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The ability to manipulate dopamine in vivo through non-invasive, reversible mechanisms has the potential to impact clinical, translational, and basic research. Recent PET studies have demonstrated increased dopamine release in the striatum after bifrontal transcranial direct current stimulation (tDCS). We sought to extend this work by examining whether bifrontal tDCS could demonstrate an effect on behavioral and physiological correlates of subcortical dopamine activity. We conducted a preliminary between-subjects study (n = 30) with active and sham tDCS and used spontaneous eye blink rate (EBR), facial attractiveness ratings, and greyscales orienting bias as indirect proxies for dopamine functioning. The initial design and analyses were pre-registered (https://osf.io/gmnpc). Stimulation did not significantly affect any of the three measures, though effect sizes were often moderately large and were all in the predicted directions. Additional exploratory analyses suggested that stimulation's effect on EBR might depend on pre-stimulation dopamine levels. Our results suggest that larger samples than those that are standard in tDCS literature should be used to assess the effect of tDCS on dopamine using indirect measures. Further, exploratory results add to a growing body of work demonstrating the importance of accounting for individual differences in tDCS response.

To date most aging research has focused on cortical systems and networks, ignoring the cerebellum which has been implicated in both cognitive and motor function. Critically, older adults (OA) show marked differences in cerebellar volume and functional networks, suggesting it may play a key role in the behavioral differences observed in advanced age. OA may be less able to recruit cerebellar resources due to network and structural differences. Here, 26 young adults (YA) and 25 OA performed a second-order learning task, known to activate the cerebellum in the fMRI environment. Behavioral results indicated that YA performed significantly better and learned more quickly compared to OA. Functional imaging detailed robust parietal and cerebellar activity during learning (compared to control) blocks within each group. OA showed increased activity (relative to YA) in the left inferior parietal lobe in response to instruction cues during learning (compared to control); whereas, YA showed increased activity (relative to OA) in the left anterior cingulate to feedback cues during learning, potentially explaining age-related performance differences. Visual interpretation of effect size maps showed more bilateral posterior cerebellar activation in OA compared to YA during learning blocks, but early learning showed widespread cerebellar activation in YA compared to OA. There were qualitatively large age-related differences in cerebellar recruitment in terms of effect sizes, yet no statistical difference. These findings serve to further elucidate age-related differences and similarities in cerebellar and cortical brain function and implicate the cerebellum and its networks as regions of interest in aging research.

BackgroundConsistent with pathophysiological models of psychosis, temporal disturbances in schizophrenia spectrum populations may reflect abnormal cortical (e.g. prefrontal cortex) and subcortical (e.g. striatum) cerebellar connectivity. However, few studies have examined associations between cerebellar connectivity and timing dysfunction in psychosis populations, and none have been conducted in youth at clinical high-risk (CHR) for psychosis. Thus, it is currently unknown if impairments in temporal processes are present in CHR youth or how they may be associated with cerebellar connectivity and worsening of symptoms.MethodsA total of 108 (56 CHR/52 controls) youth were administered an auditory temporal bisection task along with a resting state imaging scan to examine cerebellar resting state connectivity. Positive and negative symptoms at baseline and 12 months later were also quantified.ResultsControlling for alcohol and cannabis use, CHR youth exhibited poorer temporal accuracy compared to controls, and temporal accuracy deficits were associated with abnormal connectivity between the bilateral anterior cerebellum and a right caudate/nucleus accumbens striatal cluster. Poor temporal accuracy accounted for 11% of the variance in worsening of negative symptoms over 12 months.ConclusionsBehavioral findings suggest CHR youth perceive durations of auditory tones as shortened compared to objective time, which may indicate a slower internal clock. Poorer temporal accuracy in CHR youth was associated with abnormalities in brain regions involved in an important cerebellar network implicated in prominent pathophysiological models of psychosis. Lastly, temporal accuracy was associated with worsening of negative symptoms across 12 months, suggesting temporal dysfunction may be sensitive to illness progression.

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.

Highlights • Novel investigation of novel rule learning in psychosis risk. • Failed to replicate previous study comparing novel and practiced rule learning. • No significant group differences, but effect size comparison revealed differences. • Results suggest that psychosis risk group may rely on different rule retrieval strategies., Background The 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. Methods 24 control and 22 CHR adolescents underwent rapid, high-resolution fMRI while performing a paradigm which required them to apply novel or practiced task rules. Results Previous 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. Conclusions These findings suggest that flexibility is qualitatively altered in the clinical high risk state, however, more data is needed to determine whether these deficits predict disease progression.

Abnormal development of parallel cortical-striatal networks may contribute to abnormal motor, cognitive, and affective behavior prior to the onset of psychosis. Partitioning individuals at clinical high risk (CHR) using motor behavior may provide a novel perspective on different etiological pathways or patient subtypes. A k-means cluster analysis was conducted in CHR ( N = 69; 42% female, mean age = 18.67 years) young adults using theoretically distinct measures of motor behavior. The resulting subtypes were then compared on positive and negative symptoms at baseline, and 2-year risk of psychosis conversion. CHR participants were followed for 2 years to determine conversion to psychosis. CHR subtypes and healthy controls ( n = 61; 57% female, mean age = 18.58 years) were compared on multiple cognitive domains and cortical-striatal connectivity. Results suggest 3 vulnerability subtypes of CHR individuals with different profiles of motor performance, symptoms, risk for conversion to psychosis, cognition, and thalamocortical connectivity. This approach may reflect a novel strategy for promoting tailored risk assessment as well as future research developing individualized medicine.

