in brain structure, network organization, and function. Earlier work in this field was focused primarily on the prefrontal cortex and hippocampus. More recent evidence has expanded our understanding of the aging brain to also implicate the cerebellum. Recent frameworks have suggested that the cerebellum may act as scaffolding for cortical function, and there is an emerging literature implicating the structure in Alzheimer's disease. At this juncture, there is evidence highlighting the potential importance of the cerebellum in advanced age, though the field of study is relatively nascent. Here, we provide an overview of key findings in the literature as it stands now and highlight several key future directions for study with respect to the cerebellum in aging.

Cerebellar correlates of social dysfunction among individuals at clinical high risk for psychosis.

Introduction: Social deficits are a significant feature among both individuals with psychosis and those at clinical high-risk (CHR) for developing psychosis. Critically, the psychosis risk syndrome emerges in adolescence and young adulthood, when social skill development is being fine-tuned. Yet, the underlying pathophysiology of social deficits in individuals at CHR for psychosis remains unclear. Literature suggests the cerebellum plays a critical role in social functioning. Cerebellar dysfunction in psychosis and CHR individuals is well-established, yet limited research has examined links between the cerebellum and social functioning deficits in this critical population. Method: In the current study, 68 individuals at CHR for developing psychosis and 66 healthy controls (HCs) completed social processing measures (examining social interaction, social cognition, and global social functioning) and resting-state MRI scans. Seed-to-voxel resting-state connectivity analyses were employed to examine the relationship between social deficits and lobular cerebellar network connectivity. Results: Analyses indicated that within the CHR group, each social domain variable was linked to reduced connectivity between social cerebellar subregions (e.g., Crus II, lobules VIIIa and VIIIb) and cortical regions (e.g., frontal pole and frontal gyrus), but a control cerebellar subregion (e.g., lobule X) and was unrelated to these social variables. Discussion: These results indicate an association between several cerebellar lobules and specific deficits in social processing. The cerebellum, therefore, may be particularly salient to the social domain and future research is need to examine the role of the cerebellum in psychosis.

Cerebellar and basal ganglia motor network predicts trait depression and hyperactivity.

In the human brain, the cerebellum (CB) and basal ganglia (BG) are implicated in cognition-, emotion-, and motor-related cortical processes and are highly interconnected, both to cortical regions via separate, trans-thalamic pathways and to each other via subcortical disynaptic pathways. We previously demonstrated a distinction between cognitive and motor CB-BG networks (CCBN, MCBN, respectively) as it relates to cortical network integration in healthy young adults, suggesting the subcortical networks separately support cortical networks. The CB and BG are also implicated in the pathophysiology of schizophrenia, Parkinson's, and compulsive behavior; thus, integration within subcortical CB-BG networks may be related to transdiagnostic symptomology. Here, we asked whether CCBN or MCBN integration predicted Achenbach Self-Report scores for anxiety, depression, intrusive thoughts, hyperactivity and inactivity, and cognitive performance in a community sample of young adults. We computed global efficiency for each CB-BG network and 7 canonical resting-state networks for all right-handed participants in the Human Connectome Project 1200 release with a complete set of preprocessed resting-state functional MRI data (N = 783). We used multivariate regression to control for substance abuse and age, and permutation testing with exchangeability blocks to control for family relationships. MCBN integration negatively predicted depression and hyperactivity, and positively predicted cortical network integration. CCBN integration predicted cortical network integration (except for the emotional network) and marginally predicted a positive relationship with hyperactivity, indicating a potential dichotomy between cognitive and motor CB-BG networks and hyperactivity. These results highlight the importance of CB-BG interactions as they relate to motivation and symptoms of depression.

Age-volume associations in cerebellar lobules by sex and reproductive stage.

The cerebellum has established associations with motor function and a well-recognized role in cognition. In advanced age, cognitive and motor impairments contribute to reduced quality of life and are more common. Regional cerebellar volume is associated with performance across these domains and sex hormones may influence this volume. Examining sex differences in regional cerebellar volume in conjunction with age, and in the context of reproductive stage stands to improve our understanding of cerebellar aging and pathology. Data from 508 healthy adults (ages 18-88; 47% female) from the Cambridge Centre for Ageing and Neuroscience database were used here. CERES was used to assess lobular volume in T1-weighted images. We examined sex differences in adjusted regional cerebellar volume while controlling for age. A subgroup of participants (n = 370, 50% female) was used to assess group differences in female reproductive stages as compared to age-matched males. Sex differences in adjusted volume were seen across most anterior and posterior cerebellar lobules. Most of these lobules had significant linear relationships with age in males and females. While there were no interactions between sex and reproductive stage groups, exploratory analyses in females alone revealed multiple regional differences by reproductive stage. We found sex differences in volume across much of the cerebellum, linear associations with age, and did not find an interaction for sex and reproductive stage on regional cerebellar volume. Longitudinal investigation into hormonal influences on cerebellar structure and function is warranted as hormonal changes with menopause may impact cerebellar volume over time.

The association of reproductive stage with lobular cerebellar network connectivity across female adulthood.

Sex-specific differences in the aging cerebellum may be related to hormone changes with menopause. We evaluated the association between reproductive stage and lobular cerebellar network connectivity using data from the Cambridge Centre for Ageing and Neuroscience repository. We used raw structural and resting state neuroimaging data and information regarding age, sex, and menopause-related variables. Crus I and II and Lobules V and VI were our cerebellar seeds of interest. We characterized reproductive stage using the Stages of Reproductive Aging Workshop criteria. Results show that postmenopausal females have lower cerebello-striatal and cerebello-cortical connectivity, particularly in frontal regions, along with lower connectivity within the cerebellum, compared to reproductive females. Postmenopausal females also exhibit greater connectivity in some brain areas as well. Differences begin to emerge across transitional stages of menopause. Further, results reveal sex-specific differences in connectivity between female reproductive groups and age-matched male control groups. This suggests that menopause may be associated with cerebellar network connectivity in aging females, and sex differences in the aging brain may be related to this biological process.