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1.
CNS Neurosci Ther ; 30(6): e14786, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38828694

ABSTRACT

PURPOSE: To investigate dynamic functional connectivity (dFC) within the cerebellar-whole brain network and dynamic topological properties of the cerebellar network in obstructive sleep apnea (OSA) patients. METHODS: Sixty male patients and 60 male healthy controls were included. The sliding window method examined the fluctuations in cerebellum-whole brain dFC and connection strength in OSA. Furthermore, graph theory metrics evaluated the dynamic topological properties of the cerebellar network. Additionally, hidden Markov modeling validated the robustness of the dFC. The correlations between the abovementioned measures and clinical assessments were assessed. RESULTS: Two dynamic network states were characterized. State 2 exhibited a heightened frequency, longer fractional occupancy, and greater mean dwell time in OSA. The cerebellar networks and cerebrocerebellar dFC alterations were mainly located in the default mode network, frontoparietal network, somatomotor network, right cerebellar CrusI/II, and other networks. Global properties indicated aberrant cerebellar topology in OSA. Dynamic properties were correlated with clinical indicators primarily on emotion, cognition, and sleep. CONCLUSION: Abnormal dFC in male OSA may indicate an imbalance between the integration and segregation of brain networks, concurrent with global topological alterations. Abnormal default mode network interactions with high-order and low-level cognitive networks, disrupting their coordination, may impair the regulation of cognitive, emotional, and sleep functions in OSA.


Subject(s)
Cerebellum , Nerve Net , Sleep Apnea, Obstructive , Humans , Male , Sleep Apnea, Obstructive/physiopathology , Sleep Apnea, Obstructive/diagnostic imaging , Cerebellum/diagnostic imaging , Cerebellum/physiopathology , Middle Aged , Adult , Nerve Net/diagnostic imaging , Nerve Net/physiopathology , Magnetic Resonance Imaging , Connectome , Neural Pathways/physiopathology , Neural Pathways/diagnostic imaging , Default Mode Network/physiopathology , Default Mode Network/diagnostic imaging
2.
BMC Neurol ; 24(1): 205, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38879485

ABSTRACT

BACKGROUND: The application of cerebellar transcranial magnetic stimulation (TMS) in stroke patients has received increasing attention due to its neuromodulation mechanisms. However, studies on the effect and safety of cerebellar TMS to improve balance capacity and activity of daily living (ADL) for stroke patients are limited. This systematic review and meta-analysis aimed to investigate the effect and safety of cerebellar TMS on balance capacity and ADL in stroke patients. METHOD: A systematic search of seven electronic databases (PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang and Chinese Scientific Journal) were conducted from their inception to October 20, 2023. The randomized controlled trials (RCTs) of cerebellar TMS on balance capacity and/or ADL in stroke patients were enrolled. The quality of included studies were assessed by Physiotherapy Evidence Database (PEDro) scale. RESULTS: A total of 13 studies involving 542 participants were eligible. The pooled results from 8 studies with 357 participants showed that cerebellar TMS could significantly improve the post-intervention Berg balance scale (BBS) score (MD = 4.24, 95%CI = 2.19 to 6.29, P < 0.00001; heterogeneity, I2 = 74%, P = 0.0003). The pooled results from 4 studies with 173 participants showed that cerebellar TMS could significantly improve the post-intervention Time Up and Go (TUG) (MD=-1.51, 95%CI=-2.8 to -0.22, P = 0.02; heterogeneity, I2 = 0%, P = 0.41). The pooled results from 6 studies with 280 participants showed that cerebellar TMS could significantly improve the post-intervention ADL (MD = 7.75, 95%CI = 4.33 to 11.17, P < 0.00001; heterogeneity, I2 = 56%, P = 0.04). The subgroup analysis showed that cerebellar TMS could improve BBS post-intervention and ADL post-intervention for both subacute and chronic stage stroke patients. Cerebellar high frequency TMS could improve BBS post-intervention and ADL post-intervention. Cerebellar TMS could still improve BBS post-intervention and ADL post-intervention despite of different cerebellar TMS sessions (less and more than 10 TMS sessions), different total cerebellar TMS pulse per week (less and more than 4500 pulse/week), and different cerebellar TMS modes (repetitive TMS and Theta Burst Stimulation). None of the studies reported severe adverse events except mild side effects in three studies. CONCLUSIONS: Cerebellar TMS is an effective and safe technique for improving balance capacity and ADL in stroke patients. Further larger-sample, higher-quality, and longer follow-up RCTs are needed to explore the more reliable evidence of cerebellar TMS in the balance capacity and ADL, and clarify potential mechanisms.