The cerebello-thalamo-cortical circuit (CTCC) has been implicated in schizophrenia. However, this work has been limited to structural and functional networks, or behavior, and to date, has not been evaluated in clinical high-risk (CHR) youth, a group at elevated risk for psychosis. Here, we used an innovative learning paradigm known to activate the CTCC (while limiting potential motor confounds) to evaluate CHR and healthy control individuals during functional magnetic resonance imaging (fMRI). 20 CHR and 21 healthy control individuals performed a second-order rule learning task while undergoing fMRI. This was preceded and followed by the paradigm under dual-task conditions. In addition, all participants underwent structured clinical interviews to confirm a prodromal syndrome and assess symptom severity. The rate of learning did not differ between groups. However, the CHR group consistently performed more poorly under dual-task conditions, and exhibited a higher dual-task cost after learning. Further, learning rate in the CHR group was significantly associated with symptom severity. Both groups showed activation in regions of the CTCC. During early learning, the CHR group exhibited greater engagement of regions of the default mode network, suggesting that they were less able to engage the appropriate task positive networks. During late learning, there were qualitative differences wherein controls showed more prefrontal cortical activation. Higher order cognitive rule learning is related to symptom severity in CHR individuals. fMRI revealed that CHR individuals may not reliably disengage the default mode network, and during late learning high-risk youth may not engage the prefrontal cortex as extensively as controls., Highlights • There are few fMRI studies in youth at clinical high-risk (CHR) of psychosis. • This is the first task-based fMRI study of the cerebellum in a CHR population. • CHR learn at a similar rate, but not as well, as healthy controls. • Learning rate is related to disorganized symptom severity in the CHR group. • The groups engage cerebello-thalamo-cortical circuits differently during learning.

Signs of motor dysfunction are evidenced across a range of psychiatric disorders including schizophrenia. Historically, these features have been neglected but emerging theoretical and methodological advancements have shed new light on the utility of considering movement abnormalities. Indeed, the National Institute of Mental Health Research Domain Criteria initiative has recently met to develop a Motor Systems Domain. This reflects a growing appreciation for the enhanced reliability and validity that can come along with evaluating disturbances relevant to psychiatric illnesses from multiple levels of analysis, and conceptualizing these domains with respect to the complexity of their role in a broader integrated system (ie, weighing contributions and interactions between the cognitive, affective, and motor domains). This article discusses motor behaviors and seeks to explain how research into basal ganglia, cerebellar, and cortico-motor circuit function/dysfunction, grounded in brain circuit-motor behavior relationships, can elucidate our understanding of pathophysiology, provide vital links to other key systems of interest, significantly improve identification and classification, and drive development of targeted individualized treatments.

Though schizophrenia (SCZ) is classically defined based on positive symptoms and the negative symptoms of the disease prove to be debilitating for many patients, motor deficits are often present as well. A growing literature highlights the importance of motor systems and networks in the disease, and it may be the case that dysfunction in motor networks relates to the pathophysiology and etiology of SCZ. To test this and build upon recent work in SCZ and in at-risk populations, we investigated cortical and cerebellar motor functional networks at rest in SCZ and controls using publically available data. We analyzed data from 82 patients and 88 controls. We found key group differences in resting-state connectivity patterns that highlight dysfunction in motor circuits and also implicate the thalamus. Furthermore, we demonstrated that in SCZ, these resting-state networks are related to both positive and negative symptom severity. Though the ventral prefrontal cortex and corticostriatal pathways more broadly have been implicated in negative symptom severity, here we extend these findings to include motor-striatal connections, as increased connectivity between the primary motor cortex and basal ganglia was associated with more severe negative symptoms. Together, these findings implicate motor networks in the symptomatology of psychosis, and we speculate that these networks may be contributing to the etiology of the disease. Overt motor deficits in SCZ may signal underlying network dysfunction that contributes to the overall disease state. Hum Brain Mapp 38:4535-4545, 2017. © 2017 Wiley Periodicals, Inc.

Resumen Objetivo Evaluar los resultados obtenidos en la realizacion de cirugia conservadora del cancer de mama mediante el uso de malla reabsorbible de poliglactina 910. Pacientes y metodo Estudio prospectivo de serie de casos de pacientes intervenidas de cirugia conservadora de cancer de mama utilizando malla de poliglactina 910 en aquellas en las que la amplitud de la reseccion hacia prever un resultado estetico desfavorable. El estudio se llevo a cabo en un hospital de tercer nivel en el periodo 2010-2015. Resultados Se intervino mediante esta tecnica un total de 46 mujeres, con una media de edad de 57 anos. Dos pacientes (4,3%) presentaron morbilidad postoperatoria por infeccion del sitio quirurgico, requiriendo extraccion de la malla en una de ellas y resolviendose con antibioticoterapia intravenosa el otro caso. En 3 casos (6,5%) se indico mastectomia por contacto de bordes en estudio anatomopatologico diferido. No se apreciaron dificultades en el seguimiento radiologico, ni recidivas radiologicas en el parenquima mamario, aunque si se detecto una recidiva cutanea a nivel de la cicatriz de la tumorectomia. El resultado estetico obtenido fue favorable en la valoracion de las pacientes. Conclusiones La reconstruccion mediante malla de Vicryl™ en casos seleccionados se presenta como una tecnica facil, resolutiva, rapida y con buenos resultados valorados por el medico y el paciente.

