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1.
Nat Commun ; 12(1): 363, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441542

RESUMO

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder, can be transiently suppressed via transcranial electrical stimulation of the cerebellum phase-locked to the tremor. The tremor suppression is sustained shortly after the end of the stimulation and can be phenomenologically predicted. Finally, we use feature-based statistical-learning and neurophysiological-modelling to show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the aberrant oscillations in the olivocerebellar loop, thus establishing its causal role. The suppression of aberrant neural oscillation via phase-locked driven disruption of temporal coherence may in the future represent a powerful neuromodulatory strategy to treat brain disorders.


Assuntos
Encéfalo/fisiopatologia , Cerebelo/fisiopatologia , Estimulação Encefálica Profunda/métodos , Tremor Essencial/terapia , Estimulação Transcraniana por Corrente Contínua/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Tremor Essencial/diagnóstico , Tremor Essencial/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Monitorização Neurofisiológica/métodos
2.
Nat Neurosci ; 23(9): 1102-1110, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32661395

RESUMO

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


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Cerebelo/fisiopatologia , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Animais , Masculino , Camundongos , Camundongos Mutantes
3.
Sci Rep ; 10(1): 9420, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523011

RESUMO

We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. Repetitive, but not single blast exposure, induced delayed-onset BBB disruption (72 hours post-blast) in cerebellum. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) administered after blast blocked BBB disruption and prevented CD4+ T-cell infiltration into cerebellum. L-NAME also blocked blast-induced increases in intercellular adhesion molecule-1 (ICAM-1), a molecule that plays a critical role in regulating blood-to-brain immune cell trafficking. Blocking NOS-mediated BBB dysfunction during this acute/subacute post-blast interval (24-71 hours after the last blast) also prevented sensorimotor impairment on a rotarod task 30 days later, long after L-NAME cleared the body. In postmortem brains from Veterans/military Servicemembers with blast-related TBI, we found marked Purkinje cell dendritic arbor structural abnormalities, which were comparable to neuropathologic findings in the blast-exposed mice. Taken collectively, these results indicate that blast provokes delayed-onset of NOS-dependent pathogenic cascades that can later emerge as behavioral dysfunction. These results also further implicate the cerebellum as a brain region vulnerable to blast-induced mTBI.


Assuntos
Traumatismos por Explosões/metabolismo , Traumatismos por Explosões/fisiopatologia , Concussão Encefálica/fisiopatologia , Doenças Cerebelares/metabolismo , Doenças Cerebelares/fisiopatologia , Cerebelo/fisiopatologia , Óxido Nítrico Sintase/metabolismo , Animais , Traumatismos por Explosões/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Concussão Encefálica/tratamento farmacológico , Concussão Encefálica/metabolismo , Doenças Cerebelares/tratamento farmacológico , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Modelos Animais de Doenças , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NG-Nitroarginina Metil Éster/farmacologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , Células de Purkinje/patologia
4.
Rev Assoc Med Bras (1992) ; 66(3): 375-379, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32520161

RESUMO

BACKGROUND: Symptomatic Chiari Type I Malformation (CM) is treated with posterior fossa decompression with or without duroplasty. We have noticed some cases with concomitant severe cerebellar ataxia due to cerebellar atrophy. The aim of this study is to review the literature of CM associated with severe cerebellar atrophy and discuss its potential physiopathology. METHODS: A systematic literature review in the Pubmed Database was performed using the following key-terms: "cerebellar atrophy Chiari", and "cerebellar degeneration Chiari". Articles reporting the presence of cerebellar degeneration/atrophy associated with CM were included. RESULTS: We found only six studies directly discussing the association of cerebellar atrophy with CM, with a total of seven cases. We added one case of our own practice for additional discussion. Only speculative causes were described to justify cerebellar atrophy. The potential causes of cerebellar atrophy were diffuse cerebellar ischemia from chronic compression of small vessels (the most mentioned speculative cause), chronic raised intracranial pressure due to CSF block, chronic venous hypertension, and association with platybasia with ventral compression of the brainstem resulting in injury of the inferior olivary nuclei leading to mutual trophic effects in the cerebellum. Additionally, it is not impossible to rule out a degenerative cause for cerebellar atrophy without a causative reason. CONCLUSIONS: Severe cerebellar atrophy is found in some patients with CM. Although chronic ischemia due to compression is the most presumed cause, other etiologies were proposed. The real reasons for cerebellar degeneration are not known. Further studies are necessary.


