Cerebellar Clusters Research Articles

Data-Driven Subtypes of Multiple System Atrophy and Their Implications for Prognosis.

While multiple system atrophy (MSA) presents with high heterogeneous motor and nonmotor symptoms, the associations between clinical phenotypes and prognosis are unclear. We aimed to evaluate clinical phenotypes of MSA using data-driven approach and measure the impact of phenotypes on survival and bedbound status. 193 MSA patients were recruited from Xuanwu Hospital Capital Medical University, whose history, motor and non-motor symptoms were examined using cluster analysis. Ninety-five participants were followed-up via telephone after a mean of 31.87 months. We employed Kaplan- Meier analysis to examine survival and performed Cox and logistic regression analyses to identify factors associated with survival and bedbound status. We identified four clinical profiles of MSA: cerebellar symptom-dominant, sleep and mood disorder-dominant, rigid akinetic-dominant, and malignant diffuse. The overall median survival was 7.75 years (95% CI 7.19-8.31). After adjusting for years from symptom onset to diagnosis, age and sex, patients in the malignant diffuse and rigid akinetic-dominant clusters had greater risk of death than sleep and mood disorder-dominant cluster. Furthermore, patients in the malignant diffuse and rigid akinetic-dominant clusters had higher risk of being bedbound than cerebellar symptom-dominant cluster. The malignant diffuse and sleep and mood disorder-dominant were identified besides the two classical subtypes, parkinsonism, and cerebellar symptom-variant. Patients with rigid-akinetic motor profiles have a worse prognosis than cerebellar symptom-dominant profiles in general. Diffuse symptoms, especially postural instability, and cognitive alterations at diagnosis, indicate rapid functional loss and disease progression. The different profiles and prognoses might indicate varied underlying pathological mechanisms.

Pons-to-Cerebellum Hypoconnectivity Along the Psychosis Spectrum and Associations With Sensory Prediction and Hallucinations in Schizophrenia

BackgroundSensory prediction allows the brain to anticipate and parse incoming self-generated sensory information from externally generated signals. Sensory prediction breakdowns may contribute to perceptual and agency abnormalities in psychosis (hallucinations, delusions). The pons, a central node in a cortico-ponto-cerebellar-thalamo-cortical circuit, is thought to support sensory prediction. Examination of pons connectivity in schizophrenia and its role in sensory prediction abnormalities is lacking. MethodsWe examined these relationships using resting-state functional magnetic resonance imaging and the electroencephalography-based auditory N1 event-related potential in 143 participants with psychotic spectrum disorders (PSPs) (with schizophrenia, schizoaffective disorder, or bipolar disorder); 63 first-degree relatives of individuals with psychosis; 45 people at clinical high risk for psychosis; and 124 unaffected comparison participants. This unique sample allowed examination across the psychosis spectrum and illness trajectory. Seeding from the pons, we extracted average connectivity values from thalamic and cerebellar clusters showing differences between PSPs and unaffected comparison participants. We predicted N1 amplitude attenuation during a vocalization task from pons connectivity and group membership. We correlated participant-level connectivity in PSPs and people at clinical high risk for psychosis with hallucination and delusion severity. ResultsCompared to unaffected comparison participants, PSPs showed pons hypoconnectivity to 2 cerebellar clusters, and first-degree relatives of individuals with psychosis showed hypoconnectivity to 1 of these clusters. Pons-to-cerebellum connectivity was positively correlated with N1 attenuation; only PSPs with heightened pons-to-postcentral gyrus connectivity showed this pattern, suggesting a possible compensatory mechanism. Pons-to-cerebellum hypoconnectivity was correlated with greater hallucination severity specifically among PSPs with schizophrenia. ConclusionsDeficient pons-to-cerebellum connectivity linked sensory prediction network breakdowns with perceptual abnormalities in schizophrenia. Findings highlight shared features and clinical heterogeneity across the psychosis spectrum.

