Non-invasive neuromodulation of cerebello-hippocampal volume-behavior relationships.

The study here explores the link between transcranial direct current stimulation (tDCS) and brain-behavior relationships. We propose that tDCS may indirectly influence the complex relationships between brain volume and behavior. We focused on the dynamics between the hippocampus (HPC) and cerebellum (CB) in cognitive processes, a relationship with significant implications for understanding memory and motor skills. Seventy-four young adults (mean age: 22±0.42 years, mean education: 14.7±0.25 years) were randomly assigned to receive either anodal, cathodal, or sham stimulation. Following stimulation, participants completed computerized tasks assessing working memory and sequence learning in a magnetic resonance imaging (MRI) environment. We investigated the statistical interaction between CB and HPC volumes. Our findings showed that individuals with larger cerebellar volumes had shorter reaction times (RT) on a high-load working memory task in the sham stimulation group. In contrast, the anodal stimulation group exhibited faster RTs during the low-load working memory condition. These RT differences were associated with the cortical volumetric interaction between CB-HPC. Literature suggests that anodal stimulation down-regulates the CB and here, those with larger volumes perform more quickly, suggesting the potential need for additional cognitive resources to compensate for cerebellar downregulation. This new insight suggests that tDCS can aid in revealing structure-function relationships, due to greater performance variability, especially in young adults. It may also reveal new targets of interest in the study of aging or in diseases where there is also greater behavioral variability.

Time dependent effects of cerebellar tDCS on cerebello-cortical connectivity networks in young adults.

The cerebellum is involved in non-motor processing, supported by topographically distinct cerebellar activations and closed loop circuits between the cerebellum and the cortex. Disruptions to cerebellar function and network connectivity in aging or disease may negatively impact prefrontal function and processing. Cerebellar resources may be important for offloading cortical processing, providing crucial scaffolding for normative performance and function. Here, we used transcranial direct current stimulation (tDCS) to temporarily alter cerebellar function and subsequently investigated resting state network connectivity. This allows us to investigate network changes that may parallel what is seen in aging and clinical populations, providing additional insights into these key circuits. Critically, what happens to these circuits if the cerebellum is not functioning optimally remains relatively unknown. We employed a between-subjects design applying anodal (n=25), cathodal (n=25), or sham (n=24) stimulation to the cerebellum to examine the effect of stimulation on cerebello-cortical resting state connectivity in young adults. We predicted increased functional connectivity following cathodal stimulation and decreased functional connectivity following anodal stimulation. We found, anodal stimulation resulted in increased connectivity in both ipsilateral and contralateral regions of the cortex, perhaps indicative of a compensatory response to degraded cerebellar output. Additionally, a sliding window analysis also demonstrated a time dependent nature to the impacts of cerebellar tDCS on connectivity, particularly in cognitive region in the cortex. Assuming the difference in connectivity and network-behavior relationships here parallels what occurs in aging or disease, this may provide a mechanism whereby offloading of function to the cerebellum is negatively impacted, resulting in subsequent differences in prefrontal cortical activation patterns and performance deficits. These results might inform and update existing compensatory models of function to include the cerebellum as a vital structure needed for scaffolding.

Hormone-sleep interactions predict cerebellar connectivity and behavior in aging females.

Sex hormones fluctuate over the course of the female lifespan and are associated with brain health and cognition. Thus, hormonal changes throughout female adulthood, and with menopause in particular, may contribute to sex differences in brain function and behavior. Further, sex hormones have been correlated with sleep patterns, which also exhibit sex-specific impacts on the brain and behavior. As such, the interplay between hormones and sleep may contribute to late-life brain and behavioral outcomes in females. Here, in a sample of healthy adult 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 17ß-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.

Anodal cerebellar stimulation increases cortical activation: Evidence for cerebellar scaffolding of cortical processing.

While the cerebellum contributes to nonmotor task performance, the specific contributions of the structure remain unknown. One possibility is that the cerebellum allows for the offloading of cortical processing, providing support during task performance, using internal models. Here we used transcranial direct current stimulation to modulate cerebellar function and investigate the impact on cortical activation patterns. Participants (n = 74; 22.03 ± 3.44 years) received either cathodal, anodal, or sham stimulation over the right cerebellum before a functional magnetic resonance imaging scan during which they 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. Behaviorally, anodal stimulation negatively impacted behavior during late-phase sequence learning. Functionally, 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.

Using high-definition transcranial direct current stimulation to investigate the role of the dorsolateral prefrontal cortex in explicit sequence learning.

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.

The Polarity-Specific Nature of Single-Session High-definition Transcranial Direct Current Stimulation to the Cerebellum and Prefrontal Cortex on Motor and Non-motor Task Performance.

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.

Cerebellar and prefrontal-cortical engagement during higher-order rule learning in older adulthood.

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.

Shaky scaffolding: Age differences in cerebellar activation revealed through activation likelihood estimation meta-analysis.

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.

Age Differences in the Subcomponents of Executive Functioning.

OBJECTIVES: Across the life span, deficits in executive functioning (EF) are associated with poor behavioral control and failure to achieve goals. Though EF is often discussed as one broad construct, a prominent model of EF suggests that it is composed of three subdomains: inhibition, set shifting, and updating. These subdomains are seen in both younger (YA) and older adults (OA), with performance deficits across subdomains in OA. Therefore, our goal was to investigate whether subdomains of EF might be differentially affected by age, and how these differences may relate to broader global age differences in EF. METHODS: To assess these age differences, we conducted a meta-analysis at multiple levels, including task level, subdomain level, and of global EF. Based on previous work, we hypothesized that there would be overall differences in EF in OA. RESULTS: Using 1,268 effect sizes from 401 articles, we found overall differences in EF with age. Results suggested that differences in performance are not uniform, such that variability in age effects emerged at the task level, and updating was not as affected by age as other subdomains. DISCUSSION: These findings advance our understanding of age differences in EF, and stand to inform early detection of EF decline.

Single session high definition transcranial direct current stimulation to the cerebellum does not impact higher cognitive function.

The prefrontal cortex is central to higher order cognitive function. However, the cerebellum, generally thought to be involved in motor control and learning, has also been implicated in higher order cognition. Recent work using transcranial direct current stimulation (tDCS) provides some support for right cerebellar involvement in higher order cognition, though the results are mixed, and often contradictory. Here, we used cathodal high definition tDCS (HD-tDCS) over the right cerebellum to assess the impact of HD-tDCS on modulating cognitive performance. We predicted that stimulation would result in performance decreases, which would suggest that optimal cerebellar function is necessary for cognitive performance, much like the prefrontal cortex. That is, it is not simply a structure that lends support to complete difficult tasks. While the expected cognitive behavioral effects were present, we did not find effects of stimulation. This has broad implications for cerebellar tDCS research, particularly for those who are interested in using HD-tDCS as a way of examining cerebellar function. Further implications, limitations, and future directions are discussed with particular emphasis on why null findings might be critical in developing a clear picture of the effects of tDCS on the cerebellum.

Effects of cerebellar transcranial direct current stimulation on the cognitive stage of sequence learning.

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.

A case for motor network contributions to schizophrenia symptoms: Evidence from resting-state connectivity.

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.