Assuntos
Malformação de Arnold-Chiari/fisiopatologia , Doenças Cerebelares/fisiopatologia , Malformação de Arnold-Chiari/diagnóstico por imagem , Atrofia , Doenças Cerebelares/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/fisiopatologia , Cerebelo/cirurgia , Descompressão Cirúrgica , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino
5.
BMC Neurol ; 20(1): 167, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32357846

RESUMO

BACKGROUND: Stroke-like episodes (SLEs) in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with m.3243A > G mutation usually develop in the cerebral cortex. Few reports have documented SLEs in the cerebellum. The clinical neuroimaging features of cerebellar SLEs have not been fully investigated. We report distinctive features of cerebellar stroke-like lesions (SLLs) in a case of MELAS with m.3243A > G mutation. CASE PRESENTATION: A 47-year-old Japanese man with type-2 diabetes presented to our hospital with acute onset of aphasia. A brain MRI obtained on admission (day 1) showed increased diffusion-weighted imaging (DWI)/fluid-attenuated inversion recovery (FLAIR) signal in the left anterolateral temporal lobe, which subsequently spread along the cortex posteriorly accompanied by a new lesion in the right anterior temporal lobe. The patient was initially treated with acyclovir and subsequently with immunotherapy. However, on day 45, cerebellar ataxia developed. The brain MRI showed extensive increased DWI/FLAIR signals in the cerebellum along the folia without involvement of deep cerebellar nucleus or cerebellar peduncle; SLLs were incongruent with a vascular territory, similarly to classic cerebral SLLs. Apparent diffusion coefficient (ADC) map did not show reduction in ADC values in the affected folia. Genomic analysis revealed m.3243A > G mutation (heteroplasmy in leukocytes, 17%), confirming the diagnosis of MELAS. After the treatment with taurine (12,000 mg/day), L-arginine (12,000 mg/day), vitamin B1 (100 mg/day), and carnitine (3000 mg/day), the patient became able to follow simple commands, and he was transferred to a rehabilitation center on day 146. The follow-up MRI showed diffuse brain atrophy, including the cerebellum. CONCLUSIONS: SLLs develop in the cerebellum in MELAS with m.3243A > G mutation. The neuroimaging similarities to cerebral SLLs suggest the presence of the common pathophysiological mechanisms underlying both SLEs, which include microangiopathy and increased susceptibility of the cortex to metabolic derangements.


Assuntos
Cerebelo , Síndrome MELAS , Acidente Vascular Cerebral , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Cerebelo/fisiopatologia , Humanos , Síndrome MELAS/complicações , Síndrome MELAS/diagnóstico por imagem , Síndrome MELAS/genética , Síndrome MELAS/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/fisiopatologia
6.
Medicine (Baltimore) ; 99(17): e19866, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332650