Subject(s)
Activities of Daily Living , Cerebellum , Postural Balance , Stroke Rehabilitation , Stroke , Transcranial Magnetic Stimulation , Humans , Transcranial Magnetic Stimulation/methods , Postural Balance/physiology , Stroke Rehabilitation/methods , Cerebellum/physiology , Cerebellum/physiopathology , Stroke/physiopathology , Stroke/therapy , Randomized Controlled Trials as Topic/methods
3.
Nat Commun ; 15(1): 4662, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38821913

ABSTRACT

Deep Brain Stimulation can improve tremor, bradykinesia, rigidity, and axial symptoms in patients with Parkinson's disease. Potentially, improving each symptom may require stimulation of different white matter tracts. Here, we study a large cohort of patients (N = 237 from five centers) to identify tracts associated with improvements in each of the four symptom domains. Tremor improvements were associated with stimulation of tracts connected to primary motor cortex and cerebellum. In contrast, axial symptoms are associated with stimulation of tracts connected to the supplementary motor cortex and brainstem. Bradykinesia and rigidity improvements are associated with the stimulation of tracts connected to the supplementary motor and premotor cortices, respectively. We introduce an algorithm that uses these symptom-response tracts to suggest optimal stimulation parameters for DBS based on individual patient's symptom profiles. Application of the algorithm illustrates that our symptom-tract library may bear potential in personalizing stimulation treatment based on the symptoms that are most burdensome in an individual patient.


Subject(s)
Deep Brain Stimulation , Motor Cortex , Parkinson Disease , Tremor , Humans , Deep Brain Stimulation/methods , Parkinson Disease/therapy , Parkinson Disease/physiopathology , Male , Female , Middle Aged , Aged , Tremor/therapy , Tremor/physiopathology , Motor Cortex/physiopathology , Algorithms , Hypokinesia/therapy , Hypokinesia/physiopathology , White Matter/pathology , White Matter/physiopathology , Muscle Rigidity/therapy , Cerebellum/physiopathology , Cohort Studies , Treatment Outcome
4.
Neurorehabil Neural Repair ; 38(7): 539-550, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38804539

ABSTRACT

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a nonpharmacological and noninvasive brain stimulation technique that has been proven to be effective in Parkinson's disease (PD). The combination of rTMS and treadmill training improved gait function in PD greater than treadmill training alone. OBJECTIVE: The aim of our study was to evaluate the combination of a novel high-intensity, short intervention rTMS treatment and a multimodal treatment protocol including of physiotherapy, occupational therapy and language therapy, the so-called Parkinson's Disease Multimodal Complex Treatment (PD-MCT), to improve motor function. METHODS: In this randomized double-blind sham-controlled trial rTMS with 48 Hz or sham was applied over the cerebellum 3 times a day for 5 consecutive days. Patients were assessed at baseline (V0), after 5 days of treatment (V1), and 4 weeks later (V2). The primary clinical outcome measure was the motor sum-score of the Unified PD Rating Scale (UPDRSIII), secondary clinical outcomes were quantitative motor tasks. RESULTS: A total of 36 PD patients were randomly allocated either to rTMS (n = 20) or sham (n = 16), both combined with PD-MCT. rTMS improved the UDPRSIII score comparing baseline and V1 in the treatment group by -8.2 points (P = .004). The 8MW and dynamic posturography remained unchanged in both groups after intervention. Conclusion. Compressing weeks of canonical rTMS protocols into 5 days was effective and well tolerated. rTMS may serve as an add-on therapy for augmenting the multimodal complex treatment of motor symptoms, but seems to be ineffective to treat postural instability.


Subject(s)
Cerebellum , Parkinson Disease , Transcranial Magnetic Stimulation , Humans , Parkinson Disease/therapy , Parkinson Disease/physiopathology , Parkinson Disease/complications , Parkinson Disease/rehabilitation , Male , Female , Aged , Double-Blind Method , Middle Aged , Cerebellum/physiopathology , Combined Modality Therapy , Gait Disorders, Neurologic/etiology , Gait Disorders, Neurologic/rehabilitation , Gait Disorders, Neurologic/therapy , Gait Disorders, Neurologic/physiopathology , Outcome Assessment, Health Care , Treatment Outcome
5.
Sci Transl Med ; 16(747): eadl1408, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38748772

ABSTRACT

Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.


