Biology subjects

Bernard, J. A.

Publications and source records attributed to Bernard, J. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Cerebello-basal ganglia networks and behavior across adulthood and aging

The cerebellum contributes to aging, cognition, and reward related processing, but has been relatively understudied in these domains. The cerebello-basal ganglia (CB-BG) circuit may be key to better understanding how the brain ages. Prior work has implicated this circuit in aging in a small sample, though it is also of interest in age-related neurodegenerative disease, particularly Parkinson's Disease. Here, we investigated the CB-BG network, which has been implicated in modulation of cognitive, motor, and reward-related functions. In a sample of 138 participants between the ages of 35 and 86 we looked at network connectivity in cognitive and motor sub-circuits. Participants completed motor and cognitive testing batteries followed by 26 minutes of resting state functional connectivity magnetic resonance imaging (fcMRI). This data was analyzed using the CONN toolbox with an ROI-ROI approach targeting the CB-BG circuit. We replicated the previously mapped cognitive subcircuit and motor subcircuits. When examining connectivity by age group (early and late middle age and older adult hood), we found higher functional connectivity in early middle age compared to older adulthood, with no results related to late middle age. Analysis of connectivity as it relates to performance on the Stroop task showed higher connectivity-behavior associations in early middle-aged adults compared to older adults. We also explored sex differences and found higher functional connectivity in females compared to males. Analysis of steroid hormone levels revealed higher connectivity associated with progesterone in females relative to males. Together, we have replicated motor and cognitive CB-BG subcircuits and further demonstrated that this network has altered connectivity associated with age, sex, progesterone, and cognitive performance. This expanded investigation of CB-BG networks represents an essential new step in increasing our knowledge of age-related cognitive and motor declines and may be particularly relevant for consideration in Parkinson's Disease.

neuroscience↗

bioRxiv2026

Longitudinal Impacts of Sex-Steroid Hormones on Cerebellar Structure in Adulthood are Sex Differentiated

Sex-steroid hormones influence brain structure across aging, but their relationship to the cerebellum, a region implicated in cognition and vulnerable to age-related decline, remains poorly characterized, particularly longitudinally and across both sexes. We examined whether 17{beta}-estradiol, progesterone, and testosterone relate to cerebellar volume across two timepoints, and whether these relationships differ by sex. In a mixed-sex sample of aging adults (Baseline N = 137; Year 1 N = 93), free salivary hormones and cerebellar lobular volumes were quantified. Linear regression tested cross-sectional, predictive, and change-score hormone-volume associations, and formal hormone-by-sex interactions, in a priori primary and secondary cerebellar lobules of interest. Hormone-cerebellum relationships were consistently sex-differentiated. Estradiol change related to Crus I volume change in opposite directions in males and females, a dissociation extending across bilateral Crus I and Lobule VI, and Right Crus II. In females, greater increases in testosterone were associated with greater decline in Left Crus I and Right Lobule V volumes. In males, testosterone showed no significant associations in primary analyses, however, increases in estradiol were associated with larger volumes. Progesterone showed a male-specific cross-sectional association with Crus II. Several relationships ran opposite to the direction predicted by estradiols established neurotrophic role. Sex-steroid influences on the aging cerebellum are sex-differentiated, regionally specific, and may not be predicted exclusively by cortical or female-focused models. These findings establish the cerebellum as a potential site of sex-specific hormonal influence on brain aging and also further highlight the complexity of the impact of sex-steroid hormones on the aging brain.

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bioRxiv2025

Familial Risk for Dementia, Cognitive Performance, and the Human Cerebello-Hippocampal Circuit: A Study in the European Prevention of Alzheimers Disease cohort