Functional Brain Activation in Mild Cognitive Impairment With Defined Small Vessel Disease Burden

AbstractBackgroundVascular dysregulations and changes in functional brain network integrity play a fundamental role in the pathogenesis of dementia. While often identified in individuals with dementia, the role of small vessel disease (SVD) in the development of dementia is not completely understood yet. Previously, structural and functional brain connectivity was shown to be different between individuals with and without cerebral SVD, but a comprehensive measure of SVD has not been used consistently. We aim to analyze functional brain activation differences in mild cognitive impairment (MCI) individuals with defined SVD burden.MethodFunctional brain activation differences were analyzed in MCI individuals with absent or low (n = 34) or high (n = 34) SVD burden using data from the Parelsnoer Institute, a multicenter study involving eight Dutch medical centers. SVD burden was characterized using an ordinal scale ranging from 0 to 4 (Klarenbeek et al., 2013) considering the following markers: lacunes; microbleeds; perivascular spaces in the basal ganglia; white matter hyperintensities based on the Fazekas score. Two groups were identified: the absent or low SVD burden group with a score of 0 or 1 and the high SVD group with a score between 2 and 4. Activation differences were calculated using resting state fMRI data acquired using 3Tesla scanners and analyzed with group‐independent component analysis using the CONN toolbox.ResultActivation of two clusters in the high SVD burden group was lower than in the absent or low SVD group: the cerebellum (p‐FDR >. 001, F = 1.49) and the brainstem (p‐FDR >. 001, F = 2.79). The cerebellar cluster (4541 voxels, +20 ‐74 ‐38) consisted of the left cerebellum crus II, right cerebellum crus II, and left cerebellum lobule VIII. The brainstem cluster (218 voxels, +22 ‐28 +20) involved the right thalamus and the right caudate nucleus.ConclusionBrain activation differences between groups of individuals with MCI and absent or low or high SVD burden were found in the cerebellum and brainstem. These brain areas are mainly responsible for motor, attentional and executive functions, domains which were found in previous studies to be mostly associated with SVD markers.

Extended source analysis of movement related potentials (MRPs) for self-paced hand and foot movements demonstrates opposing cerebral and cerebellar laterality: a preliminary study

The cerebellum is known to have extensive reciprocal connectivity with the cerebral cortex, including with prefrontal and posterior parietal cortex, which play an important role on the planning and execution of voluntary movement. In the present article we report an exploratory non-invasive electrophysiological study of the activity of the cerebellum and cerebrum during voluntary finger and foot movements. In a sample of five healthy adult subjects, we recorded EEG and the electro-cerebellogram (ECeG) with a 10% cerebellar extension montage during voluntary left and right index finger and foot movements. EMG was recorded from finger extensors and flexors and from the tibialis anterior and soleus muscles and was used to generate triggers for movement related averaging (−2000 to +2000 ms). Source analysis was conducted over five epochs defined relative to EMG onset: whole epoch (−1000 to +1000 ms), pre-move 1000 (−1000 to 0 ms), pre-move 500 (−500 to 0 ms), post-move 500 (0 to +500 ms) and post-move 1000 (0 to +1000 ms). This yielded a total of 123 cerebral and 65 cerebellar dipole clusters from across all epochs, including the pre-movement epochs, which were then subject to statistical analysis. These demonstrated predominantly contralateral dominance for the cerebral clusters, but predominantly ipsilateral dominance for the cerebellar clusters. In addition, both cerebral and cerebellar clusters showed evidence of a somatotopic gradient, medially (X-axis) for the cerebral clusters, and medially and dorso-ventrally (Z-axis) for the cerebellar clusters. These findings support the value of recording cerebellar ECeG and demonstrate its potential to contribute to understanding cerebellar function.

Brain volumes in alcohol use disorder: Do females and males differ? A whole-brain magnetic resonance imaging mega-analysis.

Emerging evidence suggests distinct neurobiological correlates of alcohol use disorder (AUD) between sexes, which however remain largely unexplored. This work from ENIGMA Addiction Working Group aimed to characterize the sex differences in gray matter (GM) and white matter (WM) correlates of AUD using a whole-brain, voxel-based, multi-tissue mega-analytic approach, thereby extending our recent surface-based region of interest findings on a nearly matching sample using a complementary methodological approach. T1-weighted magnetic resonance imaging (MRI) data from 653 people with AUD and 326 controls was analyzed using voxel-based morphometry. The effects of group, sex, group-by-sex, and substance use severity in AUD on brain volumes were assessed using General Linear Models. Individuals with AUD relative to controls had lower GM volume in striatal, thalamic, cerebellar, and widespread cortical clusters. Group-by-sex effects were found in cerebellar GM and WM volumes, which were more affected by AUD in females than males. Smaller group-by-sex effects were also found in frontotemporal WM tracts, which were more affected in AUD females, and in temporo-occipital and midcingulate GM volumes, which were more affected in AUD males. AUD females but not males showed a negative association between monthly drinks and precentral GM volume. Our results suggest that AUD is associated with both shared and distinct widespread effects on GM and WM volumes in females and males. This evidence advances our previous region of interest knowledge, supporting the usefulness of adopting an exploratory perspective and the need to include sex as a relevant moderator variable in AUD.