Subject(s)
Cerebellum , Essential Tremor , Neurons , Olivary Nucleus , Essential Tremor/physiopathology , Animals , Humans , Olivary Nucleus/physiopathology , Cerebellum/physiopathology , Mice , Male , Optogenetics , Female , Deep Brain Stimulation , Middle Aged , Electroencephalography , Aged
6.
Cereb Cortex ; 34(5)2024 May 02.
Article in English | MEDLINE | ID: mdl-38741271

ABSTRACT

This study investigates abnormalities in cerebellar-cerebral static and dynamic functional connectivity among patients with acute pontine infarction, examining the relationship between these connectivity changes and behavioral dysfunction. Resting-state functional magnetic resonance imaging was utilized to collect data from 45 patients within seven days post-pontine infarction and 34 normal controls. Seed-based static and dynamic functional connectivity analyses identified divergences in cerebellar-cerebral connectivity features between pontine infarction patients and normal controls. Correlations between abnormal functional connectivity features and behavioral scores were explored. Compared to normal controls, left pontine infarction patients exhibited significantly increased static functional connectivity within the executive, affective-limbic, and motor networks. Conversely, right pontine infarction patients demonstrated decreased static functional connectivity in the executive, affective-limbic, and default mode networks, alongside an increase in the executive and motor networks. Decreased temporal variability of dynamic functional connectivity was observed in the executive and default mode networks among left pontine infarction patients. Furthermore, abnormalities in static and dynamic functional connectivity within the executive network correlated with motor and working memory performance in patients. These findings suggest that alterations in cerebellar-cerebral static and dynamic functional connectivity could underpin the behavioral dysfunctions observed in acute pontine infarction patients.


Subject(s)
Brain Stem Infarctions , Cerebellum , Magnetic Resonance Imaging , Neural Pathways , Pons , Humans , Male , Female , Middle Aged , Cerebellum/physiopathology , Cerebellum/diagnostic imaging , Neural Pathways/physiopathology , Neural Pathways/diagnostic imaging , Pons/diagnostic imaging , Pons/physiopathology , Brain Stem Infarctions/physiopathology , Brain Stem Infarctions/diagnostic imaging , Aged , Adult , Cerebral Cortex/physiopathology , Cerebral Cortex/diagnostic imaging , Nerve Net/physiopathology , Nerve Net/diagnostic imaging
7.
Exp Brain Res ; 242(6): 1517-1531, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38722346

ABSTRACT

Cerebellar strokes induce coordination disorders that can affect activities of daily living. Evidence-based neurorehabilitation programs are founded on motor learning principles. The cerebellum is a key neural structure in motor learning. It is unknown whether and how well chronic cerebellar stroke individuals (CCSIs) can learn to coordinate their upper limbs through bimanual motor skill learning. The aim was to determine whether CCSIs could achieve bimanual skill learning through a serious game with the REAplan® robot and to compare CCSIs with healthy individuals (HIs). Over three consecutive days, sixteen CCSIs and eighteen HIs were trained on an asymmetric bimanual coordination task ("CIRCUIT" game) with the REAplan® robot, allowing quantification of speed, accuracy and coordination. The primary outcomes were the bimanual speed/accuracy trade-off (BiSAT) and bimanual coordination factor (BiCo). They were also evaluated on a bimanual REACHING task on Days 1 and 3. Correlation analyses between the robotic outcomes and clinical scale scores were computed. Throughout the sessions, BiSAT and BiCo improved during the CIRCUIT task in both HIs and CCSIs. On Day 3, HIs and CCSIs showed generalization of BiSAT, BiCo and transferred to the REACHING task. There was no significant between-group difference in progression. Four CCSIs and two HIs were categorized as "poor learners" according to BiSAT and/or BiCo. Increasing age correlated with reduced BiSAT but not BiCo progression. Over three days of training, HIs and CCSIs improved, retained, generalized and transferred a coordinated bimanual skill. There was no between-group difference, suggesting plastic compensation in CCSIs. Clinical trial NCT04642599 approved the 24th of November 2020.


Subject(s)
Learning , Motor Skills , Stroke Rehabilitation , Stroke , Adult , Aged , Female , Humans , Male , Middle Aged , Cerebellar Diseases/physiopathology , Cerebellar Diseases/rehabilitation , Cerebellum/physiopathology , Cerebellum/physiology , Chronic Disease , Learning/physiology , Motor Skills/physiology , Psychomotor Performance/physiology , Robotics , Stroke/physiopathology , Stroke Rehabilitation/methods , Prospective Studies , Adolescent , Aged, 80 and over
8.
Schizophr Res ; 267: 497-506, 2024 May.
Article in English | MEDLINE | ID: mdl-38582653

