Disrupted executive cerebro-cerebellar functional connectivity in alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) affects 283 million people worldwide and its prevalence is increasing. Despite the role of the cerebellum in executive control and its sensitivity to alcohol, few studies have assessed its involvement in AUD-relevant functional networks. The goal of this study is to compare resting-state functional connectivity (FC) patterns in abstinent adults with a history of AUD and controls (CTL). We hypothesized that group differences in cerebro-cerebellar FC would be present, particularly within the frontoparietal/executive control network (FPN). METHODS: Twenty-eight participants completed a resting-state functional magnetic resonance imaging (rsfMRI) study. CTL participants had no history of AUD, comorbid psychological conditions, or recent heavy drinking and/or drug use. AUD participants had a history of AUD, with sobriety for at least 30 days prior to data collection. Multivariate pattern analysis, an agnostic, whole-brain approach, was used to identify regions with significant differences in FC between groups. Seed-based analyses were then conducted to determine the directionality and extent of these FC differences. Associations between FC strength and executive function were assessed using correlations with Wisconsin Card Sorting Test (WCST) performance. RESULTS: There were significant group differences in FC in nodes of the FPN, ventral attention network, and default mode network. Post hoc analyses predominantly identified FC differences within the cerebro-cerebellar FPN, with AUD showing significantly less FC within the FPN. In AUD, FC strength between FPN clusters identified in the multivariate pattern analysis (MVPA) analysis (Left Crus II, Right Frontal Cortex) was positively associated with performance on the WCST. CONCLUSIONS: Our results show less engagement of the FPN in individuals with AUD than in CTL. FC strength within this network was positively associated with performance on the WCST. These findings suggest that long-term heavy drinking alters cerebro-cerebellar FC, particularly within networks that are involved in executive function.

Sex Differences and Behavioral Associations with Typically Developing Pediatric Regional Cerebellar Gray Matter Volume.

The cerebellum contributes to motor and higher-order control throughout neurodevelopment, with marked growth during childhood. Few studies have investigated differential associations of cerebellar morphometry with function in males and females. The present study examines sex differences in regional cerebellar gray matter volume (GMV) and the moderating effect of sex on the relationship between GMV and motor, cognitive, and emotional functions in a large cohort of typically developing (TD) children. Participants included 371 TD children (123 females, age 8-12 years). A convolutional neural network-based approach was employed for cerebellar parcellation. Volumes were harmonized using ComBat to adjust for hardware-induced variations. Regression analyses examined the effect of sex on GMV and whether sex moderated the relationship between GMV and motor, cognitive, and emotional functions. Males showed larger GMV in right lobules I-V, bilateral lobules VI, crus II/VIIb, and VIII, left lobule X, and vermis regions I-V and VIII-X. Greater motor function correlated with less vermis VI-VII GMV in females. Greater cognitive function correlated with greater left lobule VI GMV in females and less left lobule VI GMV in males. Finally, greater internalizing symptoms correlated with greater bilateral lobule IX GMV in females but less in males. These findings reveal sexually dimorphic patterns of cerebellar structure and associations with motor, cognitive, and emotional functions. Males generally show larger GMV than females. Larger GMV was associated with better cognitive functioning for females and better motor/emotional functioning for males.

Mindful Movement Intervention Applied to at Risk Urban School Children for Improving Motor, Cognitive, and Emotional-Behavioral Regulation.

Objectives: Preliminary evidence has supported the notion that mindful movement-based practices may offer benefits for self-regulation, particularly for vulnerable children. However, this evidence has principally stemmed from subjective assessments of behavioral change, leaving the underlying mechanisms undetermined. The present study aimed to investigate the efficacy of an in-school mindful movement intervention (MMI) for at-risk children within an urban public school for enhancing motor, cognitive, and emotional-behavioral regulation, including control of disruptive and inattentive behaviors characteristic of ADHD. Method: Participants included 38 (age 7-8 years) children who received twice weekly, in-school MMI, including a modified Tai Chi sequence, yoga and biomechanical warm-ups, imaginative play, and reflection. Parent and teacher ratings of disruptive behaviors, and objective measures of motor and cognitive control, were collected at baseline and after 5 months of MMI. Results: Significant improvements in teacher ratings of inattentive, hyperactive/impulsive, oppositional, and other disruptive behaviors were observed. Significant improvements were also observed for objective measures of both cognitive control and motor control with particular reductions in both right and left dysrhythmia. Conclusions: MMI was associated with improvements across objective and subjective assessments of motor, cognitive, and behavioral control. This proof-of-principle investigation provides preliminary support for the efficacy and feasibility of a novel MMI implemented as part of the school day in an urban school setting with 7-8-year-old children to augment development of at-risk youth. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-02063-7.

Low glutamate diet improves working memory and contributes to altering BOLD response and functional connectivity within working memory networks in Gulf War Illness.

Gulf War Illness is a chronic multi-symptom disorder with severe cognitive impairments which may be related to glutamate excitotoxicity and central nervous system dysfunction. The low glutamate diet has been proposed as a comprehensive intervention for Gulf War Illness. We examined the effects of the low glutamate diet on verbal working memory using a fMRI N-back task. Accuracy, whole-brain blood oxygen level dependency (BOLD) response, and task-based functional connectivity were assessed at baseline and after 1 month on the diet (N = 24). Multi-voxel pattern analysis identified regions of whole-brain BOLD pattern differences after the diet to be used as seeds for subsequent seed-to-voxel functional connectivity analyses. Verbal working memory accuracy improved after the diet (+ 13%; p = 0.006). Whole-brain BOLD signal changes were observed, revealing lower activation within regions of the frontoparietal network and default mode network after the low glutamate diet. Multi-voxel pattern analysis resulted in 3 clusters comprising parts of the frontoparietal network (clusters 1 and 2) and ventral attention network (cluster 3). The seed-to-voxel analyses identified significant functional connectivity changes post-diet for clusters 1 and 2 (peak p < 0.001, cluster FDR p < 0.05). Relative to baseline, clusters 1 and 2 had decreased functional connectivity with regions in the ventral attention and somatomotor networks. Cluster 2 also had increased functional connectivity with regions of the default mode and frontoparietal networks. These findings suggest that among veterans with Gulf War Illness, the low glutamate diet improves verbal working memory accuracy, alters BOLD response, and alters functional connectivity within two networks central to working memory.