Altered cerebral blood flow in patients with spinocerebellar degeneration.

ObjectivesSpinocerebellar degeneration (SCD) comprises a multitude of disorders with sporadic and hereditary forms, including spinocerebellar ataxia (SCA). Except for progressive cerebellar ataxia and structural atrophy, hemodynamic changes have also been observed in SCD. This study aimed to explore the whole-brain patterns of altered cerebral blood flow (CBF) and its correlations with disease severity and psychological abnormalities in SCD via arterial spin labeling (ASL).MethodsThirty SCD patients and 30 age- and sex-matched healthy controls (HC) were prospectively recruited and underwent ASL examination on a 3.0T MR scanner. The Scale for Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS) scores were used to evaluate the disease severity in SCD patients. Additionally, the status of anxiety, depression and sleep among all patients were, respectively, evaluated by the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS) and Self-Rating Scale of Sleep (SRSS). We compared the whole-brain CBF value between SCD group and HC group at the voxel level. Then, the correlation analyses between CBF and disease severity, and psychological abnormalities were performed on SCD group.ResultsCompared with HC, SCD patients demonstrated decreased CBF value in two clusters (FWE corrected P < 0.05), covering bilateral dentate and fastigial nuclei, bilateral cerebellar lobules I-IV, V and IX, left lobule VI, right lobule VIIIb, lobules IX and X of the vermis in the cerebellar Cluster 1 and the dorsal part of raphe nucleus in the midbrain Cluster 2. The CBF of cerebellar Cluster 1 was negatively correlated with SARA scores (Spearman’s rho = –0.374, P = 0.042) and SDS standard scores (Spearman’s rho = –0.388, P = 0.034), respectively. And, the CBF of midbrain Cluster 2 also had negative correlations with SARA scores (Spearman’s rho = –0.370, P = 0.044) and ICARS scores (Pearson r = –0.464, P = 0.010).ConclusionThe SCD-related whole-brain CBF changes mainly involved in the cerebellum and the midbrain of brainstem, which are partially overlapped with the related function cerebellar areas of hand, foot and tongue movement. Decreased CBF was related to disease severity and depression status in SCD. Therefore, CBF may be a promising neuroimaging biomarker to reflect the severity of SCD and suggest mental changes.

Insular functional connectivity in migraine with aura

IntroductionInsula plays an integrating role in sensory, affective, emotional, cognitive and autonomic functions in migraine, especially in migraine with aura (MA). Insula is functionally divided into 3 subregions, the dorsoanterior, the ventroanterior and the posterior insula respectively related to cognition, emotion, and somatosensory functions. This study aimed at investigating functional connectivity of insula subregions in MA.MethodsTwenty-one interictal patients with MA were compared to 18 healthy controls (HC) and 12 interictal patients with migraine without aura (MO) and were scanned with functional MRI during the resting state. Functional coupling of the insula was comprehensively tested with 12 seeds located in the right and left, dorsal, middle, ventral, anterior and posterior insula, by using a seed-to-voxel analysis.ResultsSeed-to-voxel analysis revealed, in MA, a strong functional coupling of the right and left antero-dorsal insula with clusters located in the upper cerebellum. The overlap of these cerebellar clusters corresponded to the vermis VI. These functional couplings were not correlated to duration of MA, frequency of MA attacks nor time since last MA attack, and were not found in MO.DiscussionThe anterior insula and superior cerebellum, including vermis VI, are components of the central Autonomic Nervous System (ANS) network. As these regions are involved in the control of cardiovascular parasympathetic tone, we hypothesize that this connectivity may reflect the cardiovascular features of MA.ConclusionThe anterior dorsal insula is connected with vermis VI in MA patients in the resting state. This connectivity may reflect the cardiovascular features of MA.Trial registrationNCT02708797.

