Early‐Life Clinical Factors Shape Cerebellar Structure in Preterm‐Born Children

Neonatal Pain and Infection Relate to Smaller Cerebellum in Very Preterm Children at School Age

Healthy aging is associated with deficits in cognitive performance and brain changes, including in the cerebellum. Yet, the precise link between cerebellar function/structure and cognition in aging remains poorly understood. We explored this relationship in 138 healthy adults (aged 35-86, 53% female) using resting-state functional connectivity MRI (fcMRI), cerebellar volume, and cognitive and motor assessments in an aging sample. We expected to find negative relationships between lobular volume for with age, and positive relationships between specific lobular volumes with motor and cognition respectively. We predicted lower cerebellar fcMRI to cortical networks and circuits with increased age. Behaviorally, we expected higher cerebello-frontal fcMRI cerebellar connectivity with association areas to correlate with better behavioral performance. Behavioral tasks broadly assessed attention, processing speed, working memory, episodic memory, and motor abilities. Correlations were conducted between cerebellar lobules I-IV, V, Crus I, Crus II, vermis VI and behavioral measures. We found lower volumes with increased age as well as bidirectional cerebellar connectivity relationships with increased age, consistent with literature on functional connectivity and network segregation in aging. Further, we revealed unique associations for both cerebellar structure and connectivity with comprehensive behavioral measures in a healthy aging population. Our findings underscore cerebellar involvement in behavior during aging.

Cushing's syndrome (CS) is associated with neuropsychological deficits. As the cerebellum plays a key role in neuropsychological functions it may be affected in CS. The aim of this study was to investigate whether patients with CS have a smaller cerebellar volume than healthy controls, and to analyse whether cerebellar volume is associated with neuropsychological performance and clinical parameters. A cross-sectional study was performed. Thirty-six CS patients (15 with active CS and 21 with CS in remission) and 36 controls matched for age, sex, and education underwent neuropsychological testing, quality of life assessment, clinical evaluation, and magnetic resonance imaging brain scan. Cerebellar volumes (white matter and cortex, bilateral) were calculated using FreeSurfer Software. Patients with active CS showed smaller bilateral cerebellar cortex volumes than controls (left, P=0.035 and right, P=0.034), as well as a trend toward smaller right cerebellar cortex volumes than patients in remission CS (P=0.051). No differences were observed in the volume of cerebellar white matter between the three groups. Both right and left cerebellar cortex volumes correlated negatively with triglyceride levels (right: r=-0.358, P=0.002 and left: r=-0.317, P=0.005) and age at diagnosis (right: r=-0.433, P=0.008 and left: r=-0.457, P=0.005). Left cerebellar cortex volume also correlated positively with visual memory performance (r=0.245, P=0.038). Right cerebellar cortex volume positively correlated with quality-of-life scores (r=0.468, P=0.004). The cerebellar cortex volume is smaller in active CS patients than in controls. This finding is associated with poor visual memory and quality of life and is mostly pronounced in patients with higher triglyceride levels and older age at diagnosis.

In this study, we aimed to evaluate the importance of cerebellum in freezing of gait (FOG) pathophysiology. Due to the fundamental role of the cerebellum in posture and gait control, we examined cerebellar structural and functional connectivity (FC) in patients with PD and FOG. We recruited 15 PD with FOG (PD-FOG), 16 PD without FOG (PD-nFOG) patients, and 16 healthy subjects (HS). The FOG Questionnaire (FOG-Q) assessed FOG severity. Three tesla-MRI study included resting-state functional MRI, diffusion tensor imaging (DTI), and 3D T1-w images. We located seed regions in the cerebellar locomotor region, fastigial, and dentate nucleus to evaluate their FC. DTI parameters were obtained on the superior, middle, and inferior cerebellar peduncles. Global and lobular cerebellum volumes were also calculated. Cerebellar locomotor and fastigial FC was higher in cerebellar and posterior cortical areas in PD-FOG than in HS. FC of the cerebellar locomotor region with cerebellar areas positively correlated with FOG-Q. Dentate FC was lower in the prefrontal and parieto-occipital cortices in PD-FOG than in HS and in the brainstem, right basal ganglia, and frontal and parieto-occipital cortices than in PD-nFOG. DTI parameters in superior and middle cerebellar peduncles were altered in PD-FOG compared with PD-nFOG and significantly correlated with FOG-Q. There were no differences in cerebellar volumes between PD-FOG and either PD-nFOG or HS. Our results suggest that altered connectivity of the cerebellum contributes to the pathophysiology of FOG. FC of the cerebellar locomotor region and white matter (WM) properties of cerebellar peduncles correlate with FOG severity, supporting the hypothesis that abnormal cerebellar function underlies FOG in PD.

