Early Disruption of Extracellular Pleiotrophin Distribution Alters Cerebellar Neuronal Circuit Development and Function.

PubMed

Hamza, M M; Rey, S A; Hilber, P; Arabo, A; Collin, T; Vaudry, D; Burel, D

2016-10-01

The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant increase in the frequency of spontaneous excitatory postsynaptic currents in PTN-treated mice, associated with a decrease of climbing fiber innervations and an abnormal perisomatic localization of the parallel fiber contacts. At adulthood, PTN-treated mice exhibit coordination impairment on the rotarod test associated with an alteration of the synchronization gait. Altogether these histological, electrophysiological, and behavior data reveal that an early ECM disruption of PTN composition induces short- and long-term defaults in the establishment of proper functional cerebellar circuit.

Cortical Amyloid Beta in Cognitively Normal Elderly Adults is Associated with Decreased Network Efficiency within the Cerebro-Cerebellar System

PubMed Central

Steininger, Stefanie C.; Liu, Xinyang; Gietl, Anton; Wyss, Michael; Schreiner, Simon; Gruber, Esmeralda; Treyer, Valerie; Kälin, Andrea; Leh, Sandra; Buck, Alfred; Nitsch, Roger M.; Prüssmann, Klaas P.; Hock, Christoph; Unschuld, Paul G.

2014-01-01

Background: Deposition of cortical amyloid beta (Aβ) is a correlate of aging and a risk factor for Alzheimer disease (AD). While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aβ deposition on coupling within the cerebro-cerebellar system. Methods: We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aβ was quantified using (11)carbon-labeled Pittsburgh compound B positron-emission-tomography late frame signals. Volumes of brain structures were assessed by applying an automated parcelation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent resting state functional magnetic resonance imaging at the high field strength of 7 T for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aβ load on coupling. Results: Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aβ load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus, and thalamus. Conclusion: Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aβ-associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the cerebro-cerebellar system and risk for AD. PMID:24672483

Cortical Amyloid Beta in Cognitively Normal Elderly Adults is Associated with Decreased Network Efficiency within the Cerebro-Cerebellar System.

PubMed

Steininger, Stefanie C; Liu, Xinyang; Gietl, Anton; Wyss, Michael; Schreiner, Simon; Gruber, Esmeralda; Treyer, Valerie; Kälin, Andrea; Leh, Sandra; Buck, Alfred; Nitsch, Roger M; Prüssmann, Klaas P; Hock, Christoph; Unschuld, Paul G

2014-01-01

Deposition of cortical amyloid beta (Aβ) is a correlate of aging and a risk factor for Alzheimer disease (AD). While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aβ deposition on coupling within the cerebro-cerebellar system. We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aβ was quantified using (11)carbon-labeled Pittsburgh compound B positron-emission-tomography late frame signals. Volumes of brain structures were assessed by applying an automated parcelation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent resting state functional magnetic resonance imaging at the high field strength of 7 T for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aβ load on coupling. Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aβ load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus, and thalamus. Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aβ-associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the cerebro-cerebellar system and risk for AD.

Mitotic events in cerebellar granule progenitor cells that expand cerebellar surface area are critical for normal cerebellar cortical lamination in mice.

PubMed

Chang, Joshua C; Leung, Mark; Gokozan, Hamza Numan; Gygli, Patrick Edwin; Catacutan, Fay Patsy; Czeisler, Catherine; Otero, José Javier

2015-03-01

Late embryonic and postnatal cerebellar folial surface area expansion promotes cerebellar cortical cytoarchitectural lamination. We developed a streamlined sampling scheme to generate unbiased estimates of murine cerebellar surface area and volume using stereologic principles. We demonstrate that, during the proliferative phase of the external granular layer (EGL) and folial surface area expansion, EGL thickness does not change and thus is a topological proxy for progenitor self-renewal. The topological constraints indicate that, during proliferative phases, migration out of the EGL is balanced by self-renewal. Progenitor self-renewal must, therefore, include mitotic events yielding 2 cells in the same layer to increase surface area (β events) and mitotic events yielding 2 cells, with 1 cell in a superficial layer and 1 cell in a deeper layer (α events). As the cerebellum grows, therefore, β events lie upstream of α events. Using a mathematical model constrained by the measurements of volume and surface area, we could quantify intermitotic times for β events on a per-cell basis in postnatal mouse cerebellum. Furthermore, we found that loss of CCNA2, which decreases EGL proliferation and secondarily induces cerebellar cortical dyslamination, shows preserved α-type events. Thus, CCNA2-null cerebellar granule progenitor cells are capable of self-renewal of the EGL stem cell niche; this is concordant with prior findings of extensive apoptosis in CCNA2-null mice. Similar methodologies may provide another layer of depth to the interpretation of results from stereologic studies.

Maturation, Refinement, and Serotonergic Modulation of Cerebellar Cortical Circuits in Normal Development and in Murine Models of Autism.

PubMed

Hoxha, Eriola; Lippiello, Pellegrino; Scelfo, Bibiana; Tempia, Filippo; Ghirardi, Mirella; Miniaci, Maria Concetta

2017-01-01

The formation of the complex cerebellar cortical circuits follows different phases, with initial synaptogenesis and subsequent processes of refinement guided by a variety of mechanisms. The regularity of the cellular and synaptic organization of the cerebellar cortex allowed detailed studies of the structural plasticity mechanisms underlying the formation of new synapses and retraction of redundant ones. For the attainment of the monoinnervation of the Purkinje cell by a single climbing fiber, several signals are involved, including electrical activity, contact signals, homosynaptic and heterosynaptic interaction, calcium transients, postsynaptic receptors, and transduction pathways. An important role in this developmental program is played by serotonergic projections that, acting on temporally and spatially regulated postsynaptic receptors, induce and modulate the phases of synaptic formation and maturation. In the adult cerebellar cortex, many developmental mechanisms persist but play different roles, such as supporting synaptic plasticity during learning and formation of cerebellar memory traces. A dysfunction at any stage of this process can lead to disorders of cerebellar origin, which include autism spectrum disorders but are not limited to motor deficits. Recent evidence in animal models links impairment of Purkinje cell function with autism-like symptoms including sociability deficits, stereotyped movements, and interspecific communication by vocalization.

Maturation, Refinement, and Serotonergic Modulation of Cerebellar Cortical Circuits in Normal Development and in Murine Models of Autism

PubMed Central

Lippiello, Pellegrino; Scelfo, Bibiana

2017-01-01

The formation of the complex cerebellar cortical circuits follows different phases, with initial synaptogenesis and subsequent processes of refinement guided by a variety of mechanisms. The regularity of the cellular and synaptic organization of the cerebellar cortex allowed detailed studies of the structural plasticity mechanisms underlying the formation of new synapses and retraction of redundant ones. For the attainment of the monoinnervation of the Purkinje cell by a single climbing fiber, several signals are involved, including electrical activity, contact signals, homosynaptic and heterosynaptic interaction, calcium transients, postsynaptic receptors, and transduction pathways. An important role in this developmental program is played by serotonergic projections that, acting on temporally and spatially regulated postsynaptic receptors, induce and modulate the phases of synaptic formation and maturation. In the adult cerebellar cortex, many developmental mechanisms persist but play different roles, such as supporting synaptic plasticity during learning and formation of cerebellar memory traces. A dysfunction at any stage of this process can lead to disorders of cerebellar origin, which include autism spectrum disorders but are not limited to motor deficits. Recent evidence in animal models links impairment of Purkinje cell function with autism-like symptoms including sociability deficits, stereotyped movements, and interspecific communication by vocalization. PMID:28894610

Abnormal Eye Movements in Creutzfeldt-Jakob Disease

NASA Technical Reports Server (NTRS)

Grant, Michael P.; Cohen, Mark; Petersen, Robert B.; Halmagyi, G. Michael; McDougall, Alan; Tusa, Ronald J.; Leigh, R. John

1993-01-01

We report 3 patients with autopsy-proven Creutzfeldt-Jakob disease who, early in their course, developed abnormal eye movements that included periodic alternating nystagmus and slow vertical saccades. These findings suggested involvement of the cerebellar nodulus and uvula, and the brainstem reticular formation, respectively. Cerebellar ataxia was also an early manifestation and, in one patient, a frontal lobe brain biopsy was normal at a time when ocular motor and cerebellar signs were conspicuous. As the disease progressed, all saccades and quick phases of nystagmus were lost, but periodic alternating gaze deviation persisted. At autopsy, 2 of the 3 patients had pronounced involvement of the cerebellum, especially of the midline structures. Creutzfeldt-Jakob disease should be considered in patients with subacute progressive neurological disease when cognitive changes are overshadowed by ocular motor findings or ataxia.

FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation

PubMed Central

Aldinger, Kimberly A; Lehmann, Ordan J; Hudgins, Louanne; Chizhikov, Victor V; Bassuk, Alexander G; Ades, Lesley C; Krantz, Ian D; Dobyns, William B; Millen, Kathleen J

2010-01-01

Dandy-Walker malformation (DWM), the most common human cerebellar malformation, has only one characterized associated locus1,2. Here we characterize a second DWM-linked locus on 6p25.3, showing that deletions or duplications encompassing FOXC1 are associated with cerebellar and posterior fossa malformations including cerebellar vermis hypoplasia (CVH), mega-cisterna magna (MCM) and DWM. Foxc1-null mice have embryonic abnormalities of the rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 expression in vermis. Foxc1 homozygous hypomorphs have CVH with medial fusion and foliation defects. Human FOXC1 heterozygous mutations are known to affect eye development, causing a spectrum of glaucoma-associated anomalies (Axenfeld-Rieger syndrome, ARS; MIM no. 601631). We report the first brain imaging data from humans with FOXC1 mutations and show that these individuals also have CVH. We conclude that alteration of FOXC1 function alone causes CVH and contributes to MCM and DWM. Our results highlight a previously unrecognized role for mesenchyme-neuroepithelium interactions in the mid-hindbrain during early embryogenesis. PMID:19668217

Impacts on prenatal development of the human cerebellum: a systematic review.

PubMed

Koning, Irene V; Tielemans, Myrte J; Hoebeek, Freek E; Ecury-Goossen, Ginette M; Reiss, Irwin K M; Steegers-Theunissen, Regine P M; Dudink, Jeroen

2017-10-01

The cerebellum is essential for normal neurodevelopment and is particularly susceptible for intra-uterine disruptions. Although some causal prenatal exposures have been identified, the origin of neurodevelopmental disorders remains mostly unclear. Therefore, a systematic literature search was conducted to provide an overview of parental environmental exposures and intrinsic factors influencing prenatal cerebellar growth and development in humans. The literature search was limited to human studies in the English language and was conducted in Embase, Medline, Cochrane, Web of Science, Pubmed and GoogleScholar. Eligible studies were selected by three independent reviewers and study quality was scored by two independent reviewers. The search yielded 3872 articles. We found 15 eligible studies reporting associations between cerebellar development and maternal smoking (4), use of alcohol (3), in vitro fertilization mediums (1), mercury (1), mifepristone (2), aminopropionitriles (1), ethnicity (2) and cortisol levels (1). No studies reported on paternal factors. Current literature on associations between parental environmental exposures, intrinsic factors and human cerebellar development is scarce. Yet, this systematic review provided an essential overview of human studies demonstrating the vulnerability of the cerebellum to the intra-uterine environment.

Motion perception without Nystagmus--a novel manifestation of cerebellar stroke.

PubMed

Shaikh, Aasef G

2014-01-01

The motion perception and the vestibulo-ocular reflex (VOR) each serve distinct functions. The VOR keeps the gaze steady on the target of interest, whereas vestibular perception serves a number of tasks, including awareness of self-motion and orientation in space. VOR and motion perception might abide the same neurophysiological principles, but their distinct anatomical correlates were proposed. In patients with cerebellar stroke in distribution of medial division of posterior inferior cerebellar artery, we asked whether specific location of the focal lesion in vestibulocerebellum could cause impaired perception of motion but normal eye movements. Thirteen patients were studied, 5 consistently perceived spinning of surrounding environment (vertigo), but the eye movements were normal. This group was called "disease model." Remaining 8 patients were also symptomatic for vertigo, but they had spontaneous nystagmus. The latter group was called "disease control." Magnetic resonance imaging in both groups consistently revealed focal cerebellar infarct affecting posterior cerebellar vermis (lobule IX). In the "disease model" group, only part of lobule IX was affected. In the disease control group, however, complete lobule IX was involved. This study discovered a novel presentation of cerebellar stroke where only motion perception was affected, but there was an absence of objective neurologic signs. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Narcolepsy: regional cerebral blood flow during sleep and wakefulness

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakai, F.; Meyer, J.S.; Karacan, I.