Coherent theta oscillations in the cerebellum and supplementary motor area mediate visuomotor adaptation

The cerebellum and its interaction with cortical areas play a key role in our ability to flexibly adapt a motor program in response to sensory input. Current knowledge about specific neural mechanisms underlying the process of visuomotor adaptation is however lacking. Using a novel placement of EEG electrodes to record electric activity from the cerebellum, we studied local cerebellar activity, as well as its coupling with neocortical activity to obtain direct neurophysiological markers of visuomotor adaptation in humans. We found increased theta (4–8 Hz) power in “cerebellar” as well as cortical electrodes, when subjects first encountered a visual manipulation. Theta power decreased as subjects adapted to the perturbation, and rebounded when the manipulation was suddenly removed. This effect was observed in two distinct locations: a cerebellar cluster and a central cluster, which were localized in left cerebellar crus I (lCB) and right supplementary motor area (rSMA) using linear constrained minimum variance beamforming. Importantly, we found that better adaptation was associated with increased theta power in left cerebellar electrodes and a right sensorimotor cortex electrode. Finally, increased rSMA -> lCB connectivity was significantly decreased with adaptation. These results demonstrate that: (1) cerebellar theta power is markedly modulated over the course of visuomotor adaptation and (2) theta oscillations could serve as a key mechanism for communication within a cortico-cerebellar loop.

Neural Mechanisms of Prism Adaptation in Healthy Adults and Individuals with Spatial Neglect after Unilateral Stroke: A Review of fMRI Studies.

Functional disability due to spatial neglect hinders recovery in up to 30% of stroke survivors. Prism adaptation treatment (PAT) may alleviate the disabling consequences of spatial neglect, but we do not yet know why some individuals show much better outcomes following PAT than others. The goal of this scoping review and meta-analysis was to investigate the neural mechanisms underlying prism adaptation (PA). We conducted both quantitative and qualitative analyses across fMRI studies investigating brain activity before, during, and after PA, in healthy individuals and patients with right or left brain damage (RBD or LBD) due to stroke. In healthy adults, PA was linked with activity in posterior parietal and cerebellar clusters, reduced bilateral parieto-frontal connectivity, and increased fronto-limbic and sensorimotor network connectivity. In contrast, RBD individuals with spatial neglect relied on different circuits, including an activity cluster in the intact left occipital cortex. This finding is consistent with a shift in hemispheric dominance in spatial processing to the left hemisphere. However, more studies are needed to clarify the contribution of lesion location and load on the circuits involved in PA after unilateral brain damage. Future studies are also needed to clarify the relationship of decreasing resting state functional connectivity (rsFC) to visuomotor function.

Associations of Regional and Network Functional Connectivity With Exercise-Induced Low Back Pain

Musculoskeletal pain is an aversive experience that exists within a variety of conditions and can result in significant impairment for individuals. Gaining greater understanding of the factors related to pain vulnerability and resilience to musculoskeletal pain may help target at-risk individuals for early intervention. This analysis builds on our previous work identifying regions where greater gray matter density was associated with lower pain following standardized, exercise induced musculoskeletal injury. Here we sought to examine the relationship between baseline resting state functional connectivity in a priori regions and networks, and delayed onset muscle soreness (DOMS) pain intensity following a single session of eccentric exercise in healthy adults. Participants completed a baseline functional MRI scan and a high intensity trunk exercise protocol in the erector spinae. Pain intensity ratings were collected 48-hours later. Resting state functional connectivity from four seed regions and 3 networks were separately regressed on pain intensity scores. Results revealed that connectivity between left middle frontal gyrus, the left occipital gyrus and cerebellar network seeds and clusters associated with discriminative, emotional, and cognitive aspects of pain were associated with lower post-DOMS pain. Results suggest resilience to clinically relevant pain is associated with aspects of regional and network neural coherence. Investigations of pain modulatory capacity that integrate multimodal neuroimaging metrics are called for. PerspectiveOur results provide key support for the role of structural and functional coherence in regional and network connectivity in adaptive pain response and represent an important step in clarifying neural mechanisms of resilience to clinically relevant pain.