The cerebello-hippocampal (CB-HP) circuit is increasingly implicated in episodic and spatial memory, yet its role in normal aging, dementia risk, and sex differences remains unclear. Structure and function in both the hippocampus and cerebellum have been linked to mild cognitive impairment, Alzheimers Disease, and cognitive decline in healthy older adults. Literature on the CB-HP circuit is largely limited to animal studies and small samples of young adults in the context of visuospatial abilities, underscoring the need for large, diverse aging cohorts to establish CB-HP connectivity as an early, translatable marker of neurodegeneration. Here, we investigate the CB-HP circuit in the context of aging, dementia risk, behavior, and sex differences in healthy older adults to advance understanding of cognitive decline in the aging population. We explored this relationship in 857 healthy adults with and without a family history of dementia (aged 50-88, 59% female, 71% family history positive) using resting-state functional connectivity MRI (rsMRI) and behavioral assessments. We hypothesized that CB-HP functional connectivity (FC) would be lower with increased age, relate positively to cognitive performance, be lower in females positive for family history of dementia, and be lower in mild cognitive impairment (MCI)-risk than cognitively normal (CN) participants with sex differences therein. We observed selective links between CB-HP FC, cognition, and sex. MCI risk participants performed worse on spatial memory performances than CN, whereas CB-HP FC showed opposite performance slopes by risk status, suggesting the CB-HP circuit may function as a compensatory network for short-term recall. Sex differences were seen on cognitive tasks (delayed episodic memory and spatial tasks) and in CB-HP a better visuospatial index was linked to greater FC in females, while males displayed an inverse relationship. Behavioral differences by familial dementia history were shown, although CB-HP FC did not show effects here. Overall, CB-HP networks appear behaviorally silent in the aggregate but reveal risk- and sex-dependent relationships when memory demands and circuit nodes are considered.

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bioRxiv2025

Mapping the Cerebello-Hippocampal Circuit: Normative Patterns and Sex-Dependent Connectivity

Cerebello-hippocampal (CB-HP) interactions have been implicated in spatial abilities and reinforcement learning, yet their relationship to behavior and differences in connectivity with sex in early adulthood are unclear. Resting CB-HP network patterns have yet to be established in young adults. Mapping the normative resting-state CB-HP connectivity pattern is essential for identifying when CB-HP circuitry becomes behaviorally relevant across the lifespan and for detecting early circuit-level deviations that may precede neurodegenerative or endocrine disruption. We combined resting-state functional MRI (rsfMRI) with measures of cognition in 1,081 healthy young adults (22-37 years, 54% women) from the Human Connectome Project S1200 to map CB-HP functional connectivity (FC), examine sex differences, and define its relationship with performance across episodic memory, visuospatial, and executive function tasks. Region of interest (ROI)-to-ROI FC between the right cerebellum and left hippocampus were quantified. In our CB-HP mapping, we found: 1) negative relationships between the entire HP axis and cerebellar regions: vermis VII; lobules VI, VIIb, and VIII; Crus I & II, and 2) positive relationships between most of the HP axis and ventral/medial cerebellar regions. We revealed sex differences in CB-HP such that females had greater FC than males between anterior to mid-hippocampal regions and medial cerebellar regions: vermis IV-VI; lobules VI, VIII, IX; and Crus II. We predicted CB-HP FC patterns would show strong positive associations with cognitive measures (i.e., episodic memory, visuospatial processing, working memory, and executive function); however, we did not find any associations after multiple comparisons correction (pFDR > 0.05). Together, our findings detail a functional atlas of the CB-HP circuit in young adulthood and highlight sex differences within. Our results provide a foundation for understanding functionally-based gradients between these two regions.

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bioRxiv2025

The Human Cerebello-Hippocampal Circuit Across Adulthood

Direct communication between the hippocampus and cerebellum has been shown via coactivation and synchronized neuronal oscillations in animal models. Further, this novel cerebello-hippocampal circuit may be impacted by sex steroid hormones. The cerebellum and hippocampus are dense with estradiol and progesterone receptors relative to other brain regions. Females experience up to a 90% decrease in ovarian estradiol production after the menopausal transition. Postmenopausal women show lower cerebello-cortical and intracerebellar FC compared to reproductive aged females. Sex hormones are established modulators of both memory function and synaptic organization in the hippocampus in non-human animal studies. However, investigation of the cerebello-hippocampal (CB-HP) circuit has been limited to animal studies and small homogeneous samples of young adults as it relates to spatial navigation. Here, we investigate the CB-HP circuit in 138 adult humans (53% female) from 35-86 years of age, to define its FC patterns, and investigate its associations with behavior, hormone levels, and sex differences therein. We established robust FC patterns between the CB and HP in this sample. We predicted and found negative relationships between age and CB-HP FC. As expected, estradiol levels exhibited positive relationships with CB-HP. We found lower CB-HP FC with higher levels of progesterone. We provide the first characterization of the CB-HP circuit across middle and older adulthood and demonstrate that connectivity is sensitive to sex steroid hormone levels. This work provides the first clear CB-HP circuit mapping in the human brain and serves as a foundation for future work in neurological and psychiatric diseases.