Serial measurements of regional cerebral blood flow were made by the 135Xe inhalation method during the early stages of sleep and wakefulness in eight normal volunteers and 12 patients with narcolepsy. Electroencephalogram, electro-oculogram, and submental electromyogram were recorded simultaneously. In normals, mean hemispheric gray matter blood flow (Fg) during stages I and II sleep was significantly less than waking values. Maximum regional blood flow decreases during sleep occurred in the brainstem-cerebellar, right inferior temporal, and bilateral frontal regions. In patients with narcolepsy, mean hemispheric Fg while awake was 80.5 +- 13 ml per 100 gm brain per minute. During REMmore » sleep, mean hemispheric Fg increased concurrently with large increases in brainstem-cerebellar region flow. During stages I and II sleep without REM, there were significant increases in mean hemispheric Fg and brainstem-cerebellar Fg, just the opposite of changes in normals. In narcolepsy, there appears to be a reversal of normal cerebral deactivation patterns, particularly involving the brainstem, during stages I and II sleep.« less

Model-Driven Analysis of Eyeblink Classical Conditioning Reveals the Underlying Structure of Cerebellar Plasticity and Neuronal Activity.

PubMed

Antonietti, Alberto; Casellato, Claudia; D'Angelo, Egidio; Pedrocchi, Alessandra

The cerebellum plays a critical role in sensorimotor control. However, how the specific circuits and plastic mechanisms of the cerebellum are engaged in closed-loop processing is still unclear. We developed an artificial sensorimotor control system embedding a detailed spiking cerebellar microcircuit with three bidirectional plasticity sites. This proved able to reproduce a cerebellar-driven associative paradigm, the eyeblink classical conditioning (EBCC), in which a precise time relationship between an unconditioned stimulus (US) and a conditioned stimulus (CS) is established. We challenged the spiking model to fit an experimental data set from human subjects. Two subsequent sessions of EBCC acquisition and extinction were recorded and transcranial magnetic stimulation (TMS) was applied on the cerebellum to alter circuit function and plasticity. Evolutionary algorithms were used to find the near-optimal model parameters to reproduce the behaviors of subjects in the different sessions of the protocol. The main finding is that the optimized cerebellar model was able to learn to anticipate (predict) conditioned responses with accurate timing and success rate, demonstrating fast acquisition, memory stabilization, rapid extinction, and faster reacquisition as in EBCC in humans. The firing of Purkinje cells (PCs) and deep cerebellar nuclei (DCN) changed during learning under the control of synaptic plasticity, which evolved at different rates, with a faster acquisition in the cerebellar cortex than in DCN synapses. Eventually, a reduced PC activity released DCN discharge just after the CS, precisely anticipating the US and causing the eyeblink. Moreover, a specific alteration in cortical plasticity explained the EBCC changes induced by cerebellar TMS in humans. In this paper, for the first time, it is shown how closed-loop simulations, using detailed cerebellar microcircuit models, can be successfully used to fit real experimental data sets. Thus, the changes of the model parameters in the different sessions of the protocol unveil how implicit microcircuit mechanisms can generate normal and altered associative behaviors.The cerebellum plays a critical role in sensorimotor control. However, how the specific circuits and plastic mechanisms of the cerebellum are engaged in closed-loop processing is still unclear. We developed an artificial sensorimotor control system embedding a detailed spiking cerebellar microcircuit with three bidirectional plasticity sites. This proved able to reproduce a cerebellar-driven associative paradigm, the eyeblink classical conditioning (EBCC), in which a precise time relationship between an unconditioned stimulus (US) and a conditioned stimulus (CS) is established. We challenged the spiking model to fit an experimental data set from human subjects. Two subsequent sessions of EBCC acquisition and extinction were recorded and transcranial magnetic stimulation (TMS) was applied on the cerebellum to alter circuit function and plasticity. Evolutionary algorithms were used to find the near-optimal model parameters to reproduce the behaviors of subjects in the different sessions of the protocol. The main finding is that the optimized cerebellar model was able to learn to anticipate (predict) conditioned responses with accurate timing and success rate, demonstrating fast acquisition, memory stabilization, rapid extinction, and faster reacquisition as in EBCC in humans. The firing of Purkinje cells (PCs) and deep cerebellar nuclei (DCN) changed during learning under the control of synaptic plasticity, which evolved at different rates, with a faster acquisition in the cerebellar cortex than in DCN synapses. Eventually, a reduced PC activity released DCN discharge just after the CS, precisely anticipating the US and causing the eyeblink. Moreover, a specific alteration in cortical plasticity explained the EBCC changes induced by cerebellar TMS in humans. In this paper, for the first time, it is shown how closed-loop simulations, using detailed cerebellar microcircuit models, can be successfully used to fit real experimental data sets. Thus, the changes of the model parameters in the different sessions of the protocol unveil how implicit microcircuit mechanisms can generate normal and altered associative behaviors.

Postnatal Migration of Cerebellar Interneurons

PubMed Central

Galas, Ludovic; Bénard, Magalie; Lebon, Alexis; Komuro, Yutaro; Schapman, Damien; Vaudry, Hubert; Vaudry, David; Komuro, Hitoshi

2017-01-01

Due to its continuing development after birth, the cerebellum represents a unique model for studying the postnatal orchestration of interneuron migration. The combination of fluorescent labeling and ex/in vivo imaging revealed a cellular highway network within cerebellar cortical layers (the external granular layer, the molecular layer, the Purkinje cell layer, and the internal granular layer). During the first two postnatal weeks, saltatory movements, transient stop phases, cell-cell interaction/contact, and degradation of the extracellular matrix mark out the route of cerebellar interneurons, notably granule cells and basket/stellate cells, to their final location. In addition, cortical-layer specific regulatory factors such as neuropeptides (pituitary adenylate cyclase-activating polypeptide (PACAP), somatostatin) or proteins (tissue-type plasminogen activator (tPA), insulin growth factor-1 (IGF-1)) have been shown to inhibit or stimulate the migratory process of interneurons. These factors show further complexity because somatostatin, PACAP, or tPA have opposite or no effect on interneuron migration depending on which layer or cell type they act upon. External factors originating from environmental conditions (light stimuli, pollutants), nutrients or drug of abuse (alcohol) also alter normal cell migration, leading to cerebellar disorders. PMID:28587295

The Changeable Nervous System: Studies On Neuroplasticity In Cerebellar Cultures

PubMed Central

Seil, Fredrick J.

2014-01-01

Circuit reorganization after injury was studied in a cerebellar culture model. When cerebellar cultures derived from newborn mice were exposed at explantation to a preparation of cytosine arabinoside that destroyed granule cells and oligodendrocytes and compromised astrocytes, Purkinje cells surviving in greater than usual numbers were unensheathed by astrocytic processes and received twice the control number of inhibitory axosomatic synapses. Purkinje cell axon collaterals sprouted and many of their terminals formed heterotypical synapses with other Purkinje cell dendritic spines. The resulting circuit reorganization preserved inhibition in the cerebellar cortex. Following this reorganization, replacement of the missing granule cells and glia was followed by a restitution of the normal circuitry. Most of these developmental and reconstructive changes were not dependent on neuronal activity, the major exception being inhibitory synaptogenesis. The full complement of inhibitory synapses did not develop in the absence of neuronal activity, which could be mitigated by application of exogenous TrkB receptor ligands. Inhibitory synaptogenesis could also be promoted by activity-induced release of endogenous TrkB receptor ligands or by antibody activation of the TrkB receptor. PMID:24933693

Cerebellar Influence on Motor Cortex Plasticity: Behavioral Implications for Parkinson’s Disease

PubMed Central

Kishore, Asha; Meunier, Sabine; Popa, Traian

2014-01-01

Normal motor behavior involves the creation of appropriate activity patterns across motor networks, enabling firing synchrony, synaptic integration, and normal functioning of these networks. Strong topography-specific connections among the basal ganglia, cerebellum, and their projections to overlapping areas in the motor cortices suggest that these networks could influence each other’s plastic responses and functions. The defective striatal signaling in Parkinson’s disease (PD) could therefore lead to abnormal oscillatory activity and aberrant plasticity at multiple levels within the interlinked motor networks. Normal striatal dopaminergic signaling and cerebellar sensory processing functions influence the scaling and topographic specificity of M1 plasticity. Both these functions are abnormal in PD and appear to contribute to the abnormal M1 plasticity. Defective motor map plasticity and topographic specificity within M1 could lead to incorrect muscle synergies, which could manifest as abnormal or undesired movements, and as abnormal motor learning in PD. We propose that the loss of M1 plasticity in PD reflects a loss of co-ordination among the basal ganglia, cerebellar, and cortical inputs which translates to an abnormal plasticity of motor maps within M1 and eventually to some of the motor signs of PD. The initial benefits of dopamine replacement therapy on M1 plasticity and motor signs are lost during the progressive course of disease. Levodopa-induced dyskinesias in patients with advanced PD is linked to a loss of M1 sensorimotor plasticity and the attenuation of dyskinesias by cerebellar inhibitory stimulation is associated with restoration of M1 plasticity. Complimentary interventions should target reestablishing physiological communication between the striatal and cerebellar circuits, and within striato-cerebellar loop. This may facilitate correct motor synergies and reduce abnormal movements in PD. PMID:24834063

Effect of vision, touch and stance on cerebellar vermian-related sway and tremor: a quantitative physiological and MRI study.

PubMed

Sullivan, Edith V; Rose, Jessica; Pfefferbaum, Adolf

2006-08-01

Postural balance is impaired in individuals with pathology of the anterior superior vermis of the cerebellum. Chronic alcoholism, with its known vermian pathology, provides a viable model for studying the relationship between cerebellar pathology and postural stability. Decades of separate study of recovering alcoholics and post-mortem neuroanatomical analysis have demonstrated vermian pathology but few studies have used quantitative posturography, acquired concurrently with quantitative neuroimaging, to establish whether this brain structure-function relationship is selective in vivo. Here, 30 healthy men and 39 chronic alcoholic men, abstinent from alcohol for several months, underwent MRI for volumetric quantitation of the cerebellar vermis and three comparison brain regions, the cerebellar hemispheres, supratentorial cortex and corpus callosum. All subjects also participated in an experiment involving a force platform that measured sway path length and tremor during static standing balance under four sensory conditions and two stance conditions. Three novel findings emerged: (i) sway path length, a physiological index of postural control, was selectively related to volume of the cerebellar vermis and not to any comparison brain region in the alcoholics; (ii) spectral analysis revealed sway prominence in the 2-5 Hz band, another physiological sign of vermian lesions and also selectively related to vermian volume in the alcoholics; and (iii) despite substantial postural sway in the patients, they successfully used vision, touch and stance to normalize sway and reduce tremor. The selective relationship of sway path to vermian but not lateral cerebellar volume provides correlational evidence for functional differentiation of these cerebellar regions. Improvement to virtual normal levels in balance and reduction in sway and tremor with changes in vision, touch and stance provide evidence that adaptive mechanisms recruiting sensorimotor integration can be invoked to compensate for underlying cerebellar vermian-related dysfunction.

Relationship between ultrasound estimated fetal gestational age and cerebellar appearance in healthy pregnant Nigerian women.