RESUMO

The direction-changing bilateral gaze-evoked nystagmus (GEN) (BGEN) is a more specific sign for a gaze-holding deficit than unilateral GEN (UGEN) in a central lesion. We sought to clarify which cerebellar structure is responsible for the generation of BGEN compared with UGEN.We studied 47 cases of UGEN or BGEN associated with isolated unilateral cerebellar infarction in the territories of the cerebellar arteries diagnosed by brain magnetic resonance image (MRI) from June 2007 to April 2014. To identify the structures involved in the generation of BGEN, the overlapped lesions of the BGEN group were subtracted from those of UGEN group and vice versa.About half of the patients (25/47, 53%) showed BGEN and others showed UGEN. There was no difference in the interval from symptom onset to examination between 2 groups (1.3 days vs 2.5 days, P = .24). Thirty-five patients (35/47, 75%) with GEN also showed spontaneous nystagmus. Lesion subtraction analyses revealed that both of the patients with BGEN and UGEN had damage around the vermal pyramid, the uvula and the tonsil, parts of the biventer lobule, and the inferior semilunar lobule.Midline and lower cerebellar structures are related to both BGEN and UGEN in patients with unilateral cerebellar infarction. Regardless of unilateral or bilateral, GEN may represent damage of the gaze-holding neural integrator control system in human.


Assuntos
Infarto Encefálico/complicações , Cerebelo/anatomia & histologia , Nistagmo Patológico/etiologia , Idoso , Infarto Encefálico/fisiopatologia , Cerebelo/fisiopatologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Imagem por Ressonância Magnética/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Nistagmo Patológico/fisiopatologia , Sistema de Registros/estatística & dados numéricos
7.
Psychiatry Res Neuroimaging ; 300: 111079, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32283474

RESUMO

Heart rate variability (HRV), a measurement of autonomic nervous system (ANS) activity, has been found reduced in schizophrenia. The anterior cingulate cortex (ACC), which is important in regulating the ANS, is structurally and functionally affected in schizophrenia. We investigate the relationship between HRV and functional and structural connectivity of the ACC in patients with schizophrenia and healthy controls. Ten patients with a diagnosis of schizophrenia and ten healthy controls were recruited. Heart rate was monitored in a naturalistic out-of-clinic setting. Magnetic resonance imaging (MRI) was performed, including resting-state functional MRI and diffusion tensor imaging. Patients with schizophrenia had significantly lower HRV compared to controls. A positive correlation between ACC connectivity with the bilateral cerebellum and HRV was found in the patients. HRV was also positively correlated with amplitude of low frequency fluctuations (ALFF) in the cerebellum, and with axial diffusivity in the middle cerebellar peduncle, in the patients. There was a significant negative relationship between antipsychotic medication dosage, HRV and all neuroimaging measures related to HRV. We conclude that ACC connectivity seems to be affected in schizophrenia, both structurally and functionally, and that the ACC-cerebellum connectivity, as well as cerebellar function, is associated with ANS regulation in patients with schizophrenia.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Frequência Cardíaca/fisiologia , Rede Nervosa/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Antipsicóticos/uso terapêutico , Sistema Nervoso Autônomo/diagnóstico por imagem , Estudos de Casos e Controles , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Imagem de Tensor de Difusão , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico
9.
J Neurosci ; 40(14): 2943-2959, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32122952

RESUMO

Piccolo, a presynaptic active zone protein, is best known for its role in the regulated assembly and function of vertebrate synapses. Genetic studies suggest a further link to several psychiatric disorders as well as Pontocerebellar Hypoplasia type 3 (PCH3). We have characterized recently generated Piccolo KO (Pclogt/gt ) rats. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclowt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Analysis of the cerebellum and brainstem revealed a reduced granule cell layer and a reduction in size of pontine nuclei. Moreover, the maturation of mossy fiber afferents from pontine neurons and the expression of the α6 GABAA receptor subunit at the mossy fiber-granule cell synapse are perturbed, as well as the innervation of Purkinje cells by cerebellar climbing fibers. Ultrastructural and functional studies revealed a reduced size of mossy fiber boutons, with fewer synaptic vesicles and altered synaptic transmission. These data imply that Piccolo is required for the normal development, maturation, and function of neuronal networks formed between the brainstem and cerebellum. Consistently, behavioral studies demonstrated that adult Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Together, these data suggest that loss of Piccolo function in patients with PCH3 could be involved in many of the observed anatomical and behavioral symptoms, and that the further analysis of these animals could provide fundamental mechanistic insights into this devastating disorder.SIGNIFICANCE STATEMENT Pontocerebellar Hypoplasia Type 3 is a devastating developmental disorder associated with severe developmental delay, progressive microcephaly with brachycephaly, optic atrophy, seizures, and hypertonia with hyperreflexia. Recent genetic studies have identified non-sense mutations in the coding region of the PCLO gene, suggesting a functional link between this disorder and the presynaptic active zone. Our analysis of Piccolo KO rats supports this hypothesis, formally demonstrating that anatomical and behavioral phenotypes seen in patients with Pontocerebellar Hypoplasia Type 3 are also exhibited by these Piccolo deficient animals.


