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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.

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

IntroductionSocial 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.MethodIn 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.ResultsAnalyses 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.DiscussionThese 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.

The cerebellum has an increasingly recognized role in higher order cognition. Advancements in noninvasive neuromodulation techniques allow 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 with 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 stimulation 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.

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 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 MN segregation. These findings highlight the CB-BG network’s role in 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 deciphering subcortical differences seen in disease states.

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.

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 (BostanStrick, 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.

The desire to obtain social rewards (e.g. positive feedback) features prominently in our lives and relationships, and is relevant to understanding psychopathology – where behavior is often impaired. Investigating social rewards within the psychosis-spectrum offers an especially useful opportunity, given the high rates of impaired social functioning and social isolation. The goal of this study was to investigate hedonic experience associated with social reward processing as a potential biomarker for psychosis risk. This study used a task-based functional magnetic resonance imaging (fMRI) paradigm in adolescents at clinical high-risk for the development of psychosis (CHR, n = 19) and healthy unaffected peers (healthy controls – HC, n = 20). Regional activation and connectivity of the ventromedial prefrontal cortex and ventral striatum were examined in response to receiving positive social feedback relative to an ambiguous feedback condition. Expectations of impaired hedonic processes in CHR youth were generally not supported, as there were no group differences in neural response or task-based connectivity. Although interesting relationships were found linking neural reward response and connectivity with social, anticipatory, and consummatory anhedonia in the CHR group, results are difficult to interpret in light of task limitations. We discuss potential implications for future study designs that seek to investigate social reward processing as a biomarker for psychosis risk.

Background: The cognitive dysmetria theory of schizophrenia proposes that communication between the cerebellum and cerebral cortex is disrupted by structural and functional abnormalities, resulting in psychotic symptoms and cognitive deficits. Methods: Using publicly available data, resting-state functional connectivity (rsFC) was calculated from 20 hemispheric cerebellar lobules as seed regions of interest to the rest of the brain. Group differences in rsFC between individuals with schizophrenia (SZ) and healthy controls (HCs) were computed, and relationships between rsFC and symptom severity and cognitive functioning were explored. Results: HCs demonstrated stronger connectivity than SZ between several cerebellar lobules and cortical regions, most robustly between motor-related cerebellar lobules (V and VIIIa/b) and temporal and parietal cortices. In addition, seven of nine lobules in which reduced cerebellocortical connectivity was observed showed diagnosis × processing speed interactions; HC showed a positive relationship between connectivity and processing speed, whereas SZ did not show this relationship. Other cognitive domains and symptom severity did not show relationships with connectivity. Conclusions: These findings partially support the cognitive dysmetria theory, and suggest that disrupted cerebellocortical connectivity is associated with slowed processing speed in schizophrenia. IMPACT STATEMENT: We show in this work that in chronic schizophrenia, there is weaker functional connectivity between previously unstudied inferior posterior cerebellar lobules and cortical association areas. These findings align and extend previous work showing abnormal connectivity of anterior cerebellar lobules. Further, we present a novel finding that these connectivity deficits are differentially associated with processing speed in the schizophrenia versus healthy control groups. Findings provide further evidence for cerebellocortical dysconnectivity and processing speed deficits as biomarkers of schizophrenia, which may have implications for downstream effects on higher order cognitive functions, in line with the cognitive dysmetria theory.

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. However, 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 (OAs) relative to young. Conversely, we see an increase in activation overlap in OAs 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., Using activation likelihood estimation meta‐analysis, this work investigated age differences in cerebellar activation patterns in young and older adults. Unlike in the cortex where more bilateral activation is seen across task domains, in the cerebellum we found less convergence across cognitive tasks in older adults compared to young, but for motor tasks convergence in older adults was more extensive. 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

Motor dysfunction in youth at clinical high risk (CHR) for psychosis is thought to reflect abnormal neurodevelopment within cortical-subcortical motor circuits and may be important for understanding clinical trajectories of CHR individuals. However, to date, our perspective of brain-behavior relationships has been informed solely by cross-sectional correlational studies linking behavior in the lab to brain structure or respective resting-state network connectivity. Here, we assess movement dysfunction from 2 perspectives: study 1 investigates the longitudinal progression of handwriting variability and positive symptoms in a sample of 91 CHR and healthy controls during a 12-month follow-up and study 2 involves a multiband functional magnetic resonance imaging task exploring the relationship between power grip force stability and motor network brain activation in a subset of participants. In study 1, we found that greater handwriting variability was a stable feature of CHR participants who experienced worse symptom progression. Study 2 results showed that CHR individuals had greater variability in their grip force and greater variability was related to decreased activation in the associative cortico-striatal network compared to controls. Motor variability may be a stable marker of vulnerability for psychosis risk and possible indicator of a vulnerable cortico-striatal brain network functioning in CHR participants, although the effects of antipsychotic medication should be considered.