Prospective longitudinal evaluation of adolescents at ultra-high-risk (UHR) for the development of psychosis enables an enriched neurodevelopmental perspective of disease progression in the absence of many of the factors that typically confound research with formally psychotic patients (antipsychotic medications, drug/alcohol dependence). The cerebellum has been linked to cognitive dysfunction and symptom severity in schizophrenia and recent work from our team suggests that it is a promising target for investigation in UHR individuals as well. However, the cerebellum and cerebello-thalamo-cortical networks have not been investigated developmentally or with respect to disease progression in this critical population. Further, to date, the types of longitudinal multimodal connectivity studies that would substantially inform our understanding of this area have not yet been conducted. In the present investigation 26 UHR and 24 healthy control adolescents were administered structured clinical interviews and scanned at baseline and then again at 12-month time points to investigate both functional and structural connectivity development of cerebello-thalamo-cortical networks in conjunction with symptom progression. Our results provide evidence of abnormal functional and structural cerebellar network development in the UHR group. Crucially, we also found that cerebello-thalamo-cortical network development and connectivity at baseline are associated with positive symptom course, suggesting that cerebellar networks may be a biomarker of disease progression. Together, these findings provide support for neurodevelopmental models of psychotic disorders and suggest that the cerebellum and respective networks with the cortex may be especially important for elucidating the pathophysiology of psychosis and highlighting novel treatment targets., Highlights • The cerebellum is an important target of research across the psychosis spectrum. • Cerebellar networks were investigated over 12 months in youth at-risk for psychosis. • Network development differs from controls in the at-risk group. • Cerebello-cortical network connectivity predicts worsening positive symptoms. • Supports neurodevelopmental models of psychosis and implicates the cerebellum.

The diverse circuits and functional contributions of the basal ganglia, coupled with known differences in dopaminergic function in patients with schizophrenia, suggest they may be an important contributor to the etiology of the hallmark symptoms and cognitive dysfunction experienced by these patients. Using activation-likelihood-estimation meta-analysis of functional imaging research, we investigated differences in activation patterns in the basal ganglia in patients with schizophrenia, relative to healthy controls across task domains. This analysis included 42 functional neuroimaging studies, representing a variety of behavioral domains that have been linked to basal ganglia function in prior work. We provide important new information about the functional activation patterns and functional topography of the basal ganglia for different task domains in healthy controls. Crucially however, we demonstrate that across task domains, patients with schizophrenia show markedly decreased activation in the basal ganglia relative to healthy controls. Our results provide further support for basal ganglia dysfunction in patients with schizophrenia, and the broad dysfunction across task domains may contribute to the symptoms and cognitive deficits associated with schizophrenia., Highlights • The basal ganglia are connected to the cortex through multiple parallel circuits. • Basal ganglia function has been implicated in patients with schizophrenia. • Meta-analysis demonstrated a functional activation topography in the basal ganglia. • Patients with schizophrenia show a decrease in basal ganglia activity across studies. • These are important for our understanding of symptoms in this clinical population.

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.

While our understanding of cerebellar structural development through adolescence and young adulthood has expanded, we still lack knowledge of the developmental patterns of cerebellar networks during this critical portion of the lifespan. Volume in lateral posterior cerebellar regions associated with cognition and the prefrontal cortex develops more slowly, reaching their peak volume in adulthood, particularly as compared to motor Lobule V. We predicted that resting state functional connectivity of the lateral posterior regions would show a similar pattern of development during adolescence and young adulthood. That is, we expected to see changes over time in Crus I and Crus II connectivity with the cortex, but no changes in Lobule V connectivity. Additionally, we were interested in how structural connectivity changes in cerebello-thalamo-cortical white matter are related to changes in functional connectivity. A sample of 23 individuals between 12 and 21 years old underwent neuroimaging scans at baseline and 12-months later. Functional networks of Crus I and Crus II showed significant connectivity decreases over 12-months, though there were no differences in Lobule V. Furthermore, these functional connectivity changes were correlated with increases in white matter structural integrity in the corresponding cerebello-thalamo-cortical white matter tract. We suggest that these functional network changes are due to both later pruning in the prefrontal cortex as well as further development of the white matter tracts linking these brain regions.

Patients with psychosis exhibit a reduced susceptibility to depth inversion illusions (DII) in which a physically concave surface is perceived as convex (e.g., the hollow mask illusion). Here, we examined the extent to which lessened susceptibility to DII characterized youth at ultra high risk (UHR) for psychosis. In this study, 44 UHR participants and 29 healthy controls judged the apparent convexity of face-like human masks, two of which were concave and the other convex. One of the concave masks was painted with realistic texture to enhance the illusion; the other was shown without such texture. Networks involved with top-down and bottom-up processing were evaluated with resting state functional connectivity magnetic resonance imaging (fcMRI). We examined regions associated with the fronto-parietal network and the visual system and their relations with susceptibility to DII. Consistent with prior studies, the UHR group was less susceptible to DII (i.e., they were characterized by more veridical perception of the stimuli) than the healthy control group. Veridical responses were related to weaker connectivity within the fronto-parietal network, and this relationship was stronger in the UHR group, suggesting possible abnormalities of top-down modulation of sensory signals. This could serve as a vulnerability marker and a further clue to the pathogenesis of psychosis., Highlights • UHR youth and matched healthy controls were asked to make convexity judgments on three different face-like human masks. • UHR youth had significantly greater veridical responses when viewing the mask that was painted and concave compared to healthy controls. • Veridical responses were associated with weaker connectivity in regions related to the fronto-parietal network.