PubMed

Adeyekun, Ademola A; Orji, Michael O

2015-01-01

Fetal biometry by ultrasound provides reliable and important information about fetal growth and wellbeing. Evaluation of the fetal posterior fossa is useful in the assessment of neural tube-defects. Studies on normal ultrasound fetal cerebellar appearance and diameter across gestational age (GA) are scanty in the Nigerian medical literature. This study was carried out to study normal fetal cerebellar appearance and diameter at various GAs among healthy pregnant Nigerian Africans. This was a prospective study of 450 healthy singleton pregnant women between 13 and 42 weeks gestation. A curvilinear probe with a 3.5 MHz transducer of a SonoAce X6 (Medison Inc., Korea 2010) scanner was used to assess fetal transcerebellar diameter (TCD) and appearance. GA was also determined using fetal biometric parameters such as the biparietal diameter, femur length, and abdominal circumference. Fetal cerebellar appearance was correlated against GA. The cerebellar appearance was graded into: Grade I: 164 fetuses (36.4%), Grade II; 102 fetuses (22.7%) and Grade III: 184 fetuses (40.9%). Mean GA and TCD was 21 weeks and 21.2 mm for Grade I; 28 weeks and 32.6 mm for Grade II; and 35 weeks and 47.1 mm for Grade III. There was significance difference among the cerebellar grades at the GA groups and transverse cerebellar diameter (P < 0.000). There is a gradual and steady change in ultrasonographic appearance of the fetal cerebellar and diameter appearance with advancing gestation. The changes ranged from anechoic, "pair of eye glass" appearance at second trimester to relatively echogenic, "dumb-bell" appearance at early third trimester, and solid, "fan-shape" in late third trimester.

Reference range of fetal transverse cerebellar diameter between 18 and 24 weeks of pregnancy in a Brazilian population.

PubMed

Araujo Júnior, Edward; Martins, Wellington P; Nardozza, Luciano Marcondes Machado; Pires, Claudio Rodrigues; Filho, Sebastião Marques Zanforlin

2015-02-01

To determine a reference range of fetal transverse cerebellar diameter in Brazilian population. This was a retrospective cross-sectional study with 3772 normal singleton pregnancies between 18 and 24 weeks of pregnancy. The transverse cerebellar diameter was measured on the axial plane of the fetal head at the level of the lateral ventricles, including the thalamus, cavum septum pellucidum, and third ventricle. To assess the correlation between transverse cerebellar diameter and gestational age, polynomial equations were calculated, with adjustments by the determination coefficient (R2). The mean of fetal transverse cerebellar diameter ranged from 18.49 ± 1.24 mm at 18 weeks to 25.86 ± 1.66 mm at 24 weeks of pregnancy. We observed a good correlation between transverse cerebellar diameter and gestational age, which was best represented by a linear equation: transverse cerebellar diameter: -6.21 + 1.307*gestational age (R2 = 0.707). We determined a reference range of fetal transverse cerebellar diameter for the second trimester of pregnancy in Brazilian population. © The Author(s) 2014.

Progressive Non-familial Adult onset Cerebellar Degeneration: An Unusual Occurrence with Hashimoto's Thyroiditis.

PubMed

Rao, Raghavendra S; Sheshadri, Shubha; Bhattacharjee, Dipanjan; Patil, Navin; Rao, Karthik

2018-03-13

Progressive non-familial adult onset cerebellar degeneration has been rarely associated with hypothyroidism and is known to be reversible after therapy. We report a case of cerebellar atrophy in a 31 year old female whose detailed evaluation had revealed sub-clinical hypothyroidism secondary to autoimmune thyroiditis with a very high anti-TPO (anti-thyroid peroxidase) antibody levels. MRI (Magnetic Resonanace Imaging) of brain showed diffuse bilateral cerebellar atrophy. She was treated with thyroid hormone supplementation and after one year of follow up, cerebellar signs had disappeared completely with significant reduction in anti-TPO antibody levels. Imaging of the brain post one year of follow-up revealed normal cerebellum. Hence, we opine that thyroid dysfunction should always be kept in mind while evaluating patients presenting with acute onset cerebellar ataxia as it can be easily reversed with thyroid hormone replacement therapy.

Anterior cingulate cortex and cerebellar hemisphere neurometabolite changes in depression treatment: A 1H magnetic resonance spectroscopy study.

PubMed

Chen, Li-Ping; Dai, Hai-Yang; Dai, Zhuo-Zhi; Xu, Chong-Tao; Wu, Ren-Hua

2014-05-01

We utilized single-voxel 1H magnetic resonance spectroscopy to determine biochemical abnormalities related to major depressive disorder (MDD) in the bilateral dorsolateral prefrontal cortex, anterior cingulate cortex (ACC), and cerebellar hemisphere before and after antidepressant treatment. Fifteen adult MDD patients and 15 age- and sex-matched healthy controls were involved. Magnetic resonance spectroscopy of the brain was conducted in all subjects at the beginning of the study and the depressed subjects were reassessed after 8 weeks of antidepressant treatment. At baseline, N-acetyl aspartate (NAA), total glutamine plus glutamate (Glx) and myo-inositol (MI) levels in the bilateral ACC were significantly lower in MDD patients than in controls (P < 0.05/3). MI in the bilateral cerebellar hemisphere were also decreased in patients compared with controls. After the treatment, the lower NAA, Glx and MI in ACC were normalized in MDD patients and the NAA and Glx increased compared to baseline values. The MI levels in the bilateral cerebellar hemisphere were also normalized in patients. MI and choline levels in the right cerebellar hemisphere were elevated compared to those at baseline. Our study suggests that metabolic abnormalities in the ACC and cerebellar hemisphere are implicated in MDD. Antidepressants may alter the local metabolic abnormalities in these areas. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

Protein Biomarkers Associated With Growth And Synaptogenesis In a cell culture model of neuronal development

EPA Science Inventory

Cerebellar granule cells (CGC) provide a homogenous population of cells which can be used as an in vitro model for studying the cellular processes involved in the normal development of the CNS. They may also be useful for hazard identification as in vitro screens fo...

Lrp5/6 are required for cerebellar development and for suppressing TH expression in Purkinje cells via β-catenin.

PubMed

Huang, Ying; Zhang, Qiong; Song, Ning-Ning; Zhang, Lei; Sun, Yu-Ling; Hu, Ling; Chen, Jia-Ying; Zhu, Weidong; Li, Jue; Ding, Yu-Qiang

2016-01-15

The cerebellum is responsible for coordinating motor functions and has a unique laminated architecture. Purkinje cells are inhibitory neurons and represent the only output from the cerebellar cortex. Tyrosine hydroxylase (TH) is the key enzyme for the synthesis of catecholamines, including dopamine and noradrenaline, and it is normally not expressed in cerebellar neurons. We report here that the low-density lipoprotein receptors (Lrp) 5 and 6, Wnt co-receptors, are required for the development of the cerebellum and for suppressing ectopic TH expression in Purkinje cells. Simultaneous inactivation of Lrp 5 and 6 by Nestin-Cre results in defective lamination and foliation of the cerebellum during postnatal development. Surprisingly, TH is ectopically expressed by Purkinje cells, although they still keep its other neurochemical characteristics. These phenotypes are also observed in the cerebellum of GFAP-Cre;β-catenin(flox/flox) mice, and AAV2-Cre-mediated gene deletion leads to ectopic TH expression in Purkinje cells of β-catenin(flox/flox) mice as well. Our results revealed a new role of the canonical Lrp5/6-β-catenin pathway in regulating the morphogenesis of the cerebellum during postnatal development.

Cell Signaling and Neurotoxicity: 3H-Arachidonic acid release (Phospholipase A2) in cerebellar granule neurons

EPA Science Inventory

Cell signaling is a complex process which controls basic cellular activities and coordinates actions to maintain normal cellular homeostasis. Alterations in signaling processes have been associated with neurological diseases such as Alzheimer's and cerebellar ataxia, as well as, ...

Magnetic resonance imaging diagnosis of Dandy-Walker-like syndrome in a wire-haired miniature dachshund.

PubMed

Kobatake, Yui; Miyabayashi, Takayoshi; Yada, Naoko; Kachi, Shingo; Ohta, George; Sakai, Hiroki; Maeda, Sadatoshi; Kamishina, Hiroaki

2013-10-01

A 12-week-old female Wire-haired miniature dachshund presented with non-progressive ataxia and hypermetria. Due to the animal's clinical history and symptoms, cerebellar malformations were suspected. Computed tomography (CT) and magnetic resonance imaging (MRI) detected bilateral ventriculomegaly, dorsal displacement of the cerebellar tentorium, a defect in the cerebellar tentorium and a large fluid-filled cystic structure that occupied the regions where the cerebellar vermis and occipital lobes are normally located. The abovementioned cystic structure and the defect in the cerebellar tentorium were comparable to those seen in humans with Dandy-Walker syndrome. However, the presence of the cystic structure in the occipital lobe region was unique to the present case. During necropsy, the MRI findings were confirmed, but the etiology of the condition was not determined.

Human embryonic growth and development of the cerebellum using 3-dimensional ultrasound and virtual reality.

PubMed

Rousian, M; Groenenberg, I A L; Hop, W C; Koning, A H J; van der Spek, P J; Exalto, N; Steegers, E A P

2013-08-01

The aim of our study was to evaluate the first trimester cerebellar growth and development using 2 different measuring techniques: 3-dimensional (3D) and virtual reality (VR) ultrasound visualization. The cerebellum measurements were related to gestational age (GA) and crown-rump length (CRL). Finally, the reproducibility of both the methods was tested. In a prospective cohort study, we collected 630 first trimester, serially obtained, 3D ultrasound scans of 112 uncomplicated pregnancies between 7 + 0 and 12 + 6 weeks of GA. Only scans with high-quality images of the fossa posterior were selected for the analysis. Measurements were performed offline in the coronal plane using 3D (4D view) and VR (V-Scope) software. The VR enables the observer to use all available dimensions in a data set by visualizing the volume as a "hologram." Total cerebellar diameter, left, and right hemispheric diameter, and thickness were measured using both the techniques. All measurements were performed 3 times and means were used in repeated measurements analysis. After exclusion criteria were applied 177 (28%) 3D data sets were available for further analysis. The median GA was 10 + 0 weeks and the median CRL was 31.4 mm (range: 5.2-79.0 mm). The cerebellar parameters could be measured from 7 gestational weeks onward. The total cerebellar diameter increased from 2.2 mm at 7 weeks of GA to 13.9 mm at 12 weeks of GA using VR and from 2.2 to 13.8 mm using 3D ultrasound. The reproducibility, established in a subset of 35 data sets, resulted in intraclass correlation coefficient values ≥0.98. It can be concluded that cerebellar measurements performed by the 2 methods proved to be reproducible and comparable with each other. However, VR-using all three dimensions-provides a superior method for the visualization of the cerebellum. The constructed reference values can be used to study normal and abnormal cerebellar growth and development.

The Cerebellum and Neurodevelopmental Disorders.

PubMed

Stoodley, Catherine J

2016-02-01

Cerebellar dysfunction is evident in several developmental disorders, including autism, attention deficit-hyperactivity disorder (ADHD), and developmental dyslexia, and damage to the cerebellum early in development can have long-term effects on movement, cognition, and affective regulation. Early cerebellar damage is often associated with poorer outcomes than cerebellar damage in adulthood, suggesting that the cerebellum is particularly important during development. Differences in cerebellar development and/or early cerebellar damage could impact a wide range of behaviors via the closed-loop circuits connecting the cerebellum with multiple cerebral cortical regions. Based on these anatomical circuits, behavioral outcomes should depend on which cerebro-cerebellar circuits are affected. Here, we briefly review cerebellar structural and functional differences in autism, ADHD, and developmental dyslexia, and discuss clinical outcomes following pediatric cerebellar damage. These data confirm the prediction that abnormalities in different cerebellar subregions produce behavioral symptoms related to the functional disruption of specific cerebro-cerebellar circuits. These circuits might also be crucial to structural brain development, as peri-natal cerebellar lesions have been associated with impaired growth of the contralateral cerebral cortex. The specific contribution of the cerebellum to typical development may therefore involve the optimization of both the structure and function of cerebro-cerebellar circuits underlying skill acquisition in multiple domains; when this process is disrupted, particularly in early development, there could be long-term alterations of these neural circuits, with significant impacts on behavior.

The cerebellum and neurodevelopmental disorders

PubMed Central

Stoodley, Catherine J.