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bioRxiv2024

Connectivity between supplementary motor complex and primary motor cortex: a dual-coil paired-pulse TMS study

In recent years, dual-coil paired-pulse transcranial magnetic stimulation (ppTMS) has garnered interest for its potential in elucidating neural circuit dynamics. In this study, the dual-coil ppTMS was utilized to assess the effective connectivity between the supplementary motor complex (SMC) and the primary motor cortex (M1) in humans. A robust facilitatory connection between the SMC and M1 was observed, manifested as a 19% increase in mean peak-to-peak motor-evoked potentials following preconditioning of SMC 7 ms prior to M1 stimulation. Importantly, the facilitatory influence of SMC only occurred when the preconditioning stimulation was administered 4 cm anterior to Cz but not when applied at 5-cm, 6-cm, or 7-cm distance. While previous work has focused on demonstrating important temporal dynamics for SMC-M1 plasticity, the present findings highlight a critical contribution of spatial specificity for modulation of SMC-M1 circuitry. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/610643v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@12fb447org.highwire.dtl.DTLVardef@e4bfacorg.highwire.dtl.DTLVardef@1e3d262org.highwire.dtl.DTLVardef@93984_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe conditioned stimulus induced larger MEPs compared to the unconditioned stimulus C_LIO_LIThe connectivity between SMC and M1 diminished when the SMC coil was moved forward C_LIO_LIFindings highlight the importance of spatial specificity for modulation of SMC-M1 circuitry C_LI

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bioRxiv2024

Sex-steroid hormones relate to cerebellar structure and functional connectivity across adulthood

Aging involves complex biological changes that affect disease susceptibility and aging trajectories. Although females typically live longer than males, they have a higher susceptibility to diseases like Alzheimers, speculated to be influenced by menopause, and reduced ovarian hormone production. Understanding sex-specific differences is crucial for personalized medical interventions and gender equality in health. Our study aims to elucidate sex differences in regional cerebellar structure and connectivity during normal aging by investigating both structural and functional connectivity variations, with a focus on investigating these differences in the context of sex-steroid hormones. The study included 138 participants (mean age = 57(13.3) years, age range = 35-86 years, 54% women). The cohort was divided into three groups: 38 early middle-aged individuals (EMA) (mean age = 41(4.7) years), 48 late middle-aged individuals (LMA) (mean age = 58(4) years), and 42 older adults (OA) (mean age = 72(6.3) years). All participants underwent MRI scans, and saliva samples were collected for sex-steroid hormone quantification (17{beta}-estradiol (E), progesterone (P), and testosterone (T)). We found less connectivity in females between Lobule I-IV and the cuneus, and greater connectivity in females between Crus I, Crus II, and the precuneus with increased age. Higher 17{beta}-estradiol levels were linked to greater connectivity in Crus I and Crus II cerebellar subregions. Analyzing all participants together, testosterone was associated with both higher and lower connectivity in Lobule I-IV and Crus I, respectively, while higher progesterone levels were linked to lower connectivity in females. Structural differences were observed, with EMA males having larger volumes compared to LMA and OA groups, particularly in the right I-IV, right Crus I, right V, and right VI. EMA females showed higher volumes in the right lobules V and VI. These results highlight the significant role of sex hormones in modulating cerebellar connectivity and structure across adulthood, emphasizing the need to consider sex and hormonal status in neuroimaging studies to better understand age-related cognitive decline and neurological disorders.

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bioRxiv2024

Functional and Structural Cerebellar-Behavior Relationships in Aging

Healthy aging is associated with deficits in cognitive performance and brain changes, including in the cerebellum. Yet, the precise link between cerebellar function/structure and cognition in aging remains poorly understood. We explored this relationship in 138 healthy adults (aged 35-86, 53% female) using resting-state functional connectivity MRI (fcMRI), cerebellar volume, and cognitive and motor assessments in an aging sample. We expected to find negative relationships between lobular volume for with age, and positive relationships between specific lobular volumes with motor and cognition respectively. We predicted lower cerebellar fcMRI to cortical networks and circuits with increased age. Behaviorally, we expected higher cerebello-frontal fcMRI cerebellar connectivity with association areas to correlate with better behavioral performance. Behavioral tasks broadly assessed attention, processing speed, working memory, episodic memory, and motor abilities. Correlations were conducted between cerebellar lobules I-IV, V, Crus I, Crus II, vermis VI and behavioral measures. We found lower volumes with increased age as well as bidirectional cerebellar connectivity relationships with increased age, consistent with literature on functional connectivity and network segregation in aging. Further, we revealed unique associations for both cerebellar structure and connectivity with comprehensive behavioral measures in a healthy aging population. Our findings underscore cerebellar involvement in behavior during aging.