Assuntos
Cerebelo/metabolismo , Cerebelo/patologia , Cerebelo/fisiopatologia , Proteínas do Citoesqueleto/metabolismo , Neuropeptídeos/metabolismo , Atrofias Olivopontocerebelares , Animais , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Masculino , Fenótipo , Ratos
10.
Int J Mol Sci ; 21(6)2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32178459

RESUMO

Cerebellar ataxias are a heterogenous group of degenerative disorders for which we currently lack effective and disease-modifying interventions. The field of non-invasive brain stimulation has made much progress in the development of specific stimulation protocols to modulate cerebellar excitability and try to restore the physiological activity of the cerebellum in patients with ataxia. In light of limited evidence-based pharmacologic and non-pharmacologic treatment options for patients with ataxia, several different non-invasive brain stimulation protocols have emerged, particularly employing repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) techniques. In this review, we summarize the most relevant rTMS and tDCS therapeutic trials and discuss their implications in the care of patients with degenerative ataxias.


Assuntos
Ataxia Cerebelar/fisiopatologia , Cerebelo/fisiopatologia , Estimulação Transcraniana por Corrente Contínua/métodos , Estimulação Magnética Transcraniana/métodos , Humanos
11.
J Headache Pain ; 21(1): 29, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188423

RESUMO

BACKGROUND: The increase of headache frequency is associated with higher headache related disability and lower quality of life in patients with migraine. However, the pathophysiology of migraine progression, persistence, or remission is elusive. The purpose of this study is to identify the brain signatures that are predictive of the long-term outcomes among patients with high-frequency migraine (HFM: 10-30 headache days/month). METHODS: We prospectively enrolled patients with HFM and healthy controls and collected their baseline clinical profiles and brain-MRI data at first visit. We longitudinally followed the patients and determined their outcomes at 2-year follow-up. Good outcome was defined as ≥50% reduction of baseline headache days and poor outcome was defined as reduction < 50% or frequency increase. Voxel-based morphometry was used to study gray matter volume (GMV), and structural covariance was used to investigate structural connectivity. RESULTS: Among 56 patients with HFM, 37 had good outcome and 19 poor outcome. Compared to the healthy controls (n = 37), patients with poor outcome had decreased GMV over the left posterior cingulate gyrus, and increased GMV over the bilateral cerebellum and the right precentral gyrus. Further, patients with poor outcome had greater GMV over the right and the left cerebella compared to patients with good outcome, and the GMVs of the cerebella were correlated to 2-year headache frequencies (right: r = 0.38, P = 0.005; left: r = 0.35, P = 0.009). Structural connectivity were increased between the cerebellum and the cuneus, the calcarine cortex, and the temporal lobe, respectively, in patients with poor outcome, and was decreased between the cerebellum and the prefrontal cortex in patients with poor outcome. The structural covariance integrities between the right cerebellum and the right cuneus were correlated to 2-year headache frequencies (r = 0.36, P = 0.008). CONCLUSIONS: Structural volume and connectivity changes of the cerebellum may underlie headache persistence in patients with HFM.