2015-01-01

Cerebellar dysfunction is evident in several developmental disorders, including autism, attention deficit hyperactivity disorder (ADHD), and developmental dyslexia, and damage to the cerebellum early in development can have long-term effects on movement, cognition, and affective regulation. Early cerebellar damage is often associated with poorer outcomes than cerebellar damage in adulthood, suggesting that the cerebellum is particularly important during development. Differences in cerebellar development and/or early cerebellar damage could impact a wide range of behaviors via the closed-loop circuits connecting the cerebellum with multiple cerebral cortical regions. Based on these anatomical circuits, behavioral outcomes should depend on which cerebro-cerebellar circuits are affected. Here, we briefly review cerebellar structural and functional differences in autism, ADHD, and developmental dyslexia, and discuss clinical outcomes following pediatric cerebellar damage. These data confirm the prediction that abnormalities in different cerebellar subregions produce behavioral symptoms related to the functional disruption of specific cerebro-cerebellar circuits. These circuits might also be crucial to structural brain development, as peri-natal cerebellar lesions have been associated with impaired growth of the contralateral cerebral cortex. The specific contribution of the cerebellum to typical development may therefore involve the optimization of both the structure and function of cerebro-cerebellar circuits underlying skill acquisition in multiple domains; when this process is disrupted, particularly in early development, there could be long-term alterations of these neural circuits, with significant impacts on behavior. PMID:26298473

Contribution of Cerebellar Sensorimotor Adaptation to Hippocampal Spatial Memory

PubMed Central

Passot, Jean-Baptiste; Sheynikhovich, Denis; Duvelle, Éléonore; Arleo, Angelo

2012-01-01

Complementing its primary role in motor control, cerebellar learning has also a bottom-up influence on cognitive functions, where high-level representations build up from elementary sensorimotor memories. In this paper we examine the cerebellar contribution to both procedural and declarative components of spatial cognition. To do so, we model a functional interplay between the cerebellum and the hippocampal formation during goal-oriented navigation. We reinterpret and complete existing genetic behavioural observations by means of quantitative accounts that cross-link synaptic plasticity mechanisms, single cell and population coding properties, and behavioural responses. In contrast to earlier hypotheses positing only a purely procedural impact of cerebellar adaptation deficits, our results suggest a cerebellar involvement in high-level aspects of behaviour. In particular, we propose that cerebellar learning mechanisms may influence hippocampal place fields, by contributing to the path integration process. Our simulations predict differences in place-cell discharge properties between normal mice and L7-PKCI mutant mice lacking long-term depression at cerebellar parallel fibre-Purkinje cell synapses. On the behavioural level, these results suggest that, by influencing the accuracy of hippocampal spatial codes, cerebellar deficits may impact the exploration-exploitation balance during spatial navigation. PMID:22485133

Effect of hypo- and hyperthyroidism on hexokinase in the developing cerebellum of the rat.

PubMed

Gutekunst, D I; Wilson, J E

1981-05-01

Total hexokinase levels (units/g tissue) have been measured during postnatal development of the cerebellum in control, hypothyroid, and hyperthyroid rats. In addition. distribution of hexokinase in the developing cerebellum has been observed with an immunofluorescence method. Hypothyroidism delays the normally observed postnatal increase in total hexokinase activity, whereas hyperthyroidism accelerates the increase. In normal animals, hexokinase levels in maturing Purkinje cells pass through a transient increase, with maximal levels at approximately 8 days postnatally followed by rapid decline to relatively low levels by 12 days; hypothyroidism delays this transient increase and subsequent decline, but hyperthyroidism does not appear to affect markedly the timing of this phenomenon. Cerebellar glomeruli are relatively enriched in hexokinase content, as judged by their intense fluorescence. Hypothyroidism delays the development of intensely stained glomeruli. Hyperthyroidism did not appear to cause precocious increase in numbers of glomeruli but may have increased the rate at which the hexokinase was assimilated by newly formed glomeruli. The effects of hypo- and hyperthyroidism on total cerebellar hexokinase levels are interpreted in terms of the effect of thyroid hormone on the biochemical maturation of synaptic structures rich in hexokinase.

Magnetic Resonance Imaging Diagnosis of Dandy-Walker-Like Syndrome in a Wire-Haired Miniature Dachshund

PubMed Central

KOBATAKE, Yui; MIYABAYASHI, Takayoshi; YADA, Naoko; KACHI, Shingo; OHTA, George; SAKAI, Hiroki; MAEDA, Sadatoshi; KAMISHINA, Hiroaki

2013-01-01

ABSTRACT A 12-week-old female Wire-haired miniature dachshund presented with non-progressive ataxia and hypermetria. Due to the animal’s clinical history and symptoms, cerebellar malformations were suspected. Computed tomography (CT) and magnetic resonance imaging (MRI) detected bilateral ventriculomegaly, dorsal displacement of the cerebellar tentorium, a defect in the cerebellar tentorium and a large fluid-filled cystic structure that occupied the regions where the cerebellar vermis and occipital lobes are normally located. The abovementioned cystic structure and the defect in the cerebellar tentorium were comparable to those seen in humans with Dandy-Walker syndrome. However, the presence of the cystic structure in the occipital lobe region was unique to the present case. During necropsy, the MRI findings were confirmed, but the etiology of the condition was not determined. PMID:23719692

Gaze failure, drifting eye movements, and centripetal nystagmus in cerebellar disease.

PubMed Central

Leech, J; Gresty, M; Hess, K; Rudge, P

1977-01-01

Three abnormalities of eye movement in man are described which are indicative of cerebellar system disorder, namely, centripetally beating nystagmus, failure to maintain lateral gaze either in darkness or with eye closure, and slow drifting movements of the eyes in the absence of fixation. Similar eye movement signs follow cerebellectomy in the primate and the cat. These abnormalities of eye movement, together with other signs of cerebellar disease, such as rebound alternating, and gaze paretic nystagmus, are explained by the hypothesis that the cerebellum helps to maintain lateral gaze and that brain stem mechanisms which monitor gaze position generate compensatory biases in the absence of normal cerebellar function. PMID:603785

Proneurotrophin-3 promotes cell cycle withdrawal of developing cerebellar granule cell progenitors via the p75 neurotrophin receptor.

PubMed

Zanin, Juan Pablo; Abercrombie, Elizabeth; Friedman, Wilma J

2016-07-19

Cerebellar granule cell progenitors (GCP) proliferate extensively in the external granule layer (EGL) of the developing cerebellum prior to differentiating and migrating. Mechanisms that regulate the appropriate timing of cell cycle withdrawal of these neuronal progenitors during brain development are not well defined. The p75 neurotrophin receptor (p75(NTR)) is highly expressed in the proliferating GCPs, but is downregulated once the cells leave the cell cycle. This receptor has primarily been characterized as a death receptor for its ability to induce neuronal apoptosis following injury. Here we demonstrate a novel function for p75(NTR) in regulating proper cell cycle exit of neuronal progenitors in the developing rat and mouse EGL, which is stimulated by proNT3. In the absence of p75(NTR), GCPs continue to proliferate beyond their normal period, resulting in a larger cerebellum that persists into adulthood, with consequent motor deficits.

Prolonged cortical silent period but normal sensorimotor plasticity in spinocerebellar ataxia 6.

PubMed

Teo, James T H; Schneider, Susanne A; Cheeran, Binith J; Fernandez-del-Olmo, Miguel; Giunti, Paola; Rothwell, John C; Bhatia, Kailash P

2008-02-15

Spinocerebellar ataxia 6 (SCA6) is a hereditary disease characterized by a trinucleotide repeat expansion in the CACNA1A gene and late-onset bilateral cerebellar atrophy. It is unclear if there is significant pathology outside of the cerebellum. We used transcranial magnetic stimulation to assess sensorimotor cortical circuits and cortical plasticity in 8 SCA6 patients and 8 age-matched controls. Behavioral performance was assessed using a rhythmic tapping task. Neurophysiological measures of SCA6 patients showed a prolonged cortical silent period (CSP) but normal MEP recruitment curve, short-latency afferent inhibition, long-latency afferent inhibition and ipsilateral silent period. Paired-associative stimulation induction also increased motor-evoked potentials normally. SCA6 patients had greater variability with cued rhythmic tapping than normals and deteriorated when the cue was removed; in comparison, normal subjects had similar variability between cued and uncued rhythmic tapping. Analysis using a Wing-Kristofferson timing model indicated that both clock variance and motor delay variance were abnormal. Conclusion. In SCA6, the circuits for sensorimotor integration and the mechanisms for LTP-like plasticity in the sensorimotor cortex are unimpaired. A prolonged CSP in SCA6 just like in other cerebellar atrophies would suggest that this neurophysiological change typifies cerebellar dysfunction. 2007 Movement Disorder Society

Adaptations of the vestibular system to short and long-term exposures to altered gravity

NASA Astrophysics Data System (ADS)

Bruce, L.

Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival. We are studying two aspects of this vestibular adaptation: (1) How does long-term exposure to microgravity and hypergravity affect the development of vestibular afferents? (2) How does short- term exposure to extremely rapid changes in gravity, such as those that occur during launch and landing, affect the vestibular system. During space flight the gravistatic receptors in the otolith organs are effectively unloaded. In hypergravity conditions they are overloaded. However, the angular acceleration receptors of the semicircular canals receive relatively normal stimulation in both micro- and hypergravity.Rat embryos exposed to microgravity from gestation day 10 (prior to vestibular function) until gestation day 20 (vestibular system is somewhat functional) showed that afferents from the posterior vertical canal projecting to the medial vestibular nucleus developed similarly in microgravity, hypergravity, and in controls . However, afferents from the saccule showed delayed development in microgravity as compared to development in hypergravity and in controls. Cerebellar plasticity is crucial for modification of sensory-motor control and learning. Thus we explored the possibility that strong vestibular stimuli would modify cerebellar motor control (i.e., eye movement, postural control, gut motility) by altering the morphology of cerebellar Purkinje cells. To study the effects of short-term exposures to strong vestibular stimuli we focused on structural changes in the vestibulo-cerebellum that are caused by strong vestibular stimuli. Adult mice were exposed to various combinations of constant and/or rapidly changing angular and linear accelerations for 8.5 min (the time length of shuttle launch). Our data shows that these stimuli cause intense excitation of cerebellar Purkinje cells, inducing up-regulation of clathrin-mediated endocytosis. Different types of stimulation affect Purkinje cells in particular locations of the vestibulo-cerebellum. This system allows us to study how the vestibular environment can modify cerebellar function, allowing animals to adapt to new environments. Supported by NASA grant NAG2-1353.

Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates.

PubMed

Eluvathingal, Thomas J; Behen, Michael E; Chugani, Harry T; Janisse, James; Bernardi, Bruno; Chakraborty, Pulak; Juhasz, Csaba; Muzik, Otto; Chugani, Diane C

2006-10-01

We assessed the structural and functional imaging features of cerebellar lesions and their neurobehavioral correlates in a large cohort of patients with tuberous sclerosis complex. A consecutive series of 78 patients with tuberous sclerosis complex underwent magnetic resonance imaging (MRI) and positron emission tomography (PET) studies with [(18)F]fluorodeoxyglucose (FDG) and alpha-[(11)C]methyl-l-tryptophan (AMT) as part of their evaluation for epilepsy surgery. Neurobehavioral assessment included the Gilliam Autism Rating Scales (GARS) and the Vineland Adaptive Behavior Scales (VABS). Twenty-one patients (27%) had cerebellar lesions (10 boys; mean age 9 +/- 8 years; 9 had right-sided, 10 had left-sided, and 2 had bilateral cerebellar lesions). The lesions showed decreased glucose metabolism (0.79 +/- 0.10) and increased (1.04 +/- 0.10) AMT uptake compared with the normal (nonlesional) cerebellar cortex. Comparisons between patients with (n = 20) and without (n = 57) a cerebellar lesion on neurobehavioral functioning, controlling for the number and location of cortical tubers, revealed that the cerebellar lesion group had higher overall autistic symptomatology. Within-group analyses of the cerebellar lesion group revealed that children with right-sided cerebellar lesions had higher social isolation and communicative and developmental disturbance compared with children with left-sided cerebellar lesions. The side of the cerebellar lesion was not related to adaptive behavior functioning. These findings provide additional empiric support for a role of the cerebellum in autistic symptomatology. Further investigation of the potential role of the right cerebellum in autism, particularly with regard to the dentatothalamofrontal circuit, is warranted.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) with chronic cough and preserved muscle stretch reflexes: evidence for selective sparing of afferent Ia fibres.