The present double-blind crossover study examines the effects of cerebellar transcranial direct current stimulation (tDCS) in controls and in an analogue population to psychosis: individuals reporting elevated symptoms of nonclinical psychosis (NCP). A total of 18 controls and 24 NCP individuals were randomized into conditions consisting of 25 minutes of anodal (active) or sham cerebellar tDCS. Following this, both groups completed a pursuit rotor task designed to measure procedural learning performance. Participants then returned 1-week later and received the corresponding condition (either active or sham) and repeated the pursuit rotor task. Results indicate that in the sham condition, control participants showed significantly greater rates of motor learning when compared with the NCP group. In the active condition, the NCP group exhibited significant improvements in the rate of motor learning and performed at a level that was comparable to controls; these data support the link between cerebellar dysfunction and motor learning. Taken together, tDCS may be a promising treatment mechanism for patient populations and a useful experimental approach in elucidating our understanding of psychosis.

Despite the clinical impact of motor symptoms such as agitation or retardation on the course of depression, these symptoms are poorly understood. Novel developments in the field of instrumentation and mobile devices allow for dimensional and continuous recording of motor behavior in various settings, particularly outside the laboratory. Likewise, the use of novel assessments enables to combine multimodal neuroimaging with behavioral measures in order to investigate the neural correlates of motor dysfunction in depression. The research domain criteria (RDoC) framework will soon include a motor domain that will provide a framework for studying motor dysfunction in mood disorders. In addition, new studies within this framework will allow investigators to study motor symptoms across different stages of depression as well as other psychiatric diagnoses. Finally, the introduction of the RDoC motor domain will help test how motor symptoms integrate with the original five RDoC domains (negative valence, positive valence, cognitive, social processes, and arousal/regulation).

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.

Gestures represent an integral aspect of interpersonal communication, and they are closely linked with language and thought. Brain regions for language processing overlap with those for gesture processing. Two types of gesticulation, beat gestures and metaphoric gestures are particularly important for understanding the taxonomy of co-speech gestures. Here, we investigated gesture production during taped interviews with respect to regional brain volume. First, we were interested in whether beat gesture production is associated with similar regions as metaphoric gesture. Second, we investigated whether cortical regions associated with metaphoric gesture processing are linked to gesture production based on correlations with brain volumes. We found that beat gestures are uniquely related to regional volume in cerebellar regions previously implicated in discrete motor timing. We suggest that these gestures may be an artifact of the timing processes of the cerebellum that are important for the timing of vocalizations. Second, our findings indicate that brain volumes in regions of the left hemisphere previously implicated in metaphoric gesture processing are positively correlated with metaphoric gesture production. Together, this novel work extends our understanding of left hemisphere regions associated with gesture to indicate their importance in gesture production, and also suggests that beat gestures may be especially unique. This provides important insight into the taxonomy of co-speech gestures, and also further insight into the general role of the cerebellum in language.

The ERBB4 receptor tyrosine kinase promotes colonocyte survival. Herein, we tested whether ERBB4's antiapoptotic signaling promotes transformation and colorectal tumorigenesis. ERBB4 alterations in a The Cancer Genome Atlas colorectal cancer (CRC) data set stratified survival, and in a combined Moffitt Cancer Center and Vanderbilt Medical Center CRC expression data set, ERBB4 message levels were increased at all tumor stages. Similarly, western blot and immunohistochemistry on additional CRC tissue banks showed elevated ERBB4 protein in tumors. ERBB4 was highly expressed in aggressive, dedifferentiated CRC cell lines, and its knockdown in LIM2405 cells reduced anchorage-independent colony formation. In nude mouse xenograft studies, ERBB4 alone was insufficient to induce tumor establishment of non-transformed mouse colonocytes, but its over-expression in cells harboring Apc(min) and v-Ha-Ras caused a doubling of tumor size. ERBB4-expressing xenografts displayed increased activation of survival pathways, including epidermal growth factor receptor and Akt phosphorylation and COX-2 expression, and decreased apoptotic signals. Finally, ERBB4 deletion from mouse intestinal epithelium impaired stem cell replication and in vitro enteroid establishment. In summary, we report that ERBB4 is over-expressed in human CRC, and in experimental systems enhances the survival and growth of cells driven by Ras and/or WNT signaling. Chronic ERBB4 over-expression in the context of, for example, inflammation may contribute to colorectal carcinogenesis. Tumors with high receptor levels are likely to have enhanced cell survival signaling through epidermal growth factor receptor, PI3K and COX-2. These results suggest ERBB4 as a novel therapeutic target in a subset of CRC.

Impaired ability to maintain an upright posture may reflect impairment in the cerebellum, a critical structure for the fluid coordination of neural information, thought to be disrupted in psychosis. The current study utilized an instrumental measure of posture in individuals at ultrahigh risk (UHR) for psychosis (n = 43) and healthy controls (n = 44). Positive and negative symptoms were assessed twice over 12 months. Results showed that increased postural sway in the UHR group predicted changes in negative symptoms. This study provides an important prospective view on the relationship between cerebellar-sensitive behavior and integral symptoms, which until now has received limited biomarker research.