Resilience to acute musculoskeletal pain: resting-state functional connectivity of regions associated with gray matter density differences following induction of low-back pain

Musculoskeletal pain is an aversive experience that exists within a variety of conditions and can result in significant impairment for individuals. Gaining greater understanding of the factors related to pain vulnerability and resilience to musculoskeletal pain may help target at-risk individuals for early intervention. This analysis builds on our previous work identifying regions where lower gray matter density (GMD) was associated with individuals who report pain following standardized, exercise induced musculoskeletal injury. Here we sought to examine the relationship between baseline resting state functional connectivity (rsFC) in a priori regions and networks, and delayed onset muscle soreness (DOMS) pain intensity following a single session of eccentric exercise. The present study is a secondary analysis from a portion of a larger, blinded, randomized experimental trial. All participants were healthy adults between the ages of 18 and 40 years recruited from the university and surrounding community. The primary outcome measure was functional connectivity assessed by using T2 rest image. Participants completed a baseline functional MRI scan and a high intensity trunk exercise protocol to induce DOMS in the erector spinae. Pain intensity ratings were collected 48-hours later. rsFC from four seed regions and three networks were separately regressed on pain intensity scores. Our results revealed that connectivity between left middle frontal gyrus, the left occipital gyrus and cerebellar network seeds and clusters associated with discriminative, emotional, and cognitive aspects of pain were associated with lower post-DOMS pain. Our results provide key support for the role of structural and functional coherence in regional and network connectivity in adaptive pain response and represent an important step in clarifying neural mechanisms of resilience to clinically relevant pain. Resilience to clinically relevant pain is associated with aspects of regional and network neural coherence. Investigations of pain modulatory capacity that integrate multimodal neuroimaging metrics are called for. R01AT006334, PI Dr. Mark Bishop.

Functional Role of the Cerebellum in Parkinson Disease: A PET Study.

To test for cerebellar involvement in motor and nonmotor impairments in Parkinson disease (PD) and to determine patterns of metabolic correlations with supratentorial brain structures, we correlated clinical motor, cognitive, and psychiatric scales with cerebellar metabolism. We included 90 patients with PD. Motor, cognitive, and psychiatric domains were assessed, and resting-state 18FDG-PET metabolic imaging was performed. The motor, cognitive, and psychiatric scores were entered separately into a principal component analysis. We looked for correlations between these 3 principal components and cerebellar metabolism. Furthermore, we extracted the mean glucose metabolism value for each significant cerebellar cluster and looked for patterns of cerebrum-cerebellum metabolic correlations. Severity of impairment was correlated with increased metabolism in the anterior lobes and vermis (motor domain); the right crus I, crus II, and declive (cognitive domain); and the right crus I and crus II (psychiatric domain). No results survived multiple testing corrections regarding the psychiatric domain. Moreover, we found distributed and overlapping, but not identical, patterns of metabolic correlations for motor and cognitive domains. Specific supratentorial structures (cortical structures, basal ganglia, and thalamus) were strongly correlated with each of the cerebellar clusters. These results confirm the role of the cerebellum in nonmotor domains of PD, with differential but overlapping patterns of metabolic correlations suggesting the involvement of cerebello-thalamo-striatal-cortical loops.

18F-FDG brain PET hypometabolism in patients with long COVID.

PurposeIn the context of the worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), some patients report functional complaints after apparent recovery from COVID-19. This clinical presentation has been referred as “long COVID.” We here present a retrospective analysis of 18F-FDG brain PET of long COVID patients from the same center with a biologically confirmed diagnosis of SARS-CoV-2 infection and persistent functional complaints at least 3 weeks after the initial infection.MethodsPET scans of 35 patients with long COVID were compared using whole-brain voxel-based analysis to a local database of 44 healthy subjects controlled for age and sex to characterize cerebral hypometabolism. The individual relevance of this metabolic profile was evaluated to classify patients and healthy subjects. Finally, the PET abnormalities were exploratory compared with the patients’ characteristics and functional complaints.ResultsIn comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected). These metabolic clusters were highly discriminant to distinguish patients and healthy subjects (100% correct classification). These clusters of hypometabolism were significantly associated with more numerous functional complaints (brainstem and cerebellar clusters), and all associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia) (p < 0.05). In a more preliminary analysis, the metabolism of the frontal cluster which included the olfactory gyrus was worse in the 7 patients treated by ACE drugs for high blood pressure (p = 0.032), and better in the 3 patients that had used nasal decongestant spray at the infectious stage (p < 0.001).ConclusionThis study demonstrates a profile of brain PET hypometabolism in long COVID patients with biologically confirmed SARS-CoV-2 and persistent functional complaints more than 3 weeks after the initial infection symptoms, involving the olfactory gyrus and connected limbic/paralimbic regions, extended to the brainstem and the cerebellum. These hypometabolisms are associated with patients’ symptoms, with a biomarker value to identify and potentially follow these patients. The hypometabolism of the frontal cluster, which included the olfactory gyrus, seems to be linked to ACE drugs in patients with high blood pressure, with also a better metabolism of this olfactory region in patients using nasal decongestant spray, suggesting a possible role of ACE receptors as an olfactory gateway for this neurotropism.