PubMed

Infante, Jon; García, Antonio; Serrano-Cárdenas, Karla M; González-Aguado, Rocío; Gazulla, José; de Lucas, Enrique M; Berciano, José

2018-06-01

The aim of this study was to describe five patients with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) with chronic cough and preserved limb muscle stretch reflexes. All five patients were in the seventh decade of age, their gait imbalance having been initiated in the fifth decade. In four patients cough antedated gait imbalance between 15 and 29 years; cough was spasmodic and triggered by variable factors. Established clinical picture included severe hypopallesthesia predominating in the lower limbs with postural imbalance, and variable degree of cerebellar axial and appendicular ataxia, dysarthria and horizontal gaze-evoked nystagmus. Upper- and lower-limb tendon jerks were preserved, whereas jaw jerk was absent. Vestibular function testing showed bilateral impairment of the vestibulo-ocular reflex. Nerve conduction studies demonstrated normal motor conduction parameters and absence or severe attenuation of sensory nerve action potentials. Somatosensory evoked potentials were absent or severely attenuated. Biceps and femoral T-reflex recordings were normal, while masseter reflex was absent or attenuated. Sympathetic skin responses were normal. Cranial MRI showed vermian and hemispheric cerebellar atrophy predominating in lobules VI, VII and VIIa. We conclude that spasmodic cough may be an integral part of the clinical picture in CANVAS, antedating the appearance of imbalance in several decades and that sparing of muscle spindle afferents (Ia fibres) is probably the pathophysiological basis of normoreflexia.

Altered soleus responses to magnetic stimulation in pure cerebellar ataxia.

PubMed

Kurokawa-Kuroda, Tomomi; Ogata, Katsuya; Suga, Rie; Goto, Yoshinobu; Taniwaki, Takayuki; Kira, Jun-Ichi; Tobimatsu, Shozo

2007-06-01

Transcranial magnetic stimulation (TMS) over the leg motor area elicits a soleus primary response (SPR) and a soleus late response (SLR). We evaluated the influence of the cerebellofugal pathway on the SPR and SLR in patients with 'pure' cerebellar ataxia. SPRs and SLRs were recorded from 11 healthy subjects and 9 patients with 'pure' cerebellar cortical degeneration; 5 with spinocerebellar ataxia type 6 (SCA6), and 4 with late cortical cerebellar ataxia (LCCA). In addition, three patients with localized cerebellar lesions were tested. The SPR latency was significantly longer in patients than in controls, but primary responses in the tibialis anterior muscle were normal. The frequency of abnormal SLR was 38.9% in the supine position and 83.3% in the standing position. Two out of three patients with localized cerebellar lesions also showed abnormal SLR. Altered SPRs in patients may result from a dysfunction of the primary motor cortex caused by crossed cerebello-cerebral diaschisis. In addition, our results suggest that 'pure' cerebellar degeneration involves the mechanism responsible for evoking SLR which is related to the control of posture. SLR can be a useful neurophysiological parameter for evaluating cerebellofugal function.

Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet's disease.

PubMed

Kanoto, Masafumi; Hosoya, Takaaki; Toyoguchi, Yuuki; Oda, Atsuko

2013-01-01

Chronic progressive neuro-Behçet's disease (CPNBD) resembles multiple sclerosis (MS) on patient background and image findings, and therefore is difficult to diagnose. The purpose is to identify the characteristic magnetic resonance imaging (MRI) findings of CPNBD and to clarify the differences between the MRI findings of CPNBD and those of MS. The subjects consist of a CPNBD group (n=4; 1 male and 3 females; mean age, 51 y.o.), a MS group (n=19; 3 males and 16 females; mean age, 45 y.o.) and a normal control group (n=23; 10 males and 13 females; mean age, 45 y.o.). Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were retrospectively evaluated in each subjects. In middle sagittal brain MR images, the prepontine distance was measured as an indirect index of brain stem and cerebellar atrophy and the pontine and mesencephalic distance was measured as a direct index of brain stem atrophy. These indexes were statistically analyzed. Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were seen in all CPNBD cases. Prepontine distance was significantly different between the CPNBD group and the MS group (p<0.05), and between the CPNBD group and the normal control group (p<0.001). Pontine and mesencephalic distance were significantly different between the CPNBD group and the MS group (p<0.001, p<0.01 respectively), and between the CPNBD group and the normal control group (p<0.001). Chronic progressive neuro-Behçet's disease should be considered in patients with brain stem and cerebellar atrophy in addition to leukoencephalopathy similar to that seen in multiple sclerosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Variations au cours de la journée de l'incorporation in vivo de la leucine tritiée dans les protéines du cervelet et du cerveau du jeune rat normal et hypothyroïdien. Daily variations of the in vivo [3H] leucine incorporation into the cerebellar and cerebral proteins of the normal and hypothyroid young rat [(author's transl)].

PubMed

Dainat, J; Rebière, A

1978-02-15

In the normal and hypothyroid 6-day-old rat, the specific radioactivity (RSA) and the relative RSA (ratio of the RSA to the [3H] lecine concentration of the acido soluble phase) of the cerebral and cerebellar proteins, changes during the day synchronally. They show a maximum at 15.00 h and a minimum at 0.300 h. At all stages studied, these values are significantly lower in the hyothyroid animals than in normal ones.

Impaired eye-blink conditioning in waggler, a mutant mouse with cerebellar BDNF deficiency.

PubMed

Bao, S; Chen, L; Qiao, X; Knusel, B; Thompson, R F

1998-01-01

In addition to their trophic functions, neurotrophins are also implicated in synaptic modulation and learning and memory. Although gene knockout techniques have been used widely in studying the roles of neurotrophins at molecular and cellular levels, behavioral studies using neurotrophin knockouts are limited by the early-onset lethality and various sensory deficits associated with the gene knockout mice. In the present study, we found that in a spontaneous mutant mouse, waggler, the expression of brain-derived neurotrophic factor (BDNF) was selectively absent in the cerebellar granule cells. The cytoarchitecture of the waggler cerebellum appeared to be normal at the light microscope level. The mutant mice exhibited no sensory deficits to auditory stimuli or heat-induced pain. However, they were massively impaired in classic eye-blink conditioning. These results suggest that BDNF may have a role in normal cerebellar neuronal function, which, in turn, is essential for classic eye-blink conditioning.

Cellular commitment in the developing cerebellum

PubMed Central

Marzban, Hassan; Del Bigio, Marc R.; Alizadeh, Javad; Ghavami, Saeid; Zachariah, Robby M.; Rastegar, Mojgan

2014-01-01

The mammalian cerebellum is located in the posterior cranial fossa and is critical for motor coordination and non-motor functions including cognitive and emotional processes. The anatomical structure of cerebellum is distinct with a three-layered cortex. During development, neurogenesis and fate decisions of cerebellar primordium cells are orchestrated through tightly controlled molecular events involving multiple genetic pathways. In this review, we will highlight the anatomical structure of human and mouse cerebellum, the cellular composition of developing cerebellum, and the underlying gene expression programs involved in cell fate commitments in the cerebellum. A critical evaluation of the cell death literature suggests that apoptosis occurs in ~5% of cerebellar cells, most shortly after mitosis. Apoptosis and cellular autophagy likely play significant roles in cerebellar development, we provide a comprehensive discussion of their role in cerebellar development and organization. We also address the possible function of unfolded protein response in regulation of cerebellar neurogenesis. We discuss recent advancements in understanding the epigenetic signature of cerebellar compartments and possible connections between DNA methylation, microRNAs and cerebellar neurodegeneration. Finally, we discuss genetic diseases associated with cerebellar dysfunction and their role in the aging cerebellum. PMID:25628535

Pronounced reduction of acquisition of conditioned eyeblink responses in young adults with focal cerebellar lesions impedes conclusions on the role of the cerebellum in extinction and savings.

PubMed

Ernst, T M; Beyer, L; Mueller, O M; Göricke, S; Ladd, M E; Gerwig, M; Timmann, D

2016-05-01

Human cerebellar lesion studies provide good evidence that the cerebellum contributes to the acquisition of classically conditioned eyeblink responses (CRs). As yet, only one study used more advanced methods of lesion-symptom (or lesion-behavior) mapping to investigate which cerebellar areas are involved in CR acquisition in humans. Likewise, comparatively few studies investigated the contribution of the human cerebellum to CR extinction and savings. In this present study, young adults with focal cerebellar disease were tested. A subset of participants was expected to acquire enough conditioned responses to allow the investigation of extinction and saving effects. 19 participants with chronic surgical lesions of the cerebellum and 19 matched control subjects were tested. In all cerebellar subjects benign tumors of the cerebellum had been surgically removed. Eyeblink conditioning was performed using a standard short delay protocol. An initial unpaired control phase was followed by an acquisition phase, an extinction phase and a subsequent reacquisition phase. Structural 3T magnetic resonance images of the brain were acquired on the day of testing. Cerebellar lesions were normalized using methods optimized for the cerebellum. Subtraction analysis and Liebermeister tests were used to perform lesion-symptom mapping. As expected, CR acquisition was significantly reduced in cerebellar subjects compared to controls. Reduced CR acquisition was significantly more likely in participants with lesions of lobule VI and Crus I extending into Crus II (p<0.05, Liebermeister test). Cerebellar subjects could be subdivided into two groups: a smaller group (n=5) which showed acquisition, extinction and savings within the normal range; and a larger group (n=14) which did not show acquisition. In the latter, no conclusions on extinction or savings could be drawn. Previous findings were confirmed that circumscribed areas in lobule VI and Crus I are of major importance in CR acquisition. In addition, the present data suggest that if the critical regions of the cerebellar cortex are lesioned, the ability to acquire CRs is not only reduced but abolished. Subjects with lesions outside these critical areas, on the other hand show preserved acquisition, extinction and saving effects. As a consequence, studies in human subjects with cerebellar lesions do not allow drawing conclusions on CR extinction and savings. In light of the present findings, previous reports of reduced extinction in humans with circumscribed cerebellar disease need to be critically reevaluated. Copyright © 2016 Elsevier Ltd. All rights reserved.

Aryl Hydrocarbon Receptor (AhR) Deletion in Cerebellar Granule Neuron Precursors Impairs Neurogenesis

PubMed Central

Dever, Daniel P.; Adham, Zachariah O.; Thompson, Bryan; Genestine, Matthieu; Cherry, Jonathan; Olschowka, John A.; DiCicco-Bloom, Emanuel; Opanashuk, Lisa A.

2015-01-01

The aryl hydrocarbon receptor (AhR) is a ligand-activated member of the basic-helix-loop-helix (bHLH)/PER-ARNT-SIM(PAS) transcription factor superfamily that also mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence suggests that AhR influences the development of many tissues, including the central nervous system. Our previous studies suggest that sustained AhR activation by TCDD and/or AhR deletion disrupts cerebellar granule neuron precursor (GNP) development. In the current study, to determine whether endogenous AhR controls GNP development in a cell autonomous manner, we created a GNP-specific AhR deletion mouse, AhRfx/fx/Math1CRE/+ (AhR CKO). Selective AhR deletion in GNPs produced abnormalities in proliferation and differentiation. Specifically, fewer GNPs were engaged in S-phase, as demonstrated by ~25% reductions in thymidine (in vitro) and BrdU (in vivo) incorporation. Furthermore, total granule neuron numbers in the IGL at PND21 and PND60 were diminished in AhR CKO mice compared to controls. On the other hand, differentiation was enhanced, including ~40% increase in neurite outgrowth and 50% increase in GABARα6 receptor expression in deletion mutants. Our results suggest that AhR activity plays a role in regulating granule neuron number and differentiation, possibly by coordinating this GNP developmental transition. These studies provide novel insights for understanding the normal roles of AhR signaling during cerebellar granule cell neurogenesis, and may have important implications for the effects of environmental factors in cerebellar dysgenesis. PMID:26243376

Activation of the cerebellar cortex and the dentate nucleus in a prism adaptation fMRI study.