Differential Behavioral and Neural Effects of Regional Cerebellar tDCS.

The human cerebellum contributes to both motor and non-motor processes. Within the cerebellum, different subregions support sensorimotor and broader cognitive functions, due to regional patterns in anatomical connectivity with the cerebral cortex and spinal and vestibular systems. We evaluated the effects of transcranial direct current stimulation (tDCS) targeting different cerebellar regions on language task performance and whole-brain functional activation patterns. Functional MRI data were acquired while 43 healthy young adults (15 males, 28 females; 23.3 ±â€¯3.0 years) performed a sentence completion task before and after 20 min of 1.5 mA anodal tDCS. Participants received tDCS targeting either the anterior sensorimotor cerebellum (n = 11; 3 cm right of inion, over lobule V); the right posterolateral cerebellum (n = 18; 1 cm down and 4 cm right of inion, over lobule VII); or sham tDCS (n = 14). TDCS targeting the right posterolateral cerebellum improved task accuracy relative to the sham condition (p = 0.04) and increased activation in left frontal and temporal cortices relevant to task performance (post-tDCS > pre-tDCS; T 3.17, FDR p < 0.05 cluster correction). The regions of increased BOLD signal after right posterolateral cerebellar tDCS fell within the network showing functional connectivity with right cerebellar lobule VII, suggesting specific modulation of this network. In contrast, tDCS targeting the sensorimotor cerebellum did not impact task performance and increased BOLD signal only in one cluster extending into the precentral gyrus. These findings indicate that sensorimotor and cognitive functional cerebellar subregions differentially impact behavioral task performance and task-relevant activation patterns, further contributing to our understanding of the cerebellar modulation of motor and non-motor functions.

Consensus Paper: Cerebellum and Social Cognition.

The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social "mirroring") which is very close to its original role in motor learning, as well as in social understanding of other individuals' mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social "mentalizing"). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions.

Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits.

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.

Changes in Hemodynamic Response Function Resulting From Chronic Alcohol Consumption.

BACKGROUND: Functional MRI (fMRI) task-related analyses rely on an estimate of the brain's hemodynamic response function (HRF) to model the brain's response to events. Although changes in the HRF have been found after acute alcohol administration, the effects of heavy chronic alcohol consumption on the HRF have not been explored, and the potential benefits or pitfalls of estimating each individual's HRF on fMRI analyses of chronic alcohol use disorder (AUD) are not known. METHODS: Participants with AUD and controls (CTL) received structural, functional, and vascular scans. During fMRI, participants were cued to tap their fingers, and averaged responses were extracted from the motor cortex. Curve fitting on these HRFs modeled them as a difference between 2 gamma distributions, and the temporal occurrence of the main peak and undershoot of the HRF was computed from the mean of the first and second gamma distributions, respectively. RESULTS: ANOVA and regression analyses found that the timing of the HRF undershoot increased significantly as a function of total lifetime drinking. Although gray matter volume in the motor cortex decreased with lifetime drinking, this was not sufficient to explain undershoot timing shifts, and vascular factors measured in the motor cortex did not differ among groups. Comparison of random-effects analyses using custom-fitted and canonical HRFs for CTL and AUD groups showed better results throughout the brain for custom-fitted versus canonical HRFs for CTL subjects. For AUD subjects, the same was true except for the basal ganglia. CONCLUSIONS: These findings suggest that excessive alcohol consumption is associated with changes in the HRF undershoot. HRF changes could provide a possible biomarker for the effects of lifetime drinking on brain function. Changes in HRF topography affect fMRI activation measures, and subject-specific HRFs generally improve fMRI activation results.

Neural Substrates Underlying Eyeblink Classical Conditioning in Adults With Alcohol Use Disorders.

BACKGROUND: Excessive alcohol consumption produces changes in the brain that often lead to cognitive impairments. One fundamental form of learning, eyeblink classical conditioning (EBC), has been widely used to study the neurobiology of learning and memory. Participants with alcohol use disorders (AUD) have consistently shown a behavioral deficit in EBC. The present functional magnetic resonance imaging (fMRI) study is the first to examine brain function during conditioning in abstinent AUD participants and healthy participants. METHODS: AUD participants met DSM-IV criteria for alcohol dependence, had at least a 10-year history of heavy drinking, and were abstinent from alcohol for at least 30 days. During fMRI, participants received auditory tones that predicted the occurrence of corneal airpuffs. Anticipatory eyeblink responses to these tones were monitored during the experiment to assess learning-related changes. RESULTS: Behavioral results indicate that AUD participants showed significant conditioning deficits and that their history of lifetime drinks corresponded to these deficits. Despite this learning impairment, AUD participants showed hyperactivation in several key cerebellar structures (including lobule VI) during conditioning. For all participants, history of lifetime drinks corresponded with their lobule VI activity. CONCLUSIONS: These findings suggest that excessive alcohol consumption is associated with abnormal cerebellar hyperactivation and conditioning impairments.