Cerebellar morphology and function have been implicated in a variety of developmental disorders, and in healthy aging. Though recent work has sought to characterize the relationships between volume and age in this structure during adolescence, young, and older adulthood, there have been no investigations of regional cerebellar volume from adolescence through late middle age. Middle age in particular, has been largely understudied, and investigating this period of the lifespan may be especially important for our understanding of senescence. Understanding regional patterns of cerebellar volume with respect to age during this portion of the lifespan may provide important insight into healthy aging and cognitive function as well as pathology from adolescence into later life. We investigated regional cerebellar volume using a highly novel lobular segmentation approach in conjunction with a battery of cognitive tasks in a cross-sectional sample of 123 individuals from 12 to 65 years old. Our results indicated that regional cerebellar volumes show different patterns with respect to age. In particular, the more posterior aspect of the neocerebellum follows a quadratic “inverse-U” pattern, while the vermis and anterior cerebellum follow logarithmic patterns. In addition, we quantified the relationships between age and a variety of cognitive assessments and found relationships between regional cerebellar volumes and performance. Finally, exploratory analyses of sex differences in the relationships between regional cerebellar volume, age, and cognition were investigated. Taken together, these results provide key insights into the development and aging of the human cerebellum, and its role in cognitive function across the lifespan.

The cognitive dysmetria framework postulates that the deficits seen in schizophrenia are due to underlying cerebello-thalamo-cortical dysfunction. The cerebellum is thought to be crucial in the formation of internal models for both motor and cognitive behaviors. In healthy individuals there is a functional topography within the cerebellum. Alterations in the functional topography and activation of the cerebellum in schizophrenia patients may be indicative of altered internal models, providing support for this framework. Using state-of-the-art neuroimaging meta-analysis, we investigated cerebellar activation across a variety of task domains affected in schizophrenia and in comparison to healthy controls. Our results indicate an altered functional topography in patients. This was especially apparent for emotion and working memory tasks, and may be related to deficits in these domains. Results suggest that an altered cerebellar functional topography in schizophrenia may be contributing to the many deficits associated with the disease, perhaps because of dysfunctional internal models.

Though the cortical contributions to age-related declines in motor and cognitive performance are well-known, the potential contributions of the cerebellum are less clear. The diverse functions of the cerebellum make it an important structure to investigate in aging. Here, we review the extant literature on this topic. To date, there is evidence to indicate that there are morphological age differences in the cerebellum that are linked to motor and cognitive behavior. Cerebellar morphology is often as good as – or even better – at predicting performance than the prefrontal cortex. We also touch on the few studies using functional neuroimaging and connectivity analyses that further implicate the cerebellum in age-related performance declines. Importantly, we provide a conceptual framework for the cerebellum influencing age differences in performance, centered on the notion of degraded internal models. The evidence indicating that cerebellar age differences associate with performance highlights the need for additional work in this domain to further elucidate the role of the cerebellum in age differences in movement control and cognitive function.

Despite known deficits in postural control in patients with schizophrenia, this domain has not been investigated in youth at ultra high-risk (UHR) for psychosis. This is particularly relevant as postural control implicates dysfunction in the cerebellum-a region implicated in cognitive dysmetria conceptions of schizophrenia but poorly understood in the prodrome. Here, we extended our understanding of movement abnormalities in UHR individuals to include postural control, and have linked these deficits to both symptom severity and cerebello-cortical network connectivity. UHR and healthy control participants completed an instrumentally based balance task to quantify postural control along with a resting state brain imaging scan to investigate cerebellar networks. We also quantified positive and negative symptom severity with structured clinical interviews. The UHR group showed overall increased postural sway and decreased cerebello-cortical resting state connectivity, relative to controls. The decreased cerebello-cortical connectivity was seen across multiple networks. Postural sway was also correlated with cerebellar connectivity in this population and uniquely positively correlated with the severity of negative symptoms. Finally, symptom severity was also associated with cerebellar connectivity. Together, our results point to a potential deficit in sensory integration as an underlying contributor to the increased postural sway, and provide evidence of cerebellar abnormalities in UHR individuals. These results extend our understanding of the motor abnormalities of UHR individuals beyond striatum-based dyskinesias to include postural control and sensory integration deficits, and implicate the cerebellum as a distinct neural substrate preceding the onset of psychosis. Taken together, our results extend the cognitive dysmetria framework to UHR populations. Hum Brain Mapp 35:4064–4078, 2014. © 2014 Wiley Periodicals, Inc.

Conflict of interest statement: Although co-author Marie T. Banich is the Editor-in-Chief of Cognitive, Affective, and Behavioral Neuroscience, Stan Floresco served as the action editor for this manuscript.

Introduction: There is an emerging consensus that neurological soft signs (NSS) may not be “soft” at all but rather may reflect neuropathy, particularly in the cerebellum and thalamus. However, our understanding of connective tract abnormalities is limited, and to date, there have been no investigations examining NSS and longitudinal white matter development during the prodrome. Mapping the correlates of NSS in ultrahigh-risk (UHR) youth offers potential for highlighting a viable biomarker as well as for advancing understanding of pathogenic processes during the adolescent risk period. Methods: A total of 68 (33 UHR and 35 healthy control) adolescents were assessed with an NSS inventory, structured interviews, and diffusion tensor imaging. Fractional anisotropy (FA) of theoretically relevant cerebellar-thalamic tracts was calculated (left/right superior cerebellar peduncles [SCPs]). Twelve months later, a subset of 30 (15 UHR and 15 control) participants returned for follow-up diffusion tension imaging/clinical assessments. Results: UHR youth exhibited elevated NSS across domains. While there were no group differences in the integrity of the SCPs at baseline, controls showed a normative increase while the UHR group showed a decrease in FA over 12 months. NSS predicted a longitudinal decrease in cerebellar-thalamic FA and elevations in negative but not positive symptoms 12 months later. Discussion: Findings of abnormal white matter development provide direct empirical evidence to support prominent neurodevelopmental theories. The predictive relationships between NSS and longitudinal cerebellar-thalamic tract integrity and negative symptom course provide insight into the role of cognitive dysmetria in the high-risk period and inform on a unique biomarker tied to core features underlying psychosis.

