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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.

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 17β-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.HighlightsHormone-sleep interactions influence resting-state cerebellar-frontal connectivityCognitive and motor behavior are impacted by hormone-sleep relationshipsSex hormones and sleep patterns may contribute to aging outcomes in females

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 PointsSegregation of functional brain networks declines with increasing ageAge-segregation relationships are modified by biological sexReproductive stage may impact sex differences in brain network organization

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.

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.

Sex-specific differences in the aging cerebellum may be related to hormone changes with menopause. We evaluated the influence of reproductive stage on 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 influence cerebellar network connectivity in aging females, and sex differences in the aging brain may be related to this biological process.HighlightsLobular analysis of cerebellar network connectivity across reproductive stagesPostmenopausal females show lower cerebellar connectivity, compared to reproductiveConnectivity differences begin to emerge in transitional stages of menopauseAge-matched male control groups show distinct patterns of cerebellar connectivityReproductive stage influences cerebellar network connectivity in aging females

Cerebellar contributions to behavior in advanced age are of interest and importance, given its role in motor and cognitive performance. There are differences and declines in cerebellar structure in advanced age and cerebellar resting state connectivity is lower. However, the work on this area to date has focused on the cerebellar cortex. The deep cerebellar nuclei provide the primary cerebellar inputs and outputs to the cortex, as well as the spinal and vestibular systems. Dentate networks can be dissociated such that the dorsal region is associated with the motor cortex, whereas the ventral aspect is associated with the prefrontal cortex. However, whether dentato-thalamo-cortical networks differ across adulthood remains unknown. Here, using a large adult sample (n = 590) from the Cambridge Center for Ageing and Neuroscience, we investigated dentate connectivity across adulthood. We replicated past work showing dissociable resting state networks in the dorsal and ventral aspects of the dentate. In both seeds, we demonstrated that connectivity is lower with advanced age, indicating that connectivity differences extend beyond the cerebellar cortex. Finally, we demonstrated sex differences in dentate connectivity. This expands our understanding of cerebellar circuitry in advanced age and underscores the potential importance of this structure in age-related performance differences.

The cerebellum has an increasingly recognized role in higher order cognition. Advancements in noninvasive neuromodulation techniques allows one to focally create functional alterations in the cerebellum to investigate its role in cognitive functions. To this point, work in this area has been mixed, in part due to varying methodologies for stimulation, and it is unclear whether or not transcranial direct current stimulation (tDCS) effects on the cerebellum are task or load dependent. Here, we employed a between-subjects design using a high definition tDCS system to apply anodal, cathodal, or sham stimulation to the cerebellum or prefrontal cortex (PFC) to examine the role the cerebellum plays in verbal working memory, inhibition, motor learning, and balance performance, and how this interaction might interact with the cortex (i.e. PFC). We predicted performance decrements following anodal stimulation and performance increases following cathodal stimulation, compared to sham. Broadly, our work provides evidence for cerebellar contributions to cognitive processing, particularly in verbal working memory and sequence learning. Additionally, we found the effect of stimulation might be load specific, particularly when applied to the cerebellum. Critically, anodal simulation negatively impacted performance during effortful processing, but was helpful during less effortful processing. Cathodal stimulation hindered task performance, regardless of simulation region. The current results suggest an effect of stimulation on cognition, perhaps suggesting that the cerebellum is more critical when processing is less effortful but becomes less involved under higher load when processing is more prefrontally-dependent.

BackgroundThe ability to flexibly apply rules to novel situations is a critical aspect of adaptive human behavior. While executive function deficits are known to appear early in the course of psychosis, it is unclear which specific facets are affected. Identifying whether rule learning is impacted at the early stages of psychosis is necessary for truly understanding the etiology of psychosis and may be critical for designing novel treatments. Therefore, we examined rule learning in healthy adolescents and those meeting criteria for clinical high risk (CHR) for psychosis.Methods24 control and 22 CHR adolescents underwent rapid, high-resolution fMRI while performing a paradigm which required them to apply novel or practiced task rules.ResultsPrevious work has suggested that practiced rules rely on rostrolateral prefrontal cortex (RLPFC) during rule encoding and dorsolateral prefrontal cortex (DLPFC) during task performance, while novel rules show the opposite pattern. We failed to replicate this finding, with greater activity for novel rules during performance. Comparing the HC and CHR group, there were no statistically significant effects, but an effect size analysis found that the CHR group showed less activation during encoding and greater activation during performance. This suggests the CHR group may use less efficient reactive control to retrieve task rules at the time of task performance, rather than proactively during rule encoding.ConclusionsThese findings suggest that flexibility may be altered in the clinical high risk state, however, more data is needed to determine whether these deficits predict disease progression.

Though we have a general understanding of the brain areas involved in motor sequence learning, there is more to discover about the neural mechanisms behind which a new skill is learned. Initial skill acquisition may be subserved, in part, by interactions between the cerebellum (CBLM) and prefrontal cortex (PFC) through a cerebello-thalamo-prefrontal network. We investigated the consequence of stimulating the PFC using high-definition transcranial direct current stimulation (HD-tDCS) before administering an explicit motor sequence learning paradigm. Using a mixed within- and between- subjects design, we employed anodal (n = 24) and cathodal (n = 25) tDCS (relative to sham) to temporarily alter brain function and examine the effects on skill acquisition. In order to gain a comprehensive perspective on the role of this network in sequence learning, we compared the current findings to our recent research investigating the CBLM using the same experimental design. The PFC results indicate that anodal stimulation negatively impacts explicit motor sequence learning, relative to sham, while the effects of cathodal stimulation are minimal, though indicative of either a stabilizing or facilitatory influence. This is consistent with past CBLM results. Our findings, therefore, suggest polarity-specific effects of tDCS on the acquisition of a sequential pattern of finger movements, both when applied to the PFC and CBLM. Collectively, this supports the involvement of a cerebello-thalamo-prefrontal network in initial skill acquisition when cognitive processes, such as working memory, are utilized. Exploring methods that may improve motor learning is important in developing therapeutic strategies for motor-related diseases and rehabilitation.