ABSTRACTThe cerebellum, traditionally associated with motor control, is increasingly recognized for its involvement in higher‐order cognitive functions. However, the role of cerebellar subregions in cognition remains underexplored, as are the roles of genetic factors on cerebellar structure and brain‐behavioral associations. The primary goal of this study was to investigate the relationship between cerebellar subregion volumes and cognitive performance. A secondary aim was to quantify the genetic contributions to cerebellar structure and determine the degree to which any brain‐behavior associations were genetically mediated. 3T anatomic MRI data from N = 932 typically developing individuals from the Human Connectome Project were used for this study. Twenty‐seven cerebellar regions of interest (ROIs) were automatically parcellated using CerebNet. Three additional lobar‐level ROIs were derived from smaller measures. Nine functional domains (six cognitive and three motor) related to known or suspected cerebellar function were selected. Linear regression analyses were conducted to identify correlations between cerebellar volumes and cognitive outcomes, adjusting for age, sex, and overall brain volume. Univariate and bivariate quantitative genetic modeling was then performed in OpenMx. There were numerous statistically significant phenotypic associations between cognitive measures and cerebellar lobar and lobular volumes, particularly in the IPL, AL, bilateral cortices, left lobule V, right lobule VI, vermis, and vermis lobule VIII, each meeting the threshold of p < 0.02 across at least four out of nine cognitive domains. The vermis and vermis lobule VIII were of particular note, showing even stronger associations (p < 0.0009 across three domains). Cognitive measures were modestly heritable, and cerebellar ROIs were highly heritable. Quantitative genetic models suggested that brain–behavior associations are largely driven by shared environmental factors. Our findings identify novel associations between specific cerebellar subregions and cognitive performance, highlighting the vermis as a critical structure. We also provide a detailed map of the quantitative genetics of human cerebellar structure. Future studies are warranted.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group’s model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12311-024-01659-0.

BackgroundThe cerebellum’s role in neuromyelitis optica spectrum disorder (NMOSD) remains inadequately explored, despite its known contributions to cognition and motor function.MethodsThis multimodal neuroimaging study integrated voxel-based morphometry (VBM), resting-state functional MRI (fMRI), and diffusion tensor imaging (DTI) to characterize cerebellar gray matter volume (GMV), microstructure, and functional connectivity (FC) in 29 NMOSD patients and 25 matched healthy controls. Clinical assessments included the Expanded Disability Status Scale (EDSS) and Montreal Cognitive Assessment (MoCA).ResultsPatients exhibited significant cerebellar alterations, including GMV reduction in bilateral lobules VI/VIII and the vermis, decreased fractional anisotropy in Crus I, and altered FC between Crus I and occipital/frontal regions. Critically, the structural and microstructural impairments correlated with higher EDSS scores (*p < 0.05), while FC changes were associated with lower MoCA scores.ConclusionThese findings implicate the cerebellum in both motor disability and cognitive impairment in NMOSD, providing novel evidence for cerebellar pathology as a contributor to disease progression.

The present study examined the relationship between subthreshold depressive symptoms and gray matter volume in subregions of the posterior cerebellum. Structural magnetic resonance imaging data from 38 adults aged 51 to 80 years were analyzed along with participants’ responses to the Center for Epidemiologic Studies Depression Scale. Subscale scores for depressed mood, somatic symptoms, and lack of positive affect were calculated, and multiple regression analyses were used to examine the relationship between symptom dimensions and cerebellar volumes. Greater total depressive symptoms and greater somatic symptoms of depression were significantly related to larger volumes of vermis VI, a region within the salience network, which is altered in depression. Exploratory analyses revealed that higher scores on the lack of positive affect subscale were related to larger vermis VIII volumes. These results support that depressive symptom profiles have unique relationships within the cerebellum that may be important as the field move towards targeted treatment approaches for depression.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogenous disorder, commonly described for presenting difficulties in sustained attention, response inhibition, and organizing goal-oriented behaviors. However, along with its traditionally described executive dysfunction, more than half of the children diagnosed with ADHD have been reported to show difficulties with gross and fine motor skills, albeit motor impairments in ADHD continue to be a neglected area of clinical attention. The rapidly growing field of the clinical cognitive neuroscience of the cerebellum has begun to relate cerebro-cerebellar circuits to neurodevelopmental disorders. While the cerebellum's role in motor function, such as balance, motor coordination, and execution, is well recognized, ongoing research has evidenced its additional and fundamental role in neurocognitive development and executive function, including attention and social cognition, which are all areas of impairment commonly found in ADHD. Interestingly, neuroimaging studies have consistently shown differences in cerebellar volume and functional connectivity between ADHD and typically developing children. Furthermore, methylphenidate is known to act at the cerebellar level, as intrinsic cerebellar dopaminergic systems involved in attention and motor function have been identified. This article reviews some of the main findings linking cerebellar dysfunction to ADHD behavioral symptoms and incorporates the cerebellum as a possible neurological basis and differentiating indicator within the condition. We suggest considering more rigorous assessments in future ADHD studies, including cerebellar-associated skill evaluations to correlate with symptom severity and other detected outcomes, such as executive dysfunction, and study possible associative patterns that may serve as more objective measures for this diagnosis.