Sleep dysfunction is a pervasive, distressing characteristic of psychosis, yet little is known regarding sleep quality prior to illness onset. At present, it is unclear whether sleep dysfunction precedes the emergence of psychotic symptoms, signifying a core feature of the disorder, or if it represents a consequence of prolonged contact with aspects of schizophrenia and its treatment (e.g., medication use or neurotoxicity) or co-morbid symptoms (e.g., depressive and manic symptomatology). The current study examined sleep dysfunction in adolescents at ultra high-risk (UHR) for psychosis, relationships between sleep disturbances and psychosis symptoms, volume of an integral sleep-structure (thalamus), and associations between thalamic abnormalities and sleep impairment in UHR youth.Thirty-three UHR youth and 33 healthy controls (HC) participated in a self-assessment of sleep functioning (Pittsburgh Sleep Quality Index; PSQI), self and parent-report clinical interviews, and structural magnetic resonance imaging (MRI).UHR adolescents displayed increased latency to sleep onset and greater sleep disturbances/disrupted continuity compared to HC youth, over and above concurrent mood symptoms. Among UHR youth, increased sleep dysfunction was associated with greater negative symptom severity but not positive symptoms. Compared to HC adolescents, UHR participants displayed decreased bilateral thalamus volume, which was associated with increased sleep dysfunction.Sleep dysfunction occurs during the pre-psychotic period, and may play a role in the etiology and pathophysiology of psychosis. In addition, the relationship of disrupted sleep to psychosis symptoms in UHR youth indicates that prevention and intervention strategies may be improved by targeting sleep stabilization in the pre-psychotic period.

The cerebellum has been implicated in both sensorimotor and cognitive function, but is known to undergo volumetric declines with advanced age. Individual differences in regional cerebellar volume may therefore provide insight into performance variability across the lifespan, as has been shown with other brain structures and behaviors. Here, we investigated whether there are regional age differences in cerebellar volume in young and older adults, and whether these volumes explain, in part, individual differences in sensorimotor and cognitive task performance. We found that older adults had smaller cerebellar volume than young adults; specifically, lobules in the anterior cerebellum were more impacted by age. Multiple regression analyses for both age groups revealed associations between sensorimotor task performance in several domains (balance, choice reaction time, and timing) and regional cerebellar volume. There were also relationships with working memory, but none with measures of general cognitive or executive function. Follow-up analyses revealed several differential relationships with age between regional volume and sensorimotor performance. These relationships were predominantly selective to cerebellar regions that have been implicated in cognitive functions. Therefore, it may be the cognitive aspects of sensorimotor task performance that are best explained by individual differences in regional cerebellar volumes. In sum, our results demonstrate the importance of regional cerebellar volume with respect to both sensorimotor and cognitive performance, and we provide additional insight into the role of the cerebellum in age-related performance declines.

The cerebellar dentate nucleus has been reported to project to motor and prefrontal cortical regions in nonhuman primates from 2 anatomically distinct areas. However, despite a wealth of human neuroimaging data implicating the cerebellum in motor and cognitive behaviors, evidence of dissociable motor and cognitive networks comprising the human dentate is lacking. To investigate the existence of these 2 networks in the human brain, we used resting-state functional connectivity magnetic resonance imaging. The resting-state fMRI signal was extracted from regions of interest in the dorsal and ventral dentate nucleus. We report a “motor” network involving the dorsal dentate, anterior regions of the cerebellum, and the precentral gyrus, and a “cognitive” network involving the ventral dentate, Crus I, and prefrontal cortex. The existence of these 2 distinct networks supports the notion that cerebellar involvement in cognitive tasks is above and beyond that associated with motor response components.

Beat gestures, rhythmic hand movements that co-occur with speech, appear to be uniquely associated with the cerebellum in healthy individuals. This behavior may also have relevance for psychosis-risk youth, a group characterized by cerebellar dysfunction. This study examined beat gesture frequency and postural sway (a sensitive index of cerebellar functioning) in youth at ultrahigh risk (UHR) for psychosis. Results indicated that decreased beat gesture frequency, but not self-regulatory movement, is associated with elevated postural sway, suggesting that beat gestures may be an important biomarker in this critical population.