ABSTRACT

BACKGROUND: Abnormal cerebellar functional connectivity (FC) has been implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BD). However, the patterns of cerebellar dysconnectivity in these two disorders and their association with cognitive functioning and clinical symptoms have not been fully clarified. In this study, we examined cerebellar FC alterations in SCZ and BD-I and their association with cognition and psychotic symptoms. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) data of 39 SCZ, 43 BD-I, and 61 healthy controls from the Consortium for Neuropsychiatric Phenomics dataset were examined. The cerebellum was parcellated into ten functional networks, and seed-based FC was calculated for each cerebellar system. Principal component analyses were used to reduce the dimensionality of the diagnosis-related FC and cognitive variables. Multiple regression analyses were used to assess the relationship between FC and cognitive and clinical data. RESULTS: We observed decreased cerebellar FC with the frontal, temporal, occipital, and thalamic areas in individuals with SCZ, and a more widespread decrease in cerebellar FC in individuals with BD-I, involving the frontal, cingulate, parietal, temporal, occipital, and thalamic regions. SCZ had increased within-cerebellum and cerebellar frontal FC compared to BD-I. In BD-I, memory and verbal learning performances, which were higher compared to SCZ, showed a greater interaction with cerebellar FC patterns. Additionally, patterns of increased cortico-cerebellar FC were marginally associated with positive symptoms in patients. CONCLUSIONS: Our findings suggest that shared and distinct patterns of cortico-cerebellar dysconnectivity in SCZ and BD-I could underlie cognitive impairments and psychotic symptoms in these disorders.


Subject(s)
Bipolar Disorder , Cerebellum , Magnetic Resonance Imaging , Schizophrenia , Humans , Bipolar Disorder/physiopathology , Bipolar Disorder/diagnostic imaging , Schizophrenia/physiopathology , Schizophrenia/diagnostic imaging , Schizophrenia/complications , Male , Female , Adult , Cerebellum/diagnostic imaging , Cerebellum/physiopathology , Young Adult , Connectome , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/diagnostic imaging , Middle Aged
9.
Brain Cogn ; 177: 106160, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38670051

ABSTRACT

While procedural learning (PL) has been implicated in delayed motor skill observed in developmental coordination disorder (DCD), few studies have considered the impact of co-occurring attentional problems. Furthermore, the neurostructural basis of PL in children remains unclear. We investigated PL in children with DCD while controlling for inattention symptoms, and examined the role of fronto-basal ganglia-cerebellar morphology in PL. Fifty-nine children (6-14 years; nDCD = 19, ncontrol = 40) completed the serial reaction time (SRT) task to measure PL. The Attention-Deficit Hyperactivity Disorder Rating Scale-IV was administered to measure inattention symptoms. Structural T1 images were acquired for a subset of participants (nDCD = 10, ncontrol = 28), and processed using FreeSurfer. Volume was extracted for the cerebellum, basal ganglia, and frontal regions. After controlling for inattention symptoms, the reaction time profile of controls was consistent with learning on the SRT task. This was not the case for those with DCD. SRT task performance was positively correlated with cerebellar cortical volume, and children with DCD trended towards lower cerebellar volume compared to controls. Children with DCD may not engage in PL during the SRT task in the same manner as controls, with this differential performance being associated with atypical cerebellar morphology.


Subject(s)
Cerebellum , Learning , Magnetic Resonance Imaging , Motor Skills Disorders , Reaction Time , Humans , Child , Male , Female , Adolescent , Motor Skills Disorders/physiopathology , Motor Skills Disorders/diagnostic imaging , Reaction Time/physiology , Cerebellum/diagnostic imaging , Cerebellum/physiopathology , Learning/physiology , Magnetic Resonance Imaging/methods , Attention Deficit Disorder with Hyperactivity/physiopathology , Attention Deficit Disorder with Hyperactivity/diagnostic imaging , Neuroimaging/methods , Attention/physiology , Basal Ganglia/physiopathology , Basal Ganglia/diagnostic imaging , Psychomotor Performance/physiology , Motor Skills/physiology
10.
J Neurosci ; 44(17)2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38658164

ABSTRACT

Pain is considered a multidimensional experience that embodies not merely sensation, but also emotion and perception. As is appropriate for this complexity, pain is represented and processed by an extensive matrix of cortical and subcortical structures. Of these structures, the cerebellum is gaining increasing attention. Although association between the cerebellum and both acute and chronic pain have been extensively detailed in electrophysiological and neuroimaging studies, a deep understanding of what functions are mediated by these associations is lacking. Nevertheless, the available evidence implies that lobules IV-VI and Crus I are especially pertinent to pain processing, and anatomical studies reveal that these regions connect with higher-order structures of sensorimotor, emotional, and cognitive function. Therefore, we speculate that the cerebellum exerts a modulatory role in pain via its communication with sites of sensorimotor, executive, reward, and limbic function. On this basis, in this review, we propose numerous ways in which the cerebellum might contribute to both acute and chronic pain, drawing particular attention to emotional and cognitive elements of pain. In addition, we emphasise the importance of advancing our knowledge about the relationship between the cerebellum and pain by discussing novel therapeutic opportunities that capitalize on this association.