PubMed

Küper, Michael; Wünnemann, Meret J S; Thürling, Markus; Stefanescu, Roxana M; Maderwald, Stefan; Elles, Hans G; Göricke, Sophia; Ladd, Mark E; Timmann, Dagmar

2014-04-01

During prism adaptation two types of learning processes can be distinguished. First, fast strategic motor control responses are predominant in the early course of prism adaptation to achieve rapid error correction within few trials. Second, slower spatial realignment occurs among the misaligned visual and proprioceptive sensorimotor coordinate system. The aim of the present ultra-highfield (7T) functional magnetic resonance imaging (fMRI) study was to explore cerebellar cortical and dentate nucleus activation during the course of prism adaptation in relation to a similar visuomotor task without prism exposure. Nineteen young healthy participants were included into the study. Recently developed normalization procedures were applied for the cerebellar cortex and the dentate nucleus. By means of subtraction analysis (early prism adaptation > visuomotor, early prism adaptation > late prism adaptation) we identified ipsilateral activation associated with strategic motor control responses within the posterior cerebellar cortex (lobules VIII and IX) and the ventro-caudal dentate nucleus. During the late phase of adaptation we observed pronounced activation of posterior parts of lobule VI, although subtraction analyses (late prism adaptation > visuomotor) remained negative. These results are in good accordance with the concept of a representation of non-motor functions, here strategic control, within the ventro-caudal dentate nucleus. Copyright © 2013 Wiley Periodicals, Inc.

The 3-Second Rule in Hereditary Pure Cerebellar Ataxia: A Synchronized Tapping Study

PubMed Central

Matsuda, Shunichi; Matsumoto, Hideyuki; Furubayashi, Toshiaki; Hanajima, Ritsuko; Tsuji, Shoji; Ugawa, Yoshikazu; Terao, Yasuo

2015-01-01

The ‘3-second rule’ has been proposed based on miscellaneous observations that a time period of around 3 seconds constitutes the fundamental unit of time related to the neuro-cognitive machinery in normal humans. The aim of paper was to investigate the temporal processing in patients with spinocerebellar ataxia type 6 (SCA6) and SCA31, pure cerebellar types of spinocerebellar degeneration, using a synchronized tapping task. Seventeen SCA patients (11 SCA6, 6 SCA31) and 17 normal age-matched volunteers participated. The task required subjects to tap a keyboard in synchrony with sequences of auditory stimuli presented at fixed interstimulus intervals (ISIs) between 200 and 4800 ms. In this task, the subjects required non-motor components to estimate the time of forthcoming tone in addition to motor components to tap. Normal subjects synchronized their taps to the presented tones at shorter ISIs, whereas as the ISI became longer, the normal subjects displayed greater latency between the tone and the tapping (transition zone). After the transition zone, normal subjects pressed the button delayed relative to the tone. On the other hand, SCA patients could not synchronize their tapping with the tone even at shorter ISIs, although they pressed the button delayed relative to the tone earlier than normal subjects did. The earliest time of delayed tapping appearance after the transition zone was 4800 ms in normal subjects but 1800 ms in SCA patients. The span of temporal integration in SCA patients is shortened compared to that in normal subjects. This could represent non-motor cerebellar dysfunction in SCA patients. PMID:25706752

Comparison of brain MRI findings with language and motor function in the dystroglycanopathies.

PubMed

Brun, Brianna N; Mockler, Shelley R H; Laubscher, Katie M; Stephan, Carrie M; Wallace, Anne M; Collison, Julia A; Zimmerman, M Bridget; Dobyns, William B; Mathews, Katherine D

2017-02-14

To describe the spectrum of brain MRI findings in a cohort of individuals with dystroglycanopathies (DGs) and relate MRI results to function. All available brain MRIs done for clinical indications on individuals enrolled in a DG natural history study (NCT00313677) were reviewed. Reports were reviewed when MRI was not available. MRIs were categorized as follows: (1) cortical, brainstem, and cerebellar malformations; (2) cortical and cerebellar malformations; or (3) normal. Language development was assigned to 1 of 3 categories by a speech pathologist. Maximal motor function and presence of epilepsy were determined by history or examination. Twenty-five MRIs and 9 reports were reviewed. The most common MRI abnormalities were cobblestone cortex or dysgyria with an anterior-posterior gradient and cerebellar hypoplasia. Seven individuals had MRIs in group 1, 8 in group 2, and 19 in group 3. Language was impaired in 100% of those in MRI groups 1 and 2, and degree of language impairment correlated with severity of imaging. Eighty-five percent of the whole group achieved independent walking, but only 33% did in group 1. Epilepsy was present in 8% of the cohort and rose to 37% of those with an abnormal MRI. Developmental abnormalities of the brain such as cobblestone lissencephaly, cerebellar cysts, pontine hypoplasia, and brainstem bowing are hallmarks of DG and should prompt consideration of these diagnoses. Brain imaging in individuals with DG helps to predict outcomes, especially language development, aiding clinicians in prognostic counseling. © 2017 American Academy of Neurology.

Specific cerebellar regions are related to force amplitude and rate of force development

PubMed Central

Spraker, M.B.; Corcos, D.M.; Kurani, A.S.; Prodoehl, J.; Swinnen, S.P.; Vaillancourt, D.E.

2011-01-01

The human cerebellum has been implicated in the control of a wide variety of motor control parameters, such as force amplitude, movement extent, and movement velocity. These parameters often covary in both movement and isometric force production tasks, so it is difficult to resolve whether specific regions of the cerebellum relate to specific parameters. In order to address this issue, the current study used two experiments and SUIT normalization to determine whether BOLD activation in the cerebellum scales with the amplitude or rate of change of isometric force production or both. In the first experiment, subjects produced isometric pinch-grip force over a range of force amplitudes without any constraints on the rate of force development. In the second experiment, subjects varied the rate of force production, but the target force amplitude remained constant. The data demonstrate that BOLD activation in separate sub-areas of cerebellar regions lobule VI and Crus I/II scale with both force amplitude and force rate. In addition, BOLD activation in cerebellar lobule V and vermis VI was specific to force amplitude, whereas BOLD activation in lobule VIIb was specific to force rate. Overall, cerebellar activity related to force amplitude was located superior and medial, whereas activity related to force rate was inferior and lateral. These findings suggest that specific circuitry in the cerebellum may be dedicated to specific motor control parameters such as force amplitude and force rate. PMID:21963915

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

PubMed Central

Thomas, Anna C.; Williams, Hywel; Setó-Salvia, Núria; Bacchelli, Chiara; Jenkins, Dagan; O’Sullivan, Mary; Mengrelis, Konstantinos; Ishida, Miho; Ocaka, Louise; Chanudet, Estelle; James, Chela; Lescai, Francesco; Anderson, Glenn; Morrogh, Deborah; Ryten, Mina; Duncan, Andrew J.; Pai, Yun Jin; Saraiva, Jorge M.; Ramos, Fabiana; Farren, Bernadette; Saunders, Dawn; Vernay, Bertrand; Gissen, Paul; Straatmaan-Iwanowska, Anna; Baas, Frank; Wood, Nicholas W.; Hersheson, Joshua; Houlden, Henry; Hurst, Jane; Scott, Richard; Bitner-Glindzicz, Maria; Moore, Gudrun E.; Sousa, Sérgio B.; Stanier, Philip

2014-01-01

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum. PMID:25439728

Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.

PubMed

Thomas, Anna C; Williams, Hywel; Setó-Salvia, Núria; Bacchelli, Chiara; Jenkins, Dagan; O'Sullivan, Mary; Mengrelis, Konstantinos; Ishida, Miho; Ocaka, Louise; Chanudet, Estelle; James, Chela; Lescai, Francesco; Anderson, Glenn; Morrogh, Deborah; Ryten, Mina; Duncan, Andrew J; Pai, Yun Jin; Saraiva, Jorge M; Ramos, Fabiana; Farren, Bernadette; Saunders, Dawn; Vernay, Bertrand; Gissen, Paul; Straatmaan-Iwanowska, Anna; Baas, Frank; Wood, Nicholas W; Hersheson, Joshua; Houlden, Henry; Hurst, Jane; Scott, Richard; Bitner-Glindzicz, Maria; Moore, Gudrun E; Sousa, Sérgio B; Stanier, Philip

2014-11-06

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Abnormal cerebellar development and Purkinje cell defects in Lgl1-Pax2 conditional knockout mice.

PubMed

Hou, Congzhe; Ding, Lingcui; Zhang, Jian; Jin, Yecheng; Sun, Chen; Li, Zhenzu; Sun, Xiaoyang; Zhang, Tingting; Zhang, Aizhen; Li, Huashun; Gao, Jiangang

2014-11-01

Lgl1 was initially identified as a tumour suppressor in flies and is characterised as a key regulator of epithelial polarity and asymmetric cell division. A previous study indicated that More-Cre-mediated Lgl1 knockout mice exhibited significant brain dysplasia and died within 24h after birth. To overcome early neonatal lethality, we generated Lgl1 conditional knockout mice mediated by Pax2-Cre, which is expressed in almost all cells in the cerebellum, and we examined the functions of Lgl1 in the cerebellum. Impaired motor coordination was detected in the mutant mice. Consistent with this abnormal behaviour, homozygous mice possessed a smaller cerebellum with fewer lobes, reduced granule precursor cell (GPC) proliferation, decreased Purkinje cell (PC) quantity and dendritic dysplasia. Loss of Lgl1 in the cerebellum led to hyperproliferation and impaired differentiation of neural progenitors in ventricular zone. Based on the TUNEL assay, we observed increased apoptosis in the cerebellum of mutant mice. We proposed that impaired differentiation and increased apoptosis may contribute to decreased PC quantity. To clarify the effect of Lgl1 on cerebellar granule cells, we used Math1-Cre to specifically delete Lgl1 in granule cells. Interestingly, the Lgl1-Math1 conditional knockout mice exhibited normal proliferation of GPCs and cerebellar development. Thus, we speculated that the reduction in the proliferation of GPCs in Lgl1-Pax2 conditional knockout mice may be secondary to the decreased number of PCs, which secrete the mitogenic factor Sonic hedgehog to regulate GPC proliferation. Taken together, these findings suggest that Lgl1 plays a key role in cerebellar development and folia formation by regulating the development of PCs. Copyright © 2014. Published by Elsevier Inc.

Differential effects of age and sex on the cerebellar hemispheres and the vermis: a prospective MR study.

PubMed

Raz, N; Dupuis, J H; Briggs, S D; McGavran, C; Acker, J D

1998-01-01

The purpose of this study was to determine the effects of age and sex on the size of the cerebellar hemispheres, the cerebellar vermis, and the pons in healthy adults. We estimated the volumes of the cerebellar hemispheres (excluding the vermis and the peduncles), the cross-sectional area of the vermis, and the cross-sectional area of the ventral pons from MR images obtained in 146 healthy volunteers, 18 to 77 years old. We found a mild but significant age-related reduction in the volume of the cerebellar hemispheres and in the total area of the cerebellar vermis; however, the analysis of age trends in the vermian lobules revealed differential age-related declines. The areas of lobules VI and VII and of the posterior vermian lobules (VIII-X) declined significantly with age, whereas the anterior vermis (I-V) showed no significant age-related shrinkage. The volume of the cerebellar hemispheres (especially the right) and the area of the anterior vermis were greater in men, even after adjustment for height. Neither age nor sex affected the area of the ventral pons. Normal aging of the cerebellum is associated with selective regional shrinkage. The cerebellar hemispheres and the area of the anterior vermis may be larger in men than in women regardless of differences in body size.

Systemic inflammation combined with neonatal cerebellar haemorrhage aggravates long-term structural and functional outcomes in a mouse model.