Assuntos
Cerebelo/fisiopatologia , Substância Cinzenta/fisiopatologia , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/fisiopatologia , Adulto , Encéfalo/fisiopatologia , Córtex Cerebral/fisiopatologia , Progressão da Doença , Feminino , Giro do Cíngulo/fisiopatologia , Cefaleia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/fisiopatologia , Prognóstico , Qualidade de Vida , Adulto Jovem
12.
J Clin Psychiatry ; 81(2)2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32078260

RESUMO

OBJECTIVE: Reward deficits and associated striatal circuitry have been implicated in the onset and progression of major depressive disorder (MDD). This work was conducted to clarify how the striatal circuitry is involved in the established risk, acute episodes, and remission of MDD. METHODS: Striatal subregion resting-state functional connectivity (RSFC) was calculated for 29 currently depressed and 28 remitted patients diagnosed with MDD per the Structured Clinical Interview for DSM-IV, 19 first-degree relatives of these patients, and 57 healthy controls (HCs) based on resting-state fMRI data collected between May 2007 and September 2014. RESULTS: Compared with HCs, the other 3 groups showed increased RSFC between left dorsal caudate (DC) and right insula but reduced RSFC between right putamen and left cerebellum. The currently depressed group showed increased FC between right DC and superior frontal gyrus but reduced RSFC between putamen and right anterior cingulate as well as other striatal nuclei compared with the other 3 groups. Although no results were found in ventral striatum (VS) seeds during analysis of covariance, the comparison between currently depressed and remitted patients showed increased RSFC between right superior VS and left inferior frontal gyrus in currently depressed patients at a more linear threshold. Also, both superior and inferior VS showed increased RSFC with superior and inferior frontal gyri but reduced RSFC with cerebellum in relatives compared with HCs. Higher DC-superior frontal gyrus RSFC (r = 0.438, P = .022) was correlated with more severe depression, but lower within-putamen FC was correlated with more severe depression (r = -0.446, P = .02) and retardation (r = -0.465, P = .011). CONCLUSIONS: The findings suggest that reduced VS-frontal, within-putamen, and putamen-cingulate RSFC in currently depressed patients is dependent on current depressive episode and has implications for symptomatic monitoring, while increased caudate-insular and reduced VS-cerebellar RSFC in remitted patients and first-degree relatives might be related to the disease itself and have potential for predicting risk for and recurrence of MDD.


Assuntos
Cerebelo/fisiopatologia , Córtex Cerebral/fisiopatologia , Conectoma , Transtorno Depressivo Maior/fisiopatologia , Neostriado/fisiopatologia , Rede Nervosa/fisiopatologia , Recompensa , Estriado Ventral/fisiopatologia , Adulto , Cerebelo/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Família , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Neostriado/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Recidiva , Indução de Remissão , Estriado Ventral/diagnóstico por imagem
13.
Neurourol Urodyn ; 39(3): 969-977, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32032447

RESUMO

AIMS: We compared brain activation patterns between female multiple sclerosis (MS) patients with voiding dysfunction (VD) and those without. We aim to expand current knowledge of supraspinal correlates of voiding initiation within a cohort of female MS patients with and without VD. MATERIALS AND METHODS: Twenty-eight ambulatory female MS patients with stable disease and lower urinary tract dysfunction were recruited for this study. Subjects were divided into group 1, without VD (n = 14), and group 2, with VD (n = 14), defined as postvoid residual urine of ≥40% of maximum cystometric capacity or need for self-catheterization. We recorded brain activity via functional magnetic resonance imaging (fMRI) with simultaneous urodynamic testing. Average fMRI activation maps (the Student t test) were created for both groups, and areas of significant activation were identified (P < .05). A priori regions of interest (ROIs), identified by prior meta-analysis to be involved in voiding, were selected. RESULTS: Group-averaged blood-oxygen level-dependent (BOLD) activation maps demonstrated significant differences between groups 1 and 2 during initiation of voiding with group 2 showing significantly lower levels of activation in all ROIs except for the left cerebellum and right cingulate gyrus. Interestingly, group 2 displayed negative BOLD signals, while group 1 displayed positive signals in the right and left pontine micturition center, right periaqueductal gray, left thalamus, and left cingulate gyrus. The activation map of group 1 was similar to healthy controls. CONCLUSIONS: Our results support the hypothesis that distinct supraspinal activation patterns exist between female MS patients with VD and those without.