Subject(s)
Cerebellum , Pain , Humans , Cerebellum/physiopathology , Cerebellum/diagnostic imaging , Animals , Pain/physiopathology , Pain/psychology , Emotions/physiology
11.
Neuroradiology ; 66(6): 999-1012, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38671339

ABSTRACT

PURPOSE: Previous studies have demonstrated impaired cerebellar function in patients with obstructive sleep apnea (OSA), which is associated with impaired cognition. However, the effects of OSA on resting-state functional connectivity (FC) in the cerebellum has not been determined. The purpose of this study was to investigate resting-state FC of the cerebellar subregions and its relevance to clinical symptoms in patients with OSA. METHODS: Sixty-eight patients with OSA and seventy-two healthy controls (HCs) were included in the study. Eight subregions of the cerebellum were selected as regions of interest, and the FC values were calculated for each subregion with other voxels. A correlation analysis was performed to examine the relationship between clinical and cognitive data. RESULTS: Patients with OSA showed higher FC in specific regions, including the right lobule VI with the right posterior middle temporal gyrus and right angular gyrus, the right Crus I with the bilateral precuneus/left superior parietal lobule, and the right Crus II with the precuneus/right posterior cingulate cortex. Furthermore, the oxygen depletion index was negatively correlated with aberrant FC between the right Crus II and the bilateral precuneus / right posterior cingulate cortex in OSA patients (p = 0.004). CONCLUSION: The cerebellum is functionally lateralized and closely linked to the posterior default mode network. Higher FC is related to cognition, emotion, language, and sleep in OSA. Abnormal FC may offer new neuroimaging evidence and insights for a deeper comprehension of OSA-related alterations.


Subject(s)
Cerebellum , Magnetic Resonance Imaging , Sleep Apnea, Obstructive , Humans , Male , Sleep Apnea, Obstructive/physiopathology , Sleep Apnea, Obstructive/diagnostic imaging , Magnetic Resonance Imaging/methods , Cerebellum/diagnostic imaging , Cerebellum/physiopathology , Middle Aged , Adult , Case-Control Studies , Brain Mapping/methods , Rest
12.
Exp Brain Res ; 242(5): 1087-1100, 2024 May.
Article in English | MEDLINE | ID: mdl-38483566

ABSTRACT

Fatigue and balance disorders are common challenges experienced by Multiple Sclerosis (MS) individuals. The purpose of this study was to compare the concurrent effects of cerebellar and prefrontal anodal trans-cranial direct current stimulation (a-tDCS) with postural training on balance and fatigue in MS patients. 51 patients were evaluated to randomly allocation to a-tDCS over cerebellum, a-tDCS over dorsolateral prefrontal cortex (DLPFC) and sham group. 46 individuals (n = 16 in experimental groups and n = 14 in control group) followed treatment. All the groups received 10 sessions of postural training. The experimental groups underwent a-tDCS with a current of 1.5 mA for a period of 20 min. While, in the sham group, tDCS was only activated for 30 s and then turned off. The treatment included 10 sessions for four weeks. Before and after intervention, fatigue and balance were assessed using Fatigue Severity Scale (FSS), Timed Up and Go (TUG) test and Berg Balance Score (BBS), respectively. There was found a significant reduction in fatigue in the group receiving a-tDCS over the prefrontal cortex with postural training compared to the other two groups (P < 0.001). Additionally, a significant improvement was found in balance in the group receiving a-tDCS over the cerebellum concurrent with postural training in comparison to the other two groups (P < 0.001). Besides, in the sham group, the significant results were not reported in the variables. (P > 0.001). The results demonstrated that a-tDCS enhances the effects of postural training on balance and fatigue in MS patients.


Subject(s)
Cerebellum , Fatigue , Multiple Sclerosis , Postural Balance , Prefrontal Cortex , Transcranial Direct Current Stimulation , Humans , Male , Female , Postural Balance/physiology , Transcranial Direct Current Stimulation/methods , Adult , Double-Blind Method , Multiple Sclerosis/complications , Multiple Sclerosis/physiopathology , Multiple Sclerosis/therapy , Fatigue/therapy , Fatigue/physiopathology , Fatigue/etiology , Fatigue/rehabilitation , Middle Aged , Prefrontal Cortex/physiopathology , Cerebellum/physiopathology , Cerebellum/physiology , Treatment Outcome , Young Adult
13.
Mov Disord ; 39(5): 892-897, 2024 May.
Article in English | MEDLINE | ID: mdl-38480525