Brain metabolic correlates of apathy in amyotrophic lateral sclerosis: An 18F-FDG-positron emission tomography stud.

The aim of this study was to evaluate brain metabolic correlates of apathy in amyotrophic lateral sclerosis (ALS). A total of 165 ALS patients underwent 18 F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG-PET) and Frontal Systems Behaviour Scale (FrSBe) evaluation. FrSBe provides "before" and "after" apathy subscores, referring to premorbid and morbid conditions. "After" apathy subscore and "before-after" gap, i.e. the difference between "before" and "after" subscores, were regressed against whole-brain metabolism. Among patients with a pathological "after" apathy subscore (i.e., ≥65), we compared patients with "before" apathy subscores ≥65 and <65, and patients with "before-after" gaps of <22 and ≥22. In the whole sample, the "after" apathy subscore negatively correlated with metabolism in the dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), ventrolateral prefrontal cortex (VLPFC), premotor cortex (PMC) and anterior cingulate cortex (ACC), and insula bilaterally. A positive correlation was found in the cerebellum and pons. The "before-after" gap negatively correlated with metabolism in bilateral DLPFC, DMPFC and PMC, and left VLPFC and ACC, and positively correlated with cerebellar and pontine clusters. Among patients with an "after" apathy subscore ≥65, we found no difference between those with "before" apathy subscores ≥65 and <65. Patients with a "before-after" gap ≥22, compared to patients with a gap <22, showed relative hypometabolism in bilateral DLPFC and DMPFC, and left ACC and PMC, and relative cerebellar and pontine hypermetabolism. No studies on brain 18 F-2-fluoro-2-deoxy-D-glucose positron emission tomography correlates of apathy have been performed in ALS. We found that FrSBe "after" apathy subscore correlated with metabolic changes in brain regions known as neuroanatomical correlates of apathy. Furthermore, our findings support the relevance of the gap between premorbid and morbid conditions to detect behavioural changes due to the neurodegenerative process underlying ALS.

Voxel-based morphometry and task functional magnetic resonance imaging in essential tremor: evidence for a disrupted brain network

The pathophysiology of essential tremor (ET) is controversial and might be further elucidated by advanced neuroimaging. Focusing on homogenous ET patients diagnosed according to the 2018 consensus criteria, this study aimed to: (1) investigate whether task functional MRI (fMRI) can identify networks of activated and deactivated brain areas, (2) characterize morphometric and functional modulations, relative to healthy controls (HC). Ten ET patients and ten HC underwent fMRI while performing two motor tasks with their upper limb: (1) maintaining a posture (both groups); (2) simulating tremor (HC only). Activations/deactivations were obtained from General Linear Model and compared across groups/tasks. Voxel-based morphometry and linear regressions between clinical and fMRI data were also performed. Few cerebellar clusters of gray matter loss were found in ET. Conversely, widespread fMRI alterations were shown. Tremor in ET (task 1) was associated with extensive deactivations mainly involving the cerebellum, sensory-motor cortex, and basal ganglia compared to both tasks in HC, and was negatively correlated with clinical tremor scales. Homogeneous ET patients demonstrated deactivation patterns during tasks triggering tremor, encompassing a network of cortical and subcortical regions. Our results point towards a marked cerebellar involvement in ET pathophysiology and the presence of an impaired cerebello-thalamo-cortical tremor network.

Brain Plasticity in Charcot-Marie-Tooth Type 1A Patients? A Combined Structural and Diffusion MRI Study.