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bioRxiv2024

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.

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bioRxiv2024

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.

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bioRxiv2024

Functional Connectivity Differences in Distinct Dentato-Cortical Networks in Alzheimers Disease and Mild Cognitive Impairment

Recent research has implicated the cerebellum in Alzheimers disease (AD), and cerebro-cerebellar 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.

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bioRxiv2023

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.

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bioRxiv2022

Cerebello-Basal Ganglia Functional Network Integration in Psychosis

Psychotic disorders are conceptualized as brain-network diseases and both the cerebellum (CB) and basal ganglia (BG) are implicated in widely used conceptual models. Previous research has focused on these structures and their respective circuits as distinct, however, both are functionally and anatomically connected to each other and to cortical networks via domain-specific, topographically organized thalamo-cortical loops. Currently, it is unclear how CB-BG network dysfunction may play a mechanistic role in the course of psychosis; however, network global efficiency (GE), a measure of functional integration, is a novel approach that aims to represent cognitive and motor CB-BG network (CCBN, MCBN, respectively) connectivity in cross- sectional groups of healthy control (HC), clinical high-risk (CHR), early course psychosis (ECP), and chronic psychosis (CP) participants. We compared network GE between groups and inspected individual differences in CCBN- and MCBN-GE as it relates to group membership and to psychosis symptoms. We also associated CB-BG network GE with cortical network GE. Results indicated that CCBN-GE was associated with cognitive dysfunction and lower in CHR individuals, compared to HC and CP; while MCBN was associated with negative psychosis symptoms. Last, we detailed CB-BG associations with sensory, motor, default mode, and salience networks across groups, with group effects demonstrating complex differences within the ECP group. Findings indicating that CB-BG network dysfunction may play an important role in early pathogenesis and authors argue for CB-BG dysfunction to be analyzed from a network perspective. Future work is needed however to incorporate this approach into our understanding of psychosis.

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bioRxiv2022

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 17{beta}-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.

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bioRxiv2022

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 middle-aged and older 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 17{beta}-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. HighlightsO_LIHormone-sleep interactions influence resting-state cerebellar-frontal connectivity C_LIO_LICognitive and motor behavior are impacted by hormone-sleep relationships C_LIO_LISex hormones and sleep patterns may contribute to aging outcomes in females C_LI

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bioRxiv2022

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 tend to 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 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 are 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. Key PointsO_LISegregation of functional brain networks declines with increasing age C_LIO_LIAge-segregation relationships are modified by biological sex C_LIO_LIReproductive stage may impact sex differences in brain network organization C_LI

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bioRxiv2021

Age-Volume Associations in Cerebellar Regions by Sex and Reproductive Stage

IntroductionThe 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. MethodsData from 530 healthy adults (ages 18-88; 49% female) from the Cambridge Centre for Ageing and Neuroscience database were used here. CERES was utilized to assess lobular volume in T1-weighted images. We examined sex differences in adjusted regional cerebellar volume while controlling for age. A subgroup (n = 354, 50% female) was used to assess group differences in female reproductive stages as compared to age-matched males. ResultsSex differences in adjusted volume were seen across most anterior and posterior cerebellar lobules. The majority of cerebellar regions had significant linear relationships with age in males and females. However, there were no interactions between sex and reproductive stage groups (i.e., female reproductive stage did not display a relationship with regional cerebellar volume). DiscussionWe found sex differences in volume across much of the cerebellum, linear associations with age, and did not find an effect of female 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 structure over time.

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bioRxiv2021

Inhibitory Cerebellar Stimulation Increases Cortical Activation: Evidence for Cerebellar Scaffolding of Cortical Processing

While the cerebellum makes known contributions to non-motor task performance, the role of the structure remains unknown. One possibility is that the cerebellum allows for the offloading of cortical processing, providing support during task performance, using internal models. The current work used transcranial direct current stimulation to modulate cerebellar function and investigate the impact on cortical activation patterns. Participants received stimulation over the right cerebellum before a functional magnetic resonance imaging scan where participants 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. 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.

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