ABSTRACT

BACKGROUND: Little is known about the impact of the cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) on cognition. OBJECTIVE: Our objective was to determine the frequency and severity of cognitive impairment in RFC1-positive patients and describe the pattern of deficits. METHODS: Participants underwent a comprehensive neuropsychological assessment. Volume of the cerebellum and its lobules was measured in those who underwent a 3 Tesla-magnetic resonance scan. RESULTS: Twenty-one patients underwent a complete assessment, including 71% scoring lower than the cutoff at the Montreal Cognitive assessment and 71% having a definite cerebellar cognitive affective/Schmahmann syndrome. Three patients had dementia and seven met the criteria of mild cognitive impairment. Severity of cognitive impairment did not correlate with severity of clinical manifestations. Performance at memory and visuospatial functions tests negatively correlated with the severity of cerebellar manifestations. CONCLUSION: Cognitive manifestations are frequent in RFC1-related disorders. They should be included in the phenotype and screened systematically. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Subject(s)
Cerebellar Ataxia , Cognitive Dysfunction , Phenotype , Humans , Female , Male , Cognitive Dysfunction/etiology , Cognitive Dysfunction/physiopathology , Cerebellar Ataxia/physiopathology , Cerebellar Ataxia/complications , Middle Aged , Aged , Adult , Neuropsychological Tests , Replication Protein C/genetics , Magnetic Resonance Imaging , Cerebellum/diagnostic imaging , Cerebellum/physiopathology , Cerebellum/pathology , Vestibular Diseases/physiopathology
14.
J Neurol ; 271(6): 3239-3255, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38438819

ABSTRACT

BACKGROUND: Primary lateral sclerosis (PLS) is traditionally solely associated with progressive upper motor neuron dysfunction manifesting in limb spasticity, gait impairment, bulbar symptoms and pseudobulbar affect. Recent studies have described frontotemporal dysfunction in some patients resulting in cognitive manifestations. Cerebellar pathology is much less well characterised despite sporadic reports of cerebellar disease. METHODS: A multi-timepoint, longitudinal neuroimaging study was conducted to characterise the evolution of both intra-cerebellar disease burden and cerebro-cerebellar connectivity. The volumes of deep cerebellar nuclei, cerebellar cortical volumes, cerebro-cerebellar structural and functional connectivity were assessed longitudinally in a cohort of 43 individuals with PLS. RESULTS: Cerebello-frontal, -temporal, -parietal, -occipital and cerebello-thalamic structural disconnection was detected at baseline based on radial diffusivity (RD) and cerebello-frontal decoupling was also evident based on fractional anisotropy (FA) alterations. Functional connectivity changes were also detected in cerebello-frontal, parietal and occipital projections. Volume reductions were identified in the vermis, anterior lobe, posterior lobe, and crura. Among the deep cerebellar nuclei, the dorsal dentate was atrophic. Longitudinal follow-up did not capture statistically significant progressive changes. Significant primary motor cortex atrophy and inter-hemispheric transcallosal degeneration were also captured. CONCLUSIONS: PLS is not only associated with upper motor neuron dysfunction, but cerebellar cortical volume loss and deep cerebellar nuclear atrophy can also be readily detected. In addition to intra-cerebellar disease burden, cerebro-cerebellar connectivity alterations also take place. Our data add to the evolving evidence of widespread neurodegeneration in PLS beyond the primary motor regions. Cerebellar dysfunction in PLS is likely to exacerbate bulbar, gait and dexterity impairment and contribute to pseudobulbar affect.


Subject(s)
Motor Neuron Disease , Humans , Male , Middle Aged , Female , Longitudinal Studies , Aged , Motor Neuron Disease/diagnostic imaging , Motor Neuron Disease/pathology , Motor Neuron Disease/physiopathology , Cerebellum/pathology , Cerebellum/diagnostic imaging , Cerebellum/physiopathology , Adult , Diffusion Tensor Imaging , Magnetic Resonance Imaging
16.
J Neurol Sci ; 451: 120726, 2023 08 15.
Article in English | MEDLINE | ID: mdl-37421883