Central nervous system involvement has been described in peripheral neuropathies, including different forms of Charcot-Marie-Tooth (CMT) disease. The aim of our study was to systematically investigate possible brain structural modifications in CMT1A patients, using volumetric MRI, and diffusion tensor imaging (DTI). In this prospective cross-sectional study, from May 2017 to May 2019, we acquired 3T MRI brain scans of genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing motor and sensory domains. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses were performed using a non-parametric approach based on permutations, including age and sex (and total intracranial volume for VBM) as nuisance covariates. When between-group differences emerged at VBM or TBSS analyses, the first eigenvariate was extracted from the cluster and its age- and sex-adjusted standardized residuals tested for correlation with clinical and electrophysiological variables. Twenty CMT1A patients (34.5 ± 11.1 years; M/F:11/9) were enrolled, along with 20 healthy controls (30.1 ± 10.2 years; M/F:11/9). The VBM analysis revealed clusters of significantly increased GM volume in CMT1A patients compared to healthy controls, encompassing the bilateral cerebellar lobules III-VI and the left hippocampus (all ps = 0.04), with no differences in terms of DTI metrics at the TBSS analysis. A negative correlation (r = −0.502, p = 0.03) emerged between ulnar compound motor action potential and the z-scores corresponding to the right cerebellar cluster of augmented GM volume. Our data show evidence of structural reorganization in the brain of CMT1A patients, possibly reflecting neural plasticity mechanisms in response to peripheral nerve pathology and modulating the effect of axonal degeneration on functional impairment.

Functional Alterations Associated with Structural Abnormalities in Adults with High-Functioning Autism Spectrum Disorder.

Background: The combination of structural and functional analyses is a biologically valid approach that offers methodological advantages in autism spectrum disorder (ASD) neuroimaging science. The paucity of studies combining these methods constitutes an important knowledge gap. In this study, we investigate structural abnormalities and their associated functional differences in a developmentally homogeneous ASD cohort. Methods: Whole-brain voxel-based morphometry (VBM) analyses were performed on 28 ASD participants and 38 age-matched typically developing healthy controls (HC) to derive gray matter (GM) volume differences. The anatomically relevant clusters identified by VBM served as seed regions of interest (ROI) for resting-state functional-connectivity (RsFc) analysis. Results: Whole-brain VBM analyses revealed significant right lateralized GM volume abnormality in the ASD group, with lower GM volumes in cerebellar lobules VIIb/VIIIa (cluster 1) and significantly higher GM volumes in posterior middle/superior temporal gyri (Brodmann area [BA] 21/22, cluster 2) compared with HC. Whole-brain RsFc analysis in high-functioning ASD (HF-ASD) revealed significant hypoconnectivity of the cerebellar VBM cluster with the right cerebral cortical regions of superior parietal lobule (BA 7) and occipital pole (BA 19) (overlapping with dorsal attention and visual networks, respectively). Cerebral cortical VBM cluster (cluster 2) revealed significant hypoconnectivity in HF-ASD with other task-positive cerebral cortical including the left lateral prefrontal cortex (frontoparietal network) and some aspects of the insula (ventral attention network) and ectopic positive connectivity (lack of anticorrelations) with posterior cingulate cortex and medial prefrontal cortex (default mode network). Conclusions: The cerebro-cerebellar intrinsic functional dysconnectivity based on the whole-brain VBM-derived ROIs may advance our understanding of the compensatory mechanisms associated with ASD and offer cerebellum as a potential target for diagnostic, predictive, prognostic, and therapeutic interventions in ASD. Our findings also provide additional support indicating that functional abnormalities as indexed by RsFc exist in ASD, and highlight that there is likely a relationship between structural and functional abnormalities in this disorder. Impact statement Our findings indicate that functional differences as indexed by resting-state functional connectivity exist in autism spectrum disorder (ASD), and highlight that there is likely a relationship between structural and functional abnormalities in this disorder. Future developments in neuroimaging research should continue investigating structural and associated functional differences in ASD, and in this way complement the behavioral characterization of this disorder, potentially improving diagnosis, prognosis, and prediction.

Functional Connectivity Changes in Retired Rugby League Players: A Data-Driven Functional Magnetic Resonance Imaging Study.