Background Regional atrophy measures may offer useful information about the causes of specific clinical deficits in multiple sclerosis (MS). Objective To determine the magnitude of cerebellar gray and white matter (GM and WM) atrophy in patients with clinically isolated syndromes (CIS) and MS, and their role in clinical manifestations of cerebellar damage. Methods T1-weighted volumetric magnetic resonance imaging (MRI) of 73 patients [29 CIS, 33 relapsing–remitting MS (RRMS), 11 secondary progressive MS (SPMS)] was compared with 25 controls. GM and WM regions were generated using SPM5 and cerebellar regions delineated. Linear regression was used to investigate differences in tissue-specific cerebellar volumes between groups and the association with clinical measures. Results Mean cerebellar GM volume (CGMV) was 100.1 cm3 in controls, 96.4 cm3 in CIS patients, 91.8 cm3 in RRMS patients, and 88.8 cm3 in SPMS patients. Mean cerebellar WM volumes (CWMV) were 21.3 cm3, 20.4 cm3, 19.9 cm3, and 18.8 cm3, respectively. CGMV was reduced by 4.8 cm3 (P = 0.054) in RRMS patients, and 8.5 cm3 (P = 0.012) in SPMS patients, relative to controls. Only patients with SPMS showed a borderline significant reduction in CWMV compared with controls (mean 2.1 cm3, P = 0.053). CGMV was significantly smaller in patients assessed as having cerebellar dysfunction compared with patients who had normal cerebellar function. Significant associations of CGMV and CWMV with performance on the nine-hole peg test were also observed. Conclusion Clinically relevant GM atrophy occurs in the cerebellum of MS patients and is more prominent than WM atrophy. As such, it may provide complementary data to other regional atrophy and intrinsic tissue measures.

Cerebellar volume has been linked with cognitive performances in MS; however, the association in terms of fall status has never been compared. Therefore, the objective of the current study was to compare cognitive performance with cerebellar volume between MS fallers and non-fallers. The cross-sectional study included 140 PwMS (96 women). MRI volumetric analysis was based on the FreeSurfer image analysis suite. Volumes of the cerebellar gray and white matter were identified as the region of interest. Cognitive function included scores obtained from a computerized cognitive battery of tests. The sample was divided into fallers and non-fallers. MS fallers demonstrated a lower global cognitive performance and reduced gray and white matter cerebellar volumes compared to non-fallers. A significant association was found between total gray and white matter cerebellar volume and visual spatial subdomain (P value=0.044 and 0.032, respectively) in the non-fallers group. The association remained significant after controlling for the total cranial volume and neurological disability (P value=0.026 and 0.047, respectively). A relationship was found between the visual spatial score and the left gray matter cerebellum volume; R2=0.44, P value=0.021. We believe that a unique relationship exists between the cerebellum structure and cognitive processing according to fall history in PwMS and should be considered when investigating the association between brain functioning and cognitive performances in MS.

Background Children born preterm present a higher risk of psychiatric disorders during adolescence. Aim To assess whether psychiatric symptoms are associated with changes in cortical thickness and volumes of thalamus and cerebellum in very low birth weight (VLBW) adolescents. Design/methods Fifty VLBW (birth weight ≤1500 g) and 57 term control adolescents were assessed at 14–15 years of age with: Schedule for Affective Disorders and Schizophrenia for School-Age Children, Strengths and Difficulties Questionnaire (SDQ Mother Report), Autism Spectrum Screening Questionnaire (ASSQ), and Children’s Global Assessment Scale (CGAS). Cortical thickness (mm) and volumes of thalamus and cerebellum (ml) were obtained using an automated MRI segmentation technique (Freesurfer). Associations were analysed by linear and ordinal logistic regression, adjusted for age, gender and total intracranial volume, and corrected for multiple comparisons (Benjamini-Hochberg). Results VLBW adolescents had more psychiatric symptoms and diagnoses than controls. On MRI, they had several areas with thinner cortex, including the entorhinal cortex, and areas of thicker cortex, including the insula, compared to controls. Higher SDQ Emotional symptoms scores were associated with thicker insular cortex (Left: B=0.418 (0.192 to 0.644), p = 0.001; Right: B=0.243 (0.061 to 0.426), p = 0.010). Smaller cerebellar WM volumes were associated with higher SDQ Hyperactivity scores (Left: B=-0.638 (-1.101 to -0.176), p = 0.008; Right: B=-0.551 (-0.966 to -0.137), p = 0.010) and lower CGAS scores (Left: B=4.653 (2.182 to 7.123), p Conclusion Our results indicate that psychiatric symptoms in VLBW adolescents may be related to structural brain anomalies in cerebellar white matter and insular cortex.