Efficient clearance of pro-inflammatory macrophages from tissues after resolution of a challenge is critical to prevent prolonged inflammation. Defects in clearance can contribute to conditions such as inflammatory bowel disease, and thus may be therapeutically targetable. However, the signaling pathways that induce termination of pro-inflammatory macrophages are incompletely defined. We tested whether the ErbB4 receptor tyrosine kinase, previously not known to have role in macrophage biology, is involved in this process. In vitro, pro-inflammatory activation of cultured murine and human macrophages induced ErbB4 expression; in contrast, other ErbB family members were not induced in pro-inflammatory cells, and other innate immune lineages (dendritic cells, neutrophils) did not express detectable ErbB4 levels. Treatment of activated pro-inflammatory macrophages with the ErbB4 ligand neuregulin-4 (NRG4) induced apoptosis. ErbB4 localized to the mitochondria in these cells. Apoptosis was accompanied by loss of mitochondrial membrane potential, and was dependent upon the proteases that generate the cleaved ErbB4 intracellular domain fragment, suggesting a requirement for this fragment and mitochondrial pathway apoptosis. In vivo, ErbB4 was highly expressed on pro-inflammatory macrophages but not neutrophils during experimental DSS colitis in C57Bl/6 mice. Active inflammation in this model suppressed NRG4 expression, which may allow for macrophage persistence and ongoing inflammation. Consistent with this notion, NRG4 levels rebounded during the recovery phase, and administration of exogenous NRG4 during colitis reduced colonic macrophage numbers and ameliorated inflammation. These data define a novel role for ErbB4 in macrophage apoptosis, and outline a mechanism of feedback inhibition that may promote resolution of colitis.

Expression of the ErbB4 tyrosine kinase is elevated in colonic epithelial cells during inflammatory bowel disease, whereas ErbB4 overexpression in cultured colonocytes blocks TNF-induced apoptosis in a ligand-dependent manner. Together, these observations suggest that ErbB4 induction may be a protective response. However, the effects of ErbB4 signaling in the colonic epithelium in vivo are not known. Furthermore, previous work on ErbB4 used ligands shared with other receptors, raising the question of whether the observed responses are explicitly due to ErbB4. In this study, we used the ErbB4-specific ligand neuregulin-4 (NRG4) to activate ErbB4 and define its role in colonocyte biology. NRG4 treatment, either in cultured cells or in mice, blocked colonic epithelial apoptosis induced by TNF and IFN-γ. It was also protective in a murine experimental colitis model. NRG4 stimulated phosphorylation of ErbB4 but not other ErbB receptors, indicating that this is a specific response. Furthermore, in contrast to related ligands, NRG4 enhanced cell survival but not proliferation or migration, and stimulated phosphorylation of the anti-apoptotic mediator Akt but not ERK MAPK. Pharmacological inhibition of PI3K/Akt signaling reversed the anti-apoptotic effects of NRG4, confirming the role of this cascade in NRG4-induced cell survival. With regard to the potential clinical importance of this pathway, NRG4 expression was decreased in human inflammatory bowel disease samples and mouse models of colitis, suggesting that activation of ErbB4 is altered in disease. Thus, exogenous NRG4 may be beneficial for disorders in which epithelial apoptosis is part of the pathology.

Upon ligand binding, epidermal growth factor (EGF) receptor (R) autophosphorylates on COOH-terminal tyrosines, generating docking sites for signaling partners that stimulate proliferation, restitution, and chemotaxis. Specificity for individual EGFR tyrosines in cellular responses has been hypothesized but not well documented. Here we tested the requirement for particular tyrosines, and associated downstream pathways, in mouse colon epithelial cell chemotactic migration. We compared these requirements to those for the phenotypically distinct restitution (wound healing) migration. Wild-type, Y992/1173F, Y1045F, Y1068F, and Y1086F EGFR constructs were expressed in EGFR−/−cells; EGF-induced chemotaxis or restitution were determined by Boyden chamber or modified scratch wound assay, respectively. Pharmacological inhibitors of p38, phospholipase C (PLC), Src, MEK, JNK/SAPK, phosphatidylinositol 3-kinase (PI 3-kinase), and protein kinase C (PKC) were used to block EGF-stimulated signaling. Pathway activation was determined by immunoblot analysis. Unlike wild-type EGFR, Y992/1173F and Y1086F EGFR did not stimulate colon epithelial cell chemotaxis toward EGF; Y1045F and Y1068F EGFR partially stimulated chemotaxis. Only wild-type EGFR promoted colonocyte restitution. Inhibition of p38, PLC, and Src, or Grb2 knockdown, blocked chemotaxis; JNK, PI 3-kinase, and PKC inhibitors or c-Cbl knockdown blocked restitution but not chemotaxis. All four EGFR mutants stimulated downstream signaling in response to EGF, but Y992/1173F EGFR was partially defective in PLCγ activation whereas both Y1068F and Y1086F EGFR failed to activate Src. We conclude that specific EGFR tyrosines play key roles in determining cellular responses to ligand. Chemotaxis and restitution, which have different migration phenotypes and physiological consequences, have overlapping but not identical EGFR signaling requirements.

Within the NIMH Research Domain Criteria (RDoC) framework, dimensions of behavior are investigated across diagnoses with the goal of developing a better understanding of their underlying neural substrates. Currently, this framework includes five domains: cognitive, social, arousal/regulatory, negative, and positive valence systems. We argue that the inclusion of a motor systems domain is sorely needed as well. Independent of medication, distinct areas of motor dysfunction (e.g. motor planning/inhibition/learning/coordination, involuntary movements) commonly appear across a number of mental disorders (e.g. schizophrenia, bipolar disorder, autism, attention deficit hyperactivity disorder, Alzheimer's disease, depression) as well as neurological disorders accompanied by significant psychological symptoms (e.g. Parkinson's disease). In addition, motor systems are amenable to study across multiple levels of analysis from the cellular molecular level focusing on cytoarchitechtonics and neurotransmitter systems, to networks and circuits measured using neuroimaging, and finally at the level of overt behavioral performance. Critically, the neural systems associated with motor performance have been relatively well defined, and different circuits have been linked to distinct aspects of motor behavior. As such, they may also be differentially associated with symptoms and motor dysfunction across diagnoses, and be uniquely informative about underlying etiology. Importantly, motor signs can change across stages of illness; they are also often present in the prodromal phases of disease and closely linked with course, suggesting that these behaviors represent a core feature reflective of pathogenic processes. The inclusion of a motor domain would allow researchers to better understand psychopathology more broadly, and may also reveal important contributions to disease processes across diagnoses.