ABSTRACT

INTRODUCTION: Pseudobulbar affect (PBA) is a distressing symptom of a multitude of neurological conditions affecting patients with a rage of neuroinflammatory, neurovascular and neurodegenerative conditions. It manifests in disproportionate emotional responses to minimal or no contextual stimulus. It has considerable quality of life implications and treatment can be challenging. METHODS: A prospective multimodal neuroimaging study was conducted to explore the neuroanatomical underpinnings of PBA in patients with primary lateral sclerosis (PLS). All participants underwent whole genome sequencing and screening for C9orf72 hexanucleotide repeat expansions, a comprehensive neurological assessment, neuropsychological screening (ECAS, HADS, FrSBe) and PBA was evaluated by the emotional lability questionnaire. Structural, diffusivity and functional MRI data were systematically evaluated in whole-brain (WB) data-driven and region of interest (ROI) hypothesis-driven analyses. In ROI analyses, functional and structural corticobulbar connectivity and cerebello-medullary connectivity alterations were evaluated separately. RESULTS: Our data-driven whole-brain analyses revealed associations between PBA and white matter degeneration in descending corticobulbar as well as in commissural tracts. In our hypothesis-driven analyses, PBA was associated with increased right corticobulbar tract RD (p = 0.006) and decreased FA (p = 0.026). The left-hemispheric corticobulbar tract, as well as functional connectivity, showed similar tendencies. While uncorrected p-maps revealed both voxelwise and ROI trends for associations between PBA and cerebellar measures, these did not reach significance to unequivocally support the "cerebellar hypothesis". CONCLUSIONS: Our data confirm associations between cortex-brainstem disconnection and the clinical severity of PBA. While our findings may be disease-specific, they are consistent with the classical cortico-medullary model of pseudobulbar affect.


Subject(s)
Cerebellum , Cerebral Cortex , Crying , Laughter , Models, Neurological , Motor Neuron Disease , Pyramidal Tracts , Radiology , Aged , Female , Humans , Male , Middle Aged , Amyotrophic Lateral Sclerosis/complications , Amyotrophic Lateral Sclerosis/diagnostic imaging , Amyotrophic Lateral Sclerosis/pathology , Amyotrophic Lateral Sclerosis/physiopathology , Cerebellum/diagnostic imaging , Cerebellum/pathology , Cerebellum/physiopathology , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Frontal Lobe/diagnostic imaging , Frontal Lobe/pathology , Frontal Lobe/physiopathology , Magnetic Resonance Imaging , Medulla Oblongata/diagnostic imaging , Medulla Oblongata/pathology , Medulla Oblongata/physiopathology , Motor Cortex/diagnostic imaging , Motor Cortex/pathology , Motor Cortex/physiopathology , Motor Neuron Disease/complications , Motor Neuron Disease/diagnostic imaging , Motor Neuron Disease/pathology , Motor Neuron Disease/physiopathology , Pyramidal Tracts/diagnostic imaging , Pyramidal Tracts/pathology , Pyramidal Tracts/physiopathology , Quality of Life , Temporal Lobe/diagnostic imaging , Temporal Lobe/pathology , Temporal Lobe/physiopathology
17.
J Trace Elem Med Biol ; 78: 127189, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37201369

ABSTRACT

BACKGROUND: In connection with the widespread use of explosive devices in military conflicts, in particular in Ukraine, is relevant to detect the biometals changes in the cerebellum and determine the presence of their influence on the behavior changes of rats in the elevated plus maze in the acute period of a mild blast-traumatic brain injury (bTBI). METHODS: The selected rats were randomly divided into 3 groups: Group I - Experimental with bTBI (with an excess pressure of 26-36 kPa), Group II - Sham and Group III - Intact. Behavior studies was in the elevated plus maze. Brain spectral analysis was with using of energy dispersive X-ray fluorescence analysis, after obtaining the quantitative mass fractions of biometals, the ratios of Cu/Fe, Cu/Zn, Zn/Fe were calculated and the data between the three groups were compared. RESULTS: The results showed an increase in mobility in the experimental rats, which indicates functional disorders of the cerebellum in the form of maladaptation in space. Changes in cognitive activity also is an evidence of cerebellum suppression, which is indicated by changes in vertical locomotor activity. Grooming time was shortened. We established a significant increase in Cu/Fe and Zn/Fe ratios in the cerebellum, a decrease in Cu/Zn. CONCLUSIONS: Changes in the Cu/Fe, Cu/Zn, and Zn/Fe ratios in the cerebellum correlate with impaired locomotor and cognitive activity in rats in the acute posttraumatic period. Accumulation of Fe on the 1st and 3rd day leads to disturbance of the Cu and Zn balance on the 7th day and starts a "vicious cycle" of neuronal damage. Cu/Fe, Cu/Zn, and Zn/Fe imbalances are secondary factors in the pathogenesis of brain damage as a result of primary bTBI.