Autism spectrum disorder is a neurodevelopmental disorder characterized by core deficits in social functioning. Core autistics traits refer to poor social and imagination skills, poor attention-switching/strong focus of attention, exceptional attention to detail, as expressed by the autism-spectrum quotient. Over the years, the importance of the cerebellum in the aetiology of autism spectrum disorder has been acknowledged. Neuroimaging studies have provided a strong support to this view, showing both structural and functional connectivity alterations to affect the cerebellum in autism spectrum disorder. According to the underconnectivity theory, disrupted connectivity within cerebello-cerebral networks has been specifically implicated in the aetiology of autism spectrum disorder. However, inconsistent results have been generated across studies. In this study, an integrated approach has been used in a selected population of adults with autism spectrum disorder to analyse both cerebellar morphometry and functional connectivity. In individuals with autism spectrum disorder, a decreased cerebellar grey matter volume affected the right Crus II, a region showing extensive connections with cerebral areas related to social functions. This grey matter reduction correlates with the degree of autistic traits as measured by autism-spectrum quotient. Interestingly, altered functional connectivity was found between the reduced cerebellar Crus II and contralateral cerebral regions, such as frontal and temporal areas. Overall, the present data suggest that adults with autism spectrum disorder present with specific cerebellar structural alterations that may affect functional connectivity within cerebello-cerebral modules relevant to social processing and account for core autistics traits.

Socioeconomic status (SES) is a time-varying multidimensional construct with ill-defined dimension-specific and age-specific effects on brain and behavior. We investigated these effects in 4,228 young adults. From 16 socioeconomic indicators, assessed for early (0-10 years) and late (>10 years) stages, we constructed family, provincial, family adverse and neighborhood adverse socioeconomic dimensions. Generally, family SES was associated with brain structure and connectivity along with cognitive function, whereas family adverse and neighborhood adverse SES were associated with personality and emotion. Most associations were observed for both early and late-stage SES; however, adjusting for the effect of early stage SES revealed late-stage-specific SES effects. Changes in SES were associated with personality and cognitive function. Cerebellar and medial frontal volumes and functional connectivity within the left frontoparietal network mediated the associations between family SES and memory and openness. These results inform both more precise interventions for reducing the consequences of adverse SES and experimental designs for excluding confounding socioeconomic effects on human health.

This study was conducted to explore differences in gray and white matter volume between cocaine-dependent and healthy comparison subjects using optimized voxel-based morphometry (VBM). Brain magnetic resonance imaging (MRI) and neuropsychological function tests were performed for 40 cocaine-dependent subjects (41.4+/-6.9 years, 27 men) and 41 healthy age- and sex-matched comparison subjects (38.7+/-8.8 years, 26 men). Optimally normalized whole brain MR images were segmented, modulated, smoothed, and compared between groups with statistical parametric mapping. The cocaine-dependent group had lower gray matter volumes in bilateral premotor cortex (Brodmann area (BA) 6, 8; 16.6%), right orbitofrontal cortex (BA 10, 15.1%), bilateral temporal cortex (BA 20, 38; 15.9%), left thalamus (12.6%), and bilateral cerebellum (13.4%) as well as lower right cerebellar white matter volume (10.0%) relative to the comparison group at a corrected p<0.05 for multiple comparisons. Duration of cocaine use negatively correlated with right and left cerebellar gray matter volumes (r=-0.37, r=-0.39, respectively). In cocaine-dependent subjects, lower cerebellar hemispheric gray and white matter volumes were correlated with deficits in executive function and decreased motor performance. This study reports that cocaine-dependent subjects have lower gray matter volumes in cerebellar hemispheres as well as in frontal, temporal cortex, and thalamus. These findings are the first to suggest that the cerebellum may be vulnerable to cocaine-associated brain volume changes, and that cerebellar deficits may contribute to neuropsychological deficits and motor dysfunction frequently observed in cocaine-dependent subjects.