PubMed

Tremblay, Sophie; Pai, Alex; Richter, Lindsay; Vafaei, Rod; Potluri, Praneetha; Ellegood, Jacob; Lerch, Jason P; Goldowitz, Daniel

2017-11-01

Despite the increased recognition of cerebellar injury in survivors of preterm birth, the neurodevelopmental consequences of isolated cerebellar injury have been largely unexplored and our current understanding of the functional deficits requires further attention in order to translate knowledge to best practices. Preterm infants are exposed to multiple stressors during their postnatal development including perinatal cerebellar haemorrhage (CBH) and postnatal infection, two major risk factors for neurodevelopmental impairments. We developed a translational mouse model of CBH and/or inflammation to measure the short- and long-term outcomes in cerebellar structure and function. Mice exposed to early combined insults of CBH and early inflammatory state (EIS) have a delay in grasping acquisition, neonatal motor deficits and deficient long-term memory. CBH combined with late inflammatory state (LIS) does not induce neonatal motor problems but leads to poor fine motor function and long-term memory deficits at adulthood. Early combined insults result in poor cerebellar growth from postnatal day 15 until adulthood shown by MRI, which are reflected in diminished volumes of cerebellar structures. There are also decreases in volumes of gray matter and hippocampus. Cerebellar microgliosis appears 24h after the combined insults and persists until postnatal day 15 in the cerebellar molecular layer and cerebellar nuclei in association with a disrupted patterning of myelin deposition, a delay of oligodendrocyte maturation and reduced white matter cerebellar volume. Together, these findings reveal poor outcomes in developing brains exposed to combined cerebellar perinatal insults in association with cerebellar hypoplasia, persistence of microgliosis and alterations of cerebellar white matter maturation and growth. Copyright © 2017 Elsevier Inc. All rights reserved.

Functional expression of calcium-permeable canonical transient receptor potential 4-containing channels promotes migration of medulloblastoma cells.

PubMed

Wei, Wei-Chun; Huang, Wan-Chen; Lin, Yu-Ping; Becker, Esther B E; Ansorge, Olaf; Flockerzi, Veit; Conti, Daniele; Cenacchi, Giovanna; Glitsch, Maike D

2017-08-15

The proton sensing ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) promotes expression of the canonical transient receptor potential channel subunit TRPC4 in normal and transformed cerebellar granule precursor (DAOY) cells. OGR1 and TRPC4 are prominently expressed in healthy cerebellar tissue throughout postnatal development and in primary cerebellar medulloblastoma tissues. Activation of TRPC4-containing channels in DAOY cells, but not non-transformed granule precursor cells, results in prominent increases in [Ca 2+ ] i and promotes cell motility in wound healing and transwell migration assays. Medulloblastoma cells not arising from granule precursor cells show neither prominent rises in [Ca 2+ ] i nor enhanced motility in response to TRPC4 activation unless they overexpressTRPC4. Our results suggest that OGR1 enhances expression of TRPC4-containing channels that contribute to enhanced invasion and metastasis of granule precursor-derived human medulloblastoma. Aberrant intracellular Ca 2+ signalling contributes to the formation and progression of a range of distinct pathologies including cancers. Rises in intracellular Ca 2+ concentration occur in response to Ca 2+ influx through plasma membrane channels and Ca 2+ release from intracellular Ca 2+ stores, which can be mobilized in response to activation of cell surface receptors. Ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) is a proton-sensing G q -coupled receptor that is most highly expressed in cerebellum. Medulloblastoma (MB) is the most common paediatric brain tumour that arises from cerebellar precursor cells. We found that nine distinct human MB samples all expressed OGR1. In both normal granule cells and the transformed human cerebellar granule cell line DAOY, OGR1 promoted expression of the proton-potentiated member of the canonical transient receptor potential (TRPC) channel family, TRPC4. Consistent with a role for TRPC4 in MB, we found that all MB samples also expressed TRPC4. In DAOY cells, activation of TRPC4-containing channels resulted in large Ca 2+ influx and enhanced migration, while in normal cerebellar granule (precursor) cells and MB cells not derived from granule precursors, only small levels of Ca 2+ influx and no enhanced migration were observed. Our results suggest that OGR1-dependent increases in TRPC4 expression may favour formation of highly Ca 2+ -permeable TRPC4-containing channels that promote transformed granule cell migration. Increased motility of cancer cells is a prerequisite for cancer invasion and metastasis, and our findings may point towards a key role for TRPC4 in progression of certain types of MB. © 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Electrophysiological evidence of cerebellar fiber system involvement in the Miller Fisher syndrome.

PubMed

Lo, Y L; Fook-Chong, S; Chan, L L; Ong, W Y; Ratnagopal, P

2010-01-15

In the Miller Fisher syndrome (MFS), ataxia may be due involvement of Ia afferents and the cerebellum. Transcranial magnetic stimulation (TMS) over the cerebellum is known to interfere transiently with normal function. In this study, we utilized a previously described TMS protocol over the cerebellum in combination with ballistic movements to investigate cerebellar dysfunction in MFS patients. The agonist (biceps) reaction time in MFS patients during a motor cancellation task was not significantly reduced during the initial TMS study. However, during the repeat TMS study, significant reduction was seen for all patients, in tandem with clinical recovery. There was significant correlation between anti-GQ1b IgG titers and change in agonist reaction time between the initial and repeat TMS studies. TMS likely affected horizontally orientated parallel fibers in the cerebellar molecular layer. During disease onset, antibody binding may have interfered with facilitation of reaction time during motor cancellation tasks seen in normal subjects. Normalization of reaction time facilitation corresponded to resolution of antibody-mediated interference in the molecular layer. Our study has provided evidence suggesting parallel fiber involvement in MFS, and suggested a role of anti-GQ1b IgG antibody in these changes.

Reference tissue normalization in longitudinal (18)F-florbetapir positron emission tomography of late mild cognitive impairment.

PubMed

Shokouhi, Sepideh; Mckay, John W; Baker, Suzanne L; Kang, Hakmook; Brill, Aaron B; Gwirtsman, Harry E; Riddle, William R; Claassen, Daniel O; Rogers, Baxter P

2016-01-15

Semiquantitative methods such as the standardized uptake value ratio (SUVR) require normalization of the radiotracer activity to a reference tissue to monitor changes in the accumulation of amyloid-β (Aβ) plaques measured with positron emission tomography (PET). The objective of this study was to evaluate the effect of reference tissue normalization in a test-retest (18)F-florbetapir SUVR study using cerebellar gray matter, white matter (two different segmentation masks), brainstem, and corpus callosum as reference regions. We calculated the correlation between (18)F-florbetapir PET and concurrent cerebrospinal fluid (CSF) Aβ1-42 levels in a late mild cognitive impairment cohort with longitudinal PET and CSF data over the course of 2 years. In addition to conventional SUVR analysis using mean and median values of normalized brain radiotracer activity, we investigated a new image analysis technique-the weighted two-point correlation function (wS2)-to capture potentially more subtle changes in Aβ-PET data. Compared with the SUVRs normalized to cerebellar gray matter, all cerebral-to-white matter normalization schemes resulted in a higher inverse correlation between PET and CSF Aβ1-42, while the brainstem normalization gave the best results (high and most stable correlation). Compared with the SUVR mean and median values, the wS2 values were associated with the lowest coefficient of variation and highest inverse correlation to CSF Aβ1-42 levels across all time points and reference regions, including the cerebellar gray matter. The selection of reference tissue for normalization and the choice of image analysis method can affect changes in cortical (18)F-florbetapir uptake in longitudinal studies.

Exposure of rats to environmental tobacco smoke during cerebellar development alters behavior and perturbs mitochondrial energetics.

PubMed

Fuller, Brian F; Cortes, Diego F; Landis, Miranda K; Yohannes, Hiyab; Griffin, Hailey E; Stafflinger, Jillian E; Bowers, M Scott; Lewis, Mark H; Fox, Michael A; Ottens, Andrew K

2012-12-01

Environmental tobacco smoke (ETS) exposure is linked to developmental deficits and disorders with known cerebellar involvement. However, direct biological effects and underlying neurochemical mechanisms remain unclear. We sought to identify and evaluate underlying neurochemical change in the rat cerebellum with ETS exposure during critical period development. We exposed rats to daily ETS (300, 100, and 0 µg/m3 total suspended particulate) from postnatal day 8 (PD8) to PD23 and then assayed the response at the behavioral, neuroproteomic, and cellular levels. Postnatal ETS exposure induced heightened locomotor response in a novel environment on par initially with amphetamine stimulation. The cerebellar mitochondrial subproteome was significantly perturbed in the ETS-exposed rats. Findings revealed a dose-dependent up-regulation of aerobic processes through the modification and increased translocation of Hk1 to the mitochondrion with corresponding heightened ATP synthase expression. ETS exposure also induced a dose-dependent increase in total Dnm1l mitochondrial fission factor; although more active membrane-bound Dnm1l was found at the lower dose. Dnm1l activation was associated with greater mitochondrial staining, particularly in the molecular layer, which was independent of stress-induced Bcl-2 family dynamics. Further, electron microscopy associated Dnm1l-mediated mitochondrial fission with increased biogenesis, rather than fragmentation. The critical postnatal period of cerebellar development is vulnerable to the effects of ETS exposure, resulting in altered behavior. The biological effect of ETS is underlain in part by a Dnm1l-mediated mitochondrial energetic response at a time of normally tight control. These findings represent a novel mechanism by which environmental exposure can impact neurodevelopment and function.

Long-term functional outcome of patients with cerebellar pilocytic astrocytoma surgically treated in childhood.

PubMed

Ait Khelifa-Gallois, N; Laroussinie, F; Puget, S; Sainte-Rose, C; Dellatolas, G

2015-01-01

Abstract Purpose: A number of studies report neurological and cognitive deficits and behavioural disorders in children after surgical treatment for a benign cerebellar tumour. The present study explores functional outcome in adolescents and adults treated for a low-grade cerebellar astrocytoma in childhood. Participants were 18 adolescents and 46 adults treated for low-grade astrocytoma in childhood. Academic achievement, professional status and neurological, cognitive and behavioural disturbances were collected using self-completed and parental questionnaires for adolescents and phone interview for adults. For the adolescent group, a control group filled in the same questionnaires. Mean time lapse from surgery was 7.8 years for adolescents and 12.9 years for adults. Five adults (11%) had major sequelae related to post-operative complications, post-operative mutism and/or brain stem involvement. All the other participants presented close-to-normal academic achievement and normal autonomy, despite a high rate of reported cognitive difficulties and difficulties related to mild neurological sequelae (fine motor skills, balance). The long-term functional outcome of low-grade cerebellar astrocytoma is generally favourable, in the absence of post-operative complications and brain stem involvement. No major impact of neurological deficits, cognitive problems and emotional disorders on academic achievement and independent functioning was observed.

MicroRNAs Promote Granule Cell Expansion in the Cerebellum Through Gli2.

PubMed

Constantin, Lena; Wainwright, Brandon J

2015-12-01

MicroRNAs (miRNAs) are important regulators of cerebellar function and homeostasis. Their deregulation results in cerebellar neuronal degeneration and spinocerebellar ataxia type 1 and contributes to medulloblastoma. Canonical miRNA processing involves Dicer, which cleaves precursor miRNAs into mature double-stranded RNA duplexes. In order to address the role of miRNAs in cerebellar granule cell precursor development, loxP-flanked exons of Dicer1 were conditionally inactivated using the granule cell precursor-specific Atoh1-Cre recombinase. A reduction of 87% in Dicer1 transcript was achieved in this conditional Dicer knockdown model. Although knockdown resulted in normal survival, mice had disruptions to the cortical layering of the anterior cerebellum, which resulted from the premature differentiation of granule cell precursors in this region during neonatal development. This defect manifested as a thinner external granular layer with ectopic mature granule cells, and a depleted internal granular layer. We found that expression of the activator components of the Hedgehog-Patched pathway, the Gli family of transcription factors, was perturbed in conditional Dicer knockdown mice. We propose that loss of Gli2 mRNA mediated the anterior-restricted defect in conditional Dicer knockdown mice and, as proof of principle, were able to show that miR-106b positively regulated Gli2 mRNA expression. These findings confirm the importance of miRNAs as positive mediators of Hedgehog-Patched signalling during granule cell precursor development.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

PubMed Central

Whittaker, Danielle E.; Kasah, Sahrunizam; Donovan, Alex P. A.; Ellegood, Jacob; Riegman, Kimberley L. H.; Volk, Holger A.; McGonnell, Imelda; Lerch, Jason P.

2017-01-01

Mutations in the gene encoding the ATP dependent chromatin‐remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital‐urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio‐temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay. PMID:29168327

Cerebellar stroke presenting with isolated dizziness: Brain MRI in 136 patients.