There is considerable interest in the long-term brain health of retired contact and collision sport athletes; however, little is known about possible underlying changes in functional brain connectivity in this group. We evaluated whole-brain functional connectivity patterns using multi-voxel pattern analysis (MVPA) to determine whether alterations in functional connectivity distinguish retired professional athletes from a matched group of healthy community control subjects. Thirty-two retired athletes with a history of multiple self-reported sport-related concussions and 36 healthy community control subjects who were similar in age and education, completed functional magnetic resonance imaging. We identified brain regions with abnormal functional connectivity patterns using whole-brain MVPA as implemented in the Conn toolbox. First-level MVPA was performed using 64 principal component analysis (PCA) components. Second-level F test was performed using the first three MVPA components for retired athletes > controls group contrast. Post hoc seed-to-voxel analyses using the MVPA cluster results as seeds were performed to characterize functional connectivity abnormalities from brain regions identified by MVPA. MVPA revealed one cluster of abnormal functional connectivity located in cerebellar lobule V. This region of lobule V corresponded to the ventral attention network. Post hoc seed-to-voxel analysis using the cerebellar MVPA cluster as a seed revealed multiple areas of cerebral cortical hyper-connectivity and hypo-connectivity in retired athletes when compared with controls. This initial report suggests that cerebellar dysfunction might be present and clinically important in some retired athletes.

Cerebellar Contributions to Proactive and Reactive Control in the Stop Signal Task: A Systematic Review and Meta-Analysis of Functional Magnetic Resonance Imaging Studies.

The cerebellum facilitates and modulates cognitive functions using forward and inverse internal models to predict and control behavior, respectively. Despite neuroimaging evidence that regions of the cerebellum are active during executive function (EF) tasks in general, little is known about the cerebellum's role in specific EFs and their underlying neural networks. Inhibitory control specifically may be facilitated by cerebellar internal models predicting responses during proactive control (withholding), and controlling responses during reactive control (inhibiting). The stop signal task (SST) is an inhibitory control task often used in neuroimaging studies to measure neural responses to both proactive and reactive control. Thus, in this review, we examine evidence for the cerebellum's role in inhibitory control by reviewing studies of healthy adults that utilized the SST in event-related functional magnetic resonance imaging (fMRI) experiments. Twenty-one studies that demonstrated cerebellar results were eligible for review, including 749 participants, 28 contrasts, and 38 cerebellar clusters. We also performed activation likelihood estimation (ALE) meta-analysis of contrasts derived from reviewed studies. This review illustrates evidence for the cerebellum participating in inhibitory control independent of motor control. Most significant cerebellar clusters were located in the left posterior cerebellum, suggesting that it communicates with the established cortical right-lateralized inhibitory control network. Cerebellar activity was most consistently observed for contrasts that measured proactive control, and ALE analysis confirmed that left Crus I is most likely to be activated in studies of proactive control measuring monitoring and anticipation. Results suggest that the left posterior cerebellum may communicate with right frontal and parietal cortices, using forward models to predict appropriate responses. Reactive control contrasts indicated a possible role for cerebellar regions in enhancing inhibition efficiency through inverse models, but ALE meta-analysis did not confirm this hypothesis. Limitations in the current literature, clinical implications, and directions for future research are discussed.

Locus coeruleus connectivity alterations in late-life major depressive disorder during a visual oddball task

The Locus Coeruleus (LC) is the major source of noradrenergic neurotransmission. Structural alterations in the LC have been observed in neurodegenerative disorders and at-risk individuals, although functional connectivity studies between the LC and other brain areas have not been yet performed in these populations. Patients with late-life major depressive disorder (MDD) are indeed at increased risk for neurodegenerative disorders, and here we investigated LC connectivity in late-life MDD in comparison to individuals with amnestic type mild cognitive impairment (aMCI) and healthy controls (HCs). We assessed 20 patients with late-life MDD, 16 patients with aMCI, and 26 HCs, who underwent a functional magnetic resonance scan while performing a visual oddball task. We assessed task-related modulations of LC connectivity (i.e., Psychophysiological Interactions, PPI) with other brain areas. A T1-weighted fast spin-echo sequence for LC localization was also obtained. Patients with late-life MDD showed lower global connectivity during target detection in a cluster encompassing the right caudal LC. Specifically, we observed lower LC connectivity with the left anterior cingulate cortex (ACC), the right fusiform gyrus, and different cerebellar clusters. Moreover, alterations in LC-ACC connectivity correlated negatively with depression severity (i.e., Geriatric Depression Scale and number of recurrences). Reduced connectivity of the LC during oddball performance seems to specifically characterize patients with late-life MDD, but not other populations of aged individuals with cognitive alterations. Such alteration is associated with different measures of disease severity, such as the current presence of symptoms and the burden of disease (number of recurrences).