Assuntos
Encéfalo/diagnóstico por imagem , Sintomas do Trato Urinário Inferior/fisiopatologia , Esclerose Múltipla/diagnóstico por imagem , Bexiga Urinaria Neurogênica/fisiopatologia , Transtornos Urinários/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Feminino , Neuroimagem Funcional , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/fisiopatologia , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Substância Cinzenta Periaquedutal/fisiopatologia , Ponte/diagnóstico por imagem , Ponte/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/fisiopatologia , Bexiga Urinária/fisiopatologia , Bexiga Urinaria Neurogênica/etiologia , Micção/fisiologia , Transtornos Urinários/etiologia , Urodinâmica/fisiologia
14.
Brain ; 143(2): 480-490, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32040566

RESUMO

Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.


Assuntos
Ataxia/fisiopatologia , Ataxia Cerebelar/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Neuronite Vestibular/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Ataxia/complicações , Cerebelo/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico/efeitos adversos , Doenças do Sistema Nervoso Periférico/complicações , Reflexo Anormal/fisiologia , Transtornos das Sensações/etiologia , Transtornos das Sensações/fisiopatologia , Síndrome , Neuronite Vestibular/complicações
15.
BMC Med Genet ; 21(1): 18, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000717

RESUMO

BACKGROUND: Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION: We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION: This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Predisposição Genética para Doença , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adulto , Cerebelo/fisiopatologia , Criança , Éxons/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/fisiopatologia , Feminino , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mutação/genética , Linhagem , Isoformas de Proteínas/genética , Retina/metabolismo , Retina/patologia , Retina/fisiopatologia , Vietnã , Sequenciamento Completo do Exoma
16.
Toxicol Lett ; 322: 87-97, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31935479

RESUMO

1,2-Dichloroethane (1,2-DCE) is a widely used chlorinated organic toxicant, but little is known about the cerebellar dysfunction induced by excessive exposure to it. To uncover 1,2-DCE-induced neurotoxicity in cerebellar granular cells (CGCs), and to investigate the underlying mechanisms, we explored this, both in vitro and in vivo. Our findings showed significant cell viability inhibition in human CGCs (HCGCs) treated with 1,2-DCE. Flow cytometry and mitochondrial membrane potential analyses discovered an increase in apoptotic-mediated cell death in HCGCs after 1,2-DCE treatment. This HCGC apoptosis was involved in the increases of protein expression in Cytochrome c, Caspase-3, Bad, Bim, transformation related protein 53, Caspase-8, tumor necrosis factor-α, and Survivin. Quantitative real-time PCR (qPCR) and western blot confirmed the increases in Cytochrome c, Caspase-3, cleaved Caspase-3, and Bad in HCGCs after 1,2-DCE treatment. Bax inhibitor peptide V5 rescued 1,2-DCE-induced HCGC apoptosis. Furthermore, 80 CD-1 male mice were exposed to 1,2-DCE by inhalation at 0, 100, 350, and 700 mg/m3 for 6 h/day for 4 weeks. An open field test found abnormal neurobehavioral changes in the mice exposed to 1,2-DCE. Histopathological examination showed significantly shrunken and hypereosinophilic cytoplasm with nuclear pyknosis in mouse CGCs from the 700 mg/m3 1,2-DCE group. TdT-mediated dUTP nick-end labeling assay verified significant increases in apoptotic positive cells in the mouse CGCs after 1,2-DCE exposure. We confirmed the increases in the expressions of Cytochrome c, Caspase-3, cleaved Caspase-3 and Bad in the mice exposed to 1,2-DCE. These findings suggest that 1,2-DCE exposure can induce CGC apoptosis and cerebellar dysfunction, at least in part, through mitochondrial pathway.