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

With the rapidly growing population of older adults, an improved understanding of brain and cognitive aging is critical, given the impacts on health, independence, and quality of life. To this point, we have a well-developed literature on the cortical contributions to cognition in advanced age. However, while this work has been foundational for our understanding of brain and behavior in older adults, subcortical contributions, particularly those from the cerebellum, have not been integrated into these models and frameworks. Incorporating the cerebellum into models of cognitive aging is an important step for moving the field forward. There has also been recent interest in this structure in Alzheimer's dementia, indicating that such work may be beneficial to our understanding of neurodegenerative disease. Here, I provide an updated overview of the cerebellum in advanced age and propose that it serves as a critical source of scaffolding or reserve for cortical function. Age-related impacts on cerebellar function further impact cortical processing, perhaps resulting in many of the activation patterns commonly seen in aging.

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

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.

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 nonmotor behavior. Thus, this structure not only may contribute 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 (tDCS) before 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 & NOTEWORTHY The 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 high-definition transcranial direct current stimulation, 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.

Background Gyrification features reflect brain development in the early prenatal environment. Clarifying the nature of these features in psychosis can help shed light on the role of early developmental insult. However, the literature is currently widely discrepant, which may reflect confounds related to formally psychotic patient populations or overreliance on a single feature of cortical surface morphometry (CSM). Methods This study compares CSM features of gyrification in clinical high-risk (n = 43) youths during the prodromal risk period to typically developing control subjects over two time points across three metrics: local gyrification index, mean curvature index, and sulcal depth (improving resolution and examination of change over 1 year). Results Gyrification was stable over time, supporting the idea that gyrification reflects early insult rather than abnormal development or reorganization associated with the disease state. Each of the indices highlighted unique, aberrant features in the clinical high-risk group with respect to control subjects. Specifically, the local gyrification index reflected hypogyrification in the lateral orbitofrontal cortex, superior bank of the superior temporal sulcus, anterior isthmus of the cingulate gyrus, and temporal poles; the mean curvature index indicated sharper gyral and flatter or wider sulcal peaks in the cingulate, postcentral, and lingual gyrus; sulcal depth identified shallow features in the parietal, superior temporal sulcus, and cingulate regions. Further, both the mean curvature index and sulcal depth converged on abnormal features in the parietal cortex. Conclusions Gyrification metrics suggest early developmental insult and provide support for neurodevelopmental hypotheses. Observations of stable CSM features across time provide context for interpreting extant studies and speak to CSM as a promising stable marker and/or endophenotype. Collectively, findings support the importance of considering multiple CSM features.

During voluntary task selection there are a number of internal and external biases that may guide such a choice. However, it is not well understood how reward influences task selection when multiple options are possible. To address this issue, we examined brain activation in a voluntary task-switching paradigm while participants underwent fMRI (n=19). To reinforce the overall goal to choose the tasks randomly, participants were told of a large bonus they would receive at the end of the experiment for making random task choices. We also examined how occasional, random rewards influenced both task performance and brain activation. We hypothesized that these transient rewards would increase the value of the just-performed task and therefore bias participants to choose to repeat the same task on the subsequent trial. Contrary to expectations, transient reward had no consistent behavioral effect on subsequent task choice. Nevertheless, the receipt of such rewards did influence activation in brain regions associated with reward processing as well as those associated with goal-directed control. In addition, reward on a prior trial was found to influence activation during task choice on a subsequent trial, with greater activation in a number of executive function regions as compared to no-reward trials. We posit that both the random presentation of transient rewards and the overall task bonus for random task choices together reinforced the goal to choose the tasks randomly, which in turn influenced activation in both reward-related regions and those regions involved in abstract goal processing.

Proinflammatory macrophages are essential drivers of colitis and express the growth factor receptor ErbB4. This study tested the role of ErbB4 and its specific ligand, NRG4, in regulating macrophage function. We show that endogenous NRG4-ErbB4 signaling limits macrophage production of proinflammatory cytokines in vitro and limits colitis severity in vivo and thus is a potential target for therapeutic intervention.

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.

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3β inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2F/F mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease., Dynamic regulation of colonic secretory cell numbers is a critical component of the response to intestinal injury and inflammation. Here, the authors show that loss of the intracellular signalling regulator Sprouty2 in the intestinal epithelial cells is a protective response to injury that leads to increased secretory cell numbers, thus limiting colitis severity.

The cerebellum has an increasingly recognized role in higher order cognition. Advancements in noninvasive neuromodulation techniques allow 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 with 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 stimulation 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.

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.

Though we have a general understanding of the brain areas involved in motor sequence learning, there is more to discover about the neural mechanisms underlying skill acquisition. Skill acquisition may be subserved, in part, by interactions between the cerebellum and prefrontal cortex through a cerebello-thalamo-prefrontal network. In prior work, we investigated this network by targeting the cerebellum; here, we explored the consequence of stimulating the dorsolateral prefrontal cortex 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) HD-tDCS (relative to sham) to temporarily alter brain function and examine effects on skill acquisition. The results indicate that both anodal and cathodal prefrontal stimulation impedes motor sequence learning, relative to sham. These findings suggest an overall negative influence of active prefrontal stimulation on the acquisition of a sequential pattern of finger movements. Collectively, this provides novel insight on the role of the dorsolateral prefrontal cortex in initial skill acquisition, when cognitive processes such as working memory are used. Exploring methods that may improve motor learning is important in developing therapeutic strategies for motor-related diseases and rehabilitation.