PubMed

Perloff, Michael D; Patel, Nimesh S; Kase, Carlos S; Oza, Anuja U; Voetsch, Barbara; Romero, Jose R

2017-11-01

To evaluate occurrence of cerebellar stroke in Emergency Department (ED) presentations of isolated dizziness (dizziness with a normal exam and negative neurological review of systems). A 5-year retrospective study of ED patients presenting with a chief complaint of "dizziness or vertigo", without other symptoms or signs in narrative history or on exam to suggest a central nervous system lesion, and work-up included a brain MRI within 48h. Patients with symptoms commonly peripheral in etiology (nystagmus, tinnitus, gait instability, etc.) were included in the study. Patient demographics, stroke risk factors, and gait assessments were recorded. One hundred and thirty-six patients, who had a brain MRI for isolated dizziness, were included. There was a low correlation of gait assessment between ED physician and Neurologist (49 patients, Spearman's correlation r 2 =0.17). Based on MRI DWI sequence, 3.7% (5/136 patients) had acute cerebellar strokes, limited to or including, the medial posterior inferior cerebellar artery vascular territory. In the 5 cerebellar stroke patients, mean age, body mass index (BMI), hemoglobin A1c, gender distribution, and prevalence of hypertension were similar to the non-cerebellar stroke patient group. Mean LDL/HDL ratio was 3.63±0.80 and smoking prevalence was 80% in the cerebellar stroke group compared to 2.43±0.79 and 22% (respectively, p values<0.01) in the non-cerebellar stroke group. Though there was preselection bias for stroke risk factors, our study suggests an important proportion of cerebellar stroke among ED patients with isolated dizziness, considering how common this complaint is. Copyright © 2017 Elsevier Inc. All rights reserved.

Viewing the Personality Traits Through a Cerebellar Lens: a Focus on the Constructs of Novelty Seeking, Harm Avoidance, and Alexithymia.

PubMed

Petrosini, Laura; Cutuli, Debora; Picerni, Eleonora; Laricchiuta, Daniela

2017-02-01

The variance in the range of personality trait expression appears to be linked to structural variance in specific brain regions. In evidencing associations between personality factors and neurobiological measures, it seems evident that the cerebellum has not been up to now thought as having a key role in personality. This paper will review the most recent structural and functional neuroimaging literature that engages the cerebellum in personality traits, as novelty seeking and harm avoidance, and it will discuss the findings in the context of contemporary theories of affective and cognitive cerebellar function. By using region of interest (ROI)- and voxel-based approaches, we recently evidenced that the cerebellar volumes correlate positively with novelty seeking scores and negatively with harm avoidance scores. Subjects who search for new situations as a novelty seeker does (and a harm avoiding does not do) show a different engagement of their cerebellar circuitries in order to rapidly adapt to changing environments. The emerging model of cerebellar functionality may explain how the cerebellar abilities in planning, controlling, and putting into action the behavior are associated to normal or abnormal personality constructs. In this framework, it is worth reporting that increased cerebellar volumes are even associated with high scores in alexithymia, construct of personality characterized by impairment in cognitive, emotional, and affective processing. On such a basis, it seems necessary to go over the traditional cortico-centric view of personality constructs and to address the function of the cerebellar system in sustaining aspects of motivational network that characterizes the different temperamental traits.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome.

PubMed

Whittaker, Danielle E; Kasah, Sahrunizam; Donovan, Alex P A; Ellegood, Jacob; Riegman, Kimberley L H; Volk, Holger A; McGonnell, Imelda; Lerch, Jason P; Basson, M Albert

2017-12-01

Mutations in the gene encoding the ATP dependent chromatin-remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital-urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio-temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay. © 2017 The Authors. American Journal of Medical Genetics Part C Published by Wiley Periodicals, Inc.

Structure–function relationships in the developing cerebellum: evidence from early-life cerebellar injury and neurodevelopmental disorders

PubMed Central

Stoodley, Catherine J.; Limperopoulos, Catherine

2016-01-01

SUMMARY The increasing appreciation of the role of the cerebellum in motor and non-motor functions is crucial to understanding the outcomes of acquired cerebellar injury and developmental lesions in high-risk fetal and neonatal populations, children with cerebellar damage (e.g. posterior fossa tumors), and neurodevelopmental disorders (e.g. autism). We review available data regarding the relationship between the topography of cerebellar injury or abnormality and functional outcomes. We report emerging structure–function relationships with specific symptoms: cerebellar regions that interconnect with sensorimotor cortices are associated with motor impairments when damaged; disruption to posterolateral cerebellar regions that form circuits with association cortices impact long-term cognitive outcomes; and midline posterior vermal damage is associated with behavioral dysregulation and an autism-like phenotype. We also explore the impact of age and the potential role for critical periods on cerebellar structure and child function. These findings suggest that the cerebellum plays a critical role in motor, cognitive, and social–behavioral development, possibly via modulatory effects on the developing cerebral cortex. PMID:27184461

Cerebellar Development and Disease

PubMed Central

Gleeson, Joseph G.

2008-01-01

Recent Advances The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitter-specific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum. PMID:18513948

Cadherins in cerebellar development: translation of embryonic patterning into mature functional compartmentalization.

PubMed

Redies, Christoph; Neudert, Franziska; Lin, Juntang

2011-09-01

Cadherins are cell adhesion molecules with multiple morphogenic functions in brain development, for example, in neuroblast migration and aggregation, axon navigation, neural circuit formation, and synaptogenesis. More than 100 members of the cadherin superfamily are expressed in the developing and mature brain. Most of the cadherins investigated, in particular classic cadherins and δ-protocadherins, are expressed in the cerebellum. For several cadherin subtypes, expression begins at early embryonic stages and persists until mature stages of cerebellar development. At intermediate stages, distinct Purkinje cell clusters exhibit unique rostrocaudal and mediolateral expression profiles for each cadherin. In the chicken, mouse, and other species, the Purkinje cell clusters are separated by intervening raphes of migrating granule cells. This pattern of Purkinje cell clusters/raphes is, at least in part, continuous with the parasagittal striping pattern that is apparent in the mature cerebellar cortex, for example, for zebrin II/aldolase C. Moreover, subregions of the deep cerebellar nuclei, vestibular nuclei and the olivary complex also express cadherins differentially. Neuroanatomical evidence suggests that the nuclear subregions and cortical domains that express the same cadherin subtype are connected to each other, to form neural subcircuits of the cerebellar system. Cadherins thus provide a molecular code that specifies not only embryonic structures but also functional cerebellar compartmentalization. By following the implementation of this code, it can be revealed how mature functional architecture emerges from embryonic patterning during cerebellar development. Dysfunction of some cadherins is associated with psychiatric diseases and developmental impairments and may also affect cerebellar function.

Cerebellar contribution to locomotor behavior: A neurodevelopmental perspective.

PubMed

Sathyanesan, Aaron; Gallo, Vittorio

2018-04-30

The developmental trajectory of the formation of cerebellar circuitry has significant implications for locomotor plasticity and adaptive learning at later stages. While there is a wealth of knowledge on the development of locomotor behavior in human infants, children, and adolescents, pre-clinical animal models have fallen behind on the study of the emergence of behavioral motifs in locomotor function across postnatal development. Since cerebellar development is protracted, it is subject to higher risk of genetic or environmental disruption, potentially leading to abnormal behavioral development. This highlights the need for more sophisticated and specific functional analyses of adaptive cerebellar behavior within the context of whole-body locomotion across the entire span of postnatal development. Here we review evidence on cerebellar contribution to adaptive locomotor behavior, highlighting methodologies employed to quantify and categorize behavior at different developmental stages, with the ultimate goal of following the course of early behavioral alterations in neurodevelopmental disorders. Since experimental paradigms used to study cerebellar behavior are lacking in both specificity and applicability to locomotor contexts, we highlight the use of the Erasmus Ladder - an advanced, computerized, fully automated system to quantify adaptive cerebellar learning in conjunction with locomotor function. Finally, we emphasize the need to develop objective, quantitative, behavioral tasks which can track changes in developmental trajectories rather than endpoint measurement at the adult stage of behavior. Copyright © 2018 Elsevier Inc. All rights reserved.

Brain Network Activation in Patients With Movement Disorders

ClinicalTrials.gov

2017-08-29

Parkinson Disease; Essential Tremor; Dystonia; Normal Pressure Hydrocephalus; Cerebellar Ataxia; Multiple System Atrophy; Progressive Supranuclear Palsy; Corticobasal Degeneration; Dementia With Lewy Bodies

Effects of Ethanol on the Cerebellum: Advances and Prospects.

PubMed

Luo, Jia

2015-08-01

Alcohol abuse causes cerebellar dysfunction and cerebellar ataxia is a common feature in alcoholics. Alcohol exposure during development also impacts the cerebellum. Children with fetal alcohol spectrum disorder (FASD) show many symptoms associated specifically with cerebellar deficits. However, the cellular and molecular mechanisms are unclear. This special issue discusses the most recent advances in the study of mechanisms underlying alcoholinduced cerebellar deficits. The alteration in GABAA receptor-dependent neurotransmission is a potential mechanism for ethanol-induced cerebellar dysfunction. Recent advances indicate ethanol-induced increases in GABA release are not only in Purkinje cells (PCs), but also in molecular layer interneurons and granule cells. Ethanol is shown to disrupt the molecular events at the mossy fiber - granule cell - Golgi cell (MGG) synaptic site and granule cell parallel fibers - PCs (GPP) synaptic site, which may be responsible for ethanol-induced cerebellar ataxia. Aging and ethanol may affect the smooth endoplasmic reticulum (SER) of PC dendrites and cause dendritic regression. Ethanol withdrawal causes mitochondrial damage and aberrant gene modifications in the cerebellum. The interaction between these events may result in neuronal degeneration, thereby contributing to motoric deficit. Ethanol activates doublestranded RNA (dsRNA)-activated protein kinase (PKR) and PKR activation is involved ethanolinduced neuroinflammation and neurotoxicity in the developing cerebellum. Ethanol alters the development of cerebellar circuitry following the loss of PCs, which could result in modifications of the structure and function of other brain regions that receive cerebellar inputs. Lastly, choline, an essential nutrient is evaluated for its potential protection against ethanol-induced cerebellar damages. Choline is shown to ameliorate ethanol-induced cerebellar dysfunction when given before ethanol exposure.

Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression.

PubMed

Pascual, Marta; Abasolo, Ibane; Mingorance-Le Meur, Ana; Martínez, Albert; Del Rio, José A; Wright, Christopher V E; Real, Francisco X; Soriano, Eduardo

2007-03-20

We report in this study that, in the cerebellum, the pancreatic transcription factor Ptf1a is required for the specific generation of Purkinje cells (PCs) and interneurons. Moreover, granule cell progenitors in the external GCL (EGL) appear to be unaffected by deletion of Ptf1a. Cell lineage analysis in Ptf1a(Cre/Cre) mice was used to establish that, in the absence of Ptf1a expression, ventricular zone progenitors, normally fated to produce PCs and interneurons, aberrantly migrate to the EGL and express typical markers of these cells, such as Math1, Reelin, and Zic1/2. Furthermore, these cells have a fine structure typical of EGL progenitors, indicating that they adopt an EGL-like cell phenotype. These findings indicate that Ptf1a is necessary for the specification and normal production of PCs and cerebellar interneurons. Moreover, our results suggest that Ptf1a is also required for the suppression of the granule cell specification program in cerebellar ventricular zone precursors.

TBC1D24 mutation associated with focal epilepsy, cognitive impairment and a distinctive cerebro-cerebellar malformation.

PubMed

Afawi, Zaid; Mandelstam, Simone; Korczyn, Amos D; Kivity, Sara; Walid, Simri; Shalata, Adel; Oliver, Karen L; Corbett, Mark; Gecz, Jozef; Berkovic, Samuel F; Jackson, Graeme D

2013-07-01

We describe the clinical and radiological features of a family with a homozygous mutation in TBC1D24. The phenotype comprised onset of focal seizures at 2 months with prominent eye-blinking, facial and limb jerking with an oral sensory aura. These were controllable with medication but persisted into adult life. Associated features were mild to moderate intellectual disability and cerebellar features. MRI showed subtle cortical thickening with cerebellar atrophy and high signal confined to the ansiform lobule. The disorder is allelic with familial infantile myoclonic epilepsy, where intellect and neurologic examination are normal, highlighting the phenotypic variation with mutations of TBC