Biology subjects

Magalhaes, T. N. C.

Publications and source records attributed to Magalhaes, T. N. C..

7 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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