Assuntos
Apoptose/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Dicloretos de Etileno/toxicidade , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Cerebelo/metabolismo , Cerebelo/patologia , Cerebelo/fisiopatologia , Humanos , Locomoção/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Medição de Risco , Transdução de Sinais
17.
Cerebellum ; 19(2): 275-285, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31997138

RESUMO

The capacity to acquire and retain new motor skills is essential for everyday behavior and a prerequisite to regain functional independence following impairments of motor function caused by brain damage, e.g., ischemic stroke. Learning a new motor skill requires repeated skill practice and passes through different online and offline learning stages that are mediated by specific dynamic interactions between distributed brain regions including the cerebellum. Motor sequence learning is an extensively studied paradigm of motor skill learning, yet the role of the cerebellum during online and offline stages remains controversial. Here, we studied patients with chronic cerebellar stroke and healthy control participants to further elucidate the role of the cerebellum during acquisition and consolidation of sequential motor skills. Motor learning was assessed by an ecologically valid explicit sequential finger tapping paradigm and retested after an interval of 8 h to assess consolidation. Compared to healthy controls, chronic cerebellar stroke patients displayed significantly lower motor sequence performance independent of whether the ipsilesional or contralesional hand was used for task execution. However, the ability to improve performance during training (i.e., online learning) and to consolidate training-induced skill formation was similar in patients and controls. Findings point to an essential role of the cerebellum in motor sequence production that cannot be compensated, while its role in online and offline motor sequence learning seems to be either negligible or amenable to compensatory mechanisms. This further suggests that residual functional impairments caused by cerebellar stroke may be mitigated even months later by additional skill training.


Assuntos
Cerebelo/fisiopatologia , Aprendizagem/fisiologia , Consolidação da Memória/fisiologia , Destreza Motora/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Cerebellum ; 19(2): 235-242, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31925668

RESUMO

In recent years, increasing evidence of the cerebellar role in social cognition has emerged. The cerebellum has been shown to modulate cortical activity of social brain regions serving as a regulator of function-specific mentalizing and mirroring processes. In particular, a mentalizing area in the posterior cerebellum, specifically Crus II, is preferentially recruited for more complex and abstract forms of social processing, together with mentalizing cerebral areas including the dorsal medial prefrontal cortex (dmPFC), the temporo-parietal junction (TPJ), and the precuneus. In the present study, the network-based statistics approach was used to assess functional connectivity (FC) differences within this mentalizing cerebello-cerebral network associated with a specific cerebellar damage. To this aim, patients affected by spinocerebellar ataxia type 2 (SCA2), a neurodegenerative disease specifically affecting regions of the cerebellar cortex, and age-matched healthy subjects have been enrolled. The dmPFC, left and right TPJ, the precuneus, and the cerebellar Crus II were used as regions of interest to construct the mentalizing network to be analyzed and evaluate pairwise functional relations between them. When compared with controls, SCA2 patients showed altered internodal connectivity between dmPFC, left (L-) and right (R-) TPJ, and right posterior cerebellar Crus II.The present results indicate that FC changes affect a function-specific mentalizing network in patients affected by cerebellar damage. In particular, they allow to better clarify functional alteration mechanisms driven by the cerebellar damage associated with SCA2 suggesting that selective cortico-cerebellar functional disconnections may underlie patients' social impairment in domain-specific complex and abstract forms of social functioning.