Cognitive neuroscience research has provided foundational insights into aging, but has focused primarily on the cerebral cortex. However, the cerebellum is subject to the effects of aging. Given the importance of this structure in the performance of motor and cognitive tasks, cerebellar differences stand to provide critical insights into age differences in behavior. But, our understanding of cerebellar functional activation in aging is limited. Thus, we completed a meta-analysis of neuroimaging studies across task domains. Unlike in the cortex where an increase in bilateral activation is seen during cognitive task performance with advanced age, there is less overlap in cerebellar activation across tasks in older adults relative to young. Conversely, we see an increase in activation overlap in older adults during motor tasks. We propose that this is due to inputs for comparator processing in the context of control theory (cortical and spinal) that may be differentially impacted in aging. These findings advance our understanding of the aging mind and brain.

Though the cerebellum has been previously implicated in explicit sequence learning, the exact role of this structure in the acquisition of motor skills is not completely clear. The cerebellum contributes to both motor and non-motor behavior. Thus, this structure may contribute not only to the motoric aspects of sequence learning, but may also play a role in the cognitive components of these learning paradigms. Therefore, we investigated the consequence of both disrupting and facilitating cerebellar function using high definition transcranial direct current stimulation (HD-tDCS) prior to the completion of an explicit motor sequence learning paradigm. Using a mixed within- and between-subjects design, we employed cathodal (n=21) and anodal (n=23) tDCS (relative to sham), targeting the lateral posterior cerebellum, to temporarily modulate function and investigate the resulting effects on the acquisition of a sequential pattern of finger movements. Results indicate that cathodal stimulation has a positive influence on learning while anodal stimulation has the opposite effect, relative to sham. Though the cerebellum is presumed to be primarily involved in motor function and movement coordination, our results support a cognitive contribution that may come into play during the initial stages of learning. Using tDCS targeting the right posterior cerebellum, which communicates with the prefrontal cortex via closed-loop circuits, we found polarity-specific effects of cathodal and anodal stimulation on sequence learning. Thus, our results substantiate the role of the cerebellum in the cognitive aspect of motor learning and provide important new insights into the polarity-specific effects of tDCS in this area.New & NoteworthyThe cerebellum contributes to motor and cognitive processes. Investigating the cognitive contributions of the cerebellum in explicit sequence learning stands to provide new insights into this learning domain, and cerebellar function more generally. Using HD-tDCS, we demonstrated polarity-specific effects of stimulation on explicit sequence learning. We speculate that this is due to facilitation of working memory processes. This provides new evidence supporting a role for the cerebellum in the cognitive aspects of sequence learning.

To date, investigations of executive function (EF) have focused on the prefrontal cortex (PFC), and prominent theories of EF are framed with respect to this brain region. Multiple theories describe a hierarchical functional organization for the lateral PFC. However, recent evidence has indicated that the cerebellum (CB) also plays a role in EF. Posterior CB regions (Crus I & II) show structural and functional connections with the PFC, and CB networks are associated with individual differences in EF in healthy adults. However, it is unclear whether the cerebellum shows a similar functional gradient as does the PFC. Here, we investigated high-resolution resting-state data from 225 participants in the Human Connectome Project. We compared resting-state connectivity from posterior cerebellar ROIs, and examined functional data from several tasks that activate the lateral PFC. Demonstrating preliminary evidence for parallel PFC and CB gradients, Crus I was functionally connected with rostrolateral PFC, Crus II with middle and ventral PFC, and Lobule VI with posterior PFC. Contrary to previous work, the activation of the task thought to activate rostrolateral PFC resembled the connectivity maps of Crus II, not Crus I; similarly, the activation of the task thought to activate middle PFC resembled the connectivity maps of Crus I, not Crus II. Nevertheless, there was evidence for dissociable CB-PFC networks. Further work is necessary to understand the functional role of these networks.

Resting state functional magnetic resonance imaging (rs-fMRI) has indicated disruptions in functional connectivity in older (OA) relative to young adults (YA). While age differences in cortical networks are well studied, differences in subcortical networks are poorly understood. Both the cerebellum and the basal ganglia are of particular interest given their role in cognitive and motor functions, and work in non-human primates has demonstrated direct reciprocal connections between these regions. Here, our goal was twofold. First, we were interested in delineating connectivity patterns between distinct regions of the cerebellum and basal ganglia, known to have topologically distinct connectivity patterns with cortex. Our second goal was to quantify age-differences in these cerebellar-striatal circuits. We performed a targeted rs-fMRI analysis of the cerebellum and basal ganglia in 33 YA and 31 OA individuals. In the YA, we found significant connectivity both within and between the cerebellum and basal ganglia, in patterns supporting semi-discrete circuits that may differentially subserve motor and cognitive performance. We found a shift in connectivity, from one of synchrony in YA, to asynchrony in OA, resulting in substantial age differences. Connectivity was also associated with behavior. These findings significantly advance our understanding of cerebellar-basal ganglia interactions in the human brain.