The ErbB4 receptor tyrosine kinase is induced in the colonic epithelium in inflammatory bowel disease (IBD), and the ErbB4-specific ligand neuregulin-4 is protective in murine colitis models. Inter...

Social processes are key to navigating the world, and investigating their underlying mechanisms and cognitive architecture can aid in understanding disease states such as schizophrenia, where social processes are highly impacted. Evidence suggests that social processes are impaired in individuals at ultra high-risk for the development of psychosis (UHR). Understanding these phenomena in UHR youth may clarify disease etiology and social processes in a period that is characterized by significantly fewer confounds than schizophrenia. Furthermore, understanding social processing deficits in this population will help explain these processes in healthy individuals. The current study examined resting state connectivity of the salience (SN) and default mode networks (DMN) in association with facial emotion recognition (FER), an integral aspect of social processes, as well as broader social functioning (SF) in UHR individuals and healthy controls. Consistent with the existing literature, UHR youth were impaired in FER and SF when compared with controls. In the UHR group, we found increased connectivity between the SN and the medial prefrontal cortex, an area of the DMN relative to controls. In UHR youth, the DMN exhibited both positive and negative correlations with the somatosensory cortex/cerebellum and precuneus, respectively, which was linked with better FER performance. For SF, results showed that sensory processing links with the SN might be important in allowing for better SF for both groups, but especially in controls where sensory processing is likely to be unimpaired. These findings clarify how social processing deficits may manifest in psychosis, and underscore the importance of SN and DMN connectivity for social processing more generally.

Summary Memories are formed, stabilized in a time-dependent manner, and stored in neural networks. In Drosophila , retrieval of punitive and rewarded odor memories depends on output from mushroom body (MB) neurons [1–5], consistent with the idea that both types of memory are represented there. Dorsal Paired Medial (DPM) neurons innervate the mushroom bodies, and DPM neuron output is required for the stability of punished odor memory [6, 7]. Here we show that stable reward-odor memory is also DPM neuron dependent. DPM neuron expression of amnesiac ( amn ) in amn mutant flies restores wild-type memory. In addition, disrupting DPM neurotransmission between training and testing abolishes reward-odor memory, just as it does with punished memory [7]. We further examined DPM-MB connectivity by overexpressing a DScam variant that reduces DPM neuron projections to the MB α, β, and γ lobes. DPM neurons that primarily project to MB α′ and β′ lobes are capable of stabilizing punitive- and reward-odor memory, implying that both forms of memory have similar circuit requirements. Therefore, our results suggest that the fly employs the local DPM-MB circuit to stabilize punitive- and reward-odor memories and that stable aspects of both forms of memory may reside in mushroom body α′ and β′ lobe neurons.

Background: According to the cognitive dysmetria theory, symptom and behavioral features of psychosis are influenced dysfunctional connections between the cerebellum and cortex. Insight into illness may be one such thought process, and in schizophrenia, is associated with brain function of large-scale networks involved in self-reflection and cognitive control. However, while there is also limited evidence that insight is impaired in the prodromal phase of psychosis, there have been no studies examining underlying brain connectivity. We investigated whether insight is associated with cerebellocortical connectivity of major brain networks in adolescents at ultra high risk (UHR) of schizophrenia, as this may be an early indicator of psychosis risk.

Working memory training has been the focus of intense research interest. Despite accumulating behavioral work, knowledge about the neural mechanisms underlying training effects is scarce. Here, we show that 7 days of training on an n-back task led to substantial performance improvements in the trained task; furthermore, the experimental group showed cross-modal transfer, as compared with an active control group. In addition, there were two neural effects that emerged as a function of training: first, increased perfusion during task performance in selected regions, reflecting a neural response to cope with high task demand; second, increased blood flow at rest in regions where training effects were apparent. We also found that perfusion at rest was correlated with task proficiency, probably reflecting an improved neural readiness to perform. Our findings are discussed within the context of the available neuroimaging literature on n-back training.

Healthy aging is marked by declines in a variety of cognitive and motor abilities. A better understanding of the aging brain may aid in elucidating the neural substrates of these behavioral effects. Investigations of resting state functional brain connectivity have provided insights into pathology, and to some degree, healthy aging. Given the role of the cerebellum in both motor and cognitive behaviors, as well as its known volumetric declines with age, investigating cerebellar networks may shed light on the neural bases of age-related functional declines. We mapped the resting state networks of the lobules of the right hemisphere and the vermis of the cerebellum in a group of healthy older adults and compared them to those of young adults. We report disrupted cortico-cerebellar resting state network connectivity in older adults. These results remain even when controlling for cerebellar volume, signal-to-noise ratio, and signal-to-fluctuation noise ratio. Specifically, there was consistent disruption of cerebellar connectivity with both the striatum and the medial temporal lobe. Associations between connectivity strength and both sensorimotor and cognitive task performances indicate that cerebellar engagement with the default mode network and striatal pathways is associated with better performance for older adults. These results extend our understanding of the resting state networks of the aging brain to include cortico-cerebellar networks, and indicate that age differences in network connectivity strength are important for behavior.