Assuntos
Cerebelo/fisiopatologia , Mentalização/fisiologia , Rede Nervosa/fisiologia , Vias Neurais/fisiopatologia , Ataxias Espinocerebelares/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
J Stroke Cerebrovasc Dis ; 29(3): 104586, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31928864

RESUMO

BACKGROUND: Poststroke dysphagia is common, associated with a poor outcome and has no definitive treatments. Repetitive transcranial magnetic stimulation (rTMS) targeting the cerebellum is a noninvasive technique requiring minimal physical or cognitive input from the patient, and has been shown to induce positive swallow-related brain changes in physiological studies as measured by increased cortical excitability. AIM: To explore in patients with acute/sub-acute poststroke dysphagia: (1) the feasibility and immediate effect; and (2) the optimal dose for long-term benefit, of cerebellar rTMS in patients with dysphagia in acute/sub-acute stroke. METHODS: Two double-blind sham-controlled randomized phase II trials. Participants will be recruited from stroke units in Nottingham and Greater Manchester. Dysphagia will be confirmed via baseline videofluoroscopy (VFS). Participants will be blinded to treatment and receive cerebellar rTMS or sham stimulation: (1) single treatment of (10Hz, 250 pulse) in 24 participants; (2) daily for 3 days, twice-daily for 5 days, or twice-daily sham treatment for 5 days, in 48 participants. RESULTS: The severity of dysphagia will be assessed with VFS, using the penetration aspiration scale (PAS) at: (1) 1-hour, (2) 2-weeks, post-treatment. Additional comparative measures will be taken from: (1) pharyngeal motor evoked potential (MEP) amplitudes, (2) the functional oral intake score and dysphagia severity rating scale. CONCLUSIONS: If these studies demonstrate feasibility and identify optimal dosing, further trials to assess the safety and efficacy of cerebellar rTMS as a treatment for poststroke dysphagia will be warranted.


Assuntos
Cerebelo/fisiopatologia , Transtornos de Deglutição/terapia , Deglutição , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/terapia , Estimulação Magnética Transcraniana , Ensaios Clínicos Fase II como Assunto , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Avaliação da Deficiência , Método Duplo-Cego , Inglaterra , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
20.
Neurol Res ; 42(1): 62-67, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31900094

RESUMO

Objective: Frequent falls are common in Parkinson's disease (PD). Resting-state fMRI (rs-fMRI) studies have found differences in functional connectivity between PD patients and healthy controls. However, whether functional connectivity in PD patients with frequent falls (PD-fallers) differs from those without falls (PD-non fallers) is unknown. Therefore, to elucidate the underlying mechanisms leading to postural instability in PD patients with frequent falls, we compared changes in functional connectivity between PD-fallers, PD-non fallers and healthy controls.Methods: Thirteen healthy controls (70.7 ± 7.2 years) were compared to thirteen PD-fallers (70.6 ± 5.9 years) and 19 PD-non fallers (71.61 ± 5.8 years) without cognitive impairment. We performed 1.5T rs-fMRI scans and evaluated gait and balance, motor symptoms and cognitive functions.Results: Cerebellar seed regions showed increased functional connectivity in PD-fallers compared to controls in two connections between the cerebellar cortex and vermis (p-value = 0.02). Conversely, in comparison to controls, functional connectivity between the precuneus and caudate nucleus was decreased in PD-non fallers (p-value = 0.015). A similar trend was also observed between controls and PD-fallers, although this difference did not reach statistical significance.Discussion: We found increased functional connectivity among cerebellar structures in PD, which may reflect an adaptive (compensatory) mechanism through activation of additional brain structures to restore gait function. In contrast, a relative disconnection between the precuneus and caudate nucleus in PD patients might indicate an impaired brain network unrelated to the risk of falls. Cerebellar areas might thus be considered as future therapeutic targets for neuromodulatory treatment of postural instability in PD.Abbreviations: DMN: default mode network; FC: functional connectivity; IPL: inferior parietal lobule; MMSE: Minimal Mental Status Examination; PD: Parkinson's disease; rs-fMRI: resting-state functional Magnetic Resonance Imaging; UPDRSIII: Unified Parkinson's disease ranking scale.


Assuntos
Núcleo Caudado/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Rede Nervosa/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Descanso , Idoso , Núcleo Caudado/fisiopatologia , Cerebelo/fisiopatologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Rede Nervosa/fisiopatologia , Doença de Parkinson/fisiopatologia
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