Subject(s)
Blast Injuries , Brain Injuries , Cerebellum , Copper , Iron , Trace Elements , Zinc , Trace Elements/analysis , Trace Elements/metabolism , Animals , Rats , Brain Injuries/metabolism , Brain Injuries/physiopathology , Blast Injuries/metabolism , Blast Injuries/physiopathology , Cerebellum/chemistry , Cerebellum/metabolism , Cerebellum/physiopathology , Male , Rats, Wistar , Copper/analysis , Copper/metabolism , Iron/analysis , Iron/metabolism , Zinc/analysis , Zinc/metabolism , Grooming , Locomotion , Spectrometry, X-Ray Emission
18.
Parkinsonism Relat Disord ; 99: 1-7, 2022 06.
Article in English | MEDLINE | ID: mdl-35537274

ABSTRACT

INTRODUCTION: The pathophysiology of paroxysmal kinesigenic dyskinesia (PKD) remains elusive to date; however, several lines of evidence from neuroimaging studies suggest involvement of the basal ganglia-thalamocortical network in PKD. We combined fractional amplitude of low-frequency fluctuation (fALFF) and seed-based functional connectivity (FC) analyses in order to comprehensively investigate intrinsic brain activity alterations and their relationships with disease severity in patients with idiopathic PKD. METHODS: Resting-state functional MRI data were obtained and processed in 34 PKD patients and 34 matched controls. fALFF and seed-based FC maps were computed and compared between patients and controls. Linear regression analysis was further performed between regional fALFF values or FC strengths and clinical parameters in patients. RESULTS: PKD patients had a significant increase in fALFF in bilateral thalamus and cerebellum compared with controls. FC analysis seeding at the thalamic clusters revealed significant FC increases in motor cortex and supplementary motor area in PKD patients relative to controls. Longer disease duration was associated with increasing FC strength between the thalamus and motor cortex. CONCLUSION: We have provided evidence for abnormal intrinsic activity in the cerebello-thalamic circuit and increased thalamofrontal FC in PKD patients, implicating interictal cerebello-thalamofrontal dysconnectivity in the pathophysiology of PKD. Given the increasing FC strength in proportion to disease duration, the thalamofrontal hyperconnectivity might reflect either a consequence of recurrent dyskinesias on the brain or an innate pathology causing dyskinesias in PKD.


Subject(s)
Cerebellum , Dystonia , Magnetic Resonance Imaging , Case-Control Studies , Cerebellum/pathology , Cerebellum/physiopathology , Humans , Magnetic Resonance Imaging/methods , Thalamus/pathology , Thalamus/physiopathology
19.
J Neuroimmunol ; 367: 577870, 2022 06 15.
Article in English | MEDLINE | ID: mdl-35468417

ABSTRACT

Immune system dysfunction has been described in autism spectrum disorder. Here we tested the hypothesis that cerebellar defects are accompanied by immune dysfunction in adult mice lacking the autism-candidate gene Engrailed 2 (En2). Gene ontology analyses revealed that biological processes related to immune function were over-represented in the cerebellar transcriptome of En2-/- mice. Pro-inflammatory molecules and chemokines were reduced in the En2-/- cerebellum compared to controls. Conversely, pro-inflammatory molecules were increased in the peripheral blood of mutant mice. Our results suggest a link between immune dysfunction and cerebellar defects detected in En2-/- mice.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Homeodomain Proteins , Nerve Tissue Proteins , Animals , Autistic Disorder/genetics , Cerebellum/immunology , Cerebellum/physiopathology , Homeodomain Proteins/genetics , Mice , Mice, Knockout , Nerve Tissue Proteins/genetics
20.
J Integr Neurosci ; 21(1): 30, 2022 Jan 28.
Article in English | MEDLINE | ID: mdl-35164466

ABSTRACT

Apoptosis, autophagy and necrosis are the three main types of programmed cell death. One or more of these types of programmed cell death may take place in neurons leading to their death in various neurodegenerative disorders in humans. Purkinje neurons (PNs) are among the most highly vulnerable population of neurons to cell death in response to intrinsic hereditary diseases or extrinsic toxic, hypoxic, ischemic, and traumatic injury. In this review, we will describe the three main types of programmed cell death, including the molecular mechanisms and the sequence of events in each of them, and thus illustrating the intracellular proteins that mediate and regulate each of these types. Then, we will discuss the role of Ca2+ in PN function and increased vulnerability to cell death. Additionally, PN death will be described in animal models, namely lurcher mutant mouse and shaker mutant rat, in order to illustrate the potential therapeutic implications of programmed cell death in PNs by reviewing the previous studies that were carried out to interfere with the programmed cell death in an attempt to rescue PNs from death.


Subject(s)
Apoptosis , Autophagy , Cerebellum , Necrosis , Neurodegenerative Diseases , Purkinje Cells , Animals , Apoptosis/physiology , Autophagy/physiology , Cerebellum/cytology , Cerebellum/metabolism , Cerebellum/pathology , Cerebellum/physiopathology , Humans , Mice , Necrosis/metabolism , Necrosis/pathology , Necrosis/physiopathology , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/physiopathology , Purkinje Cells/cytology , Purkinje Cells/metabolism , Purkinje Cells/pathology , Purkinje Cells/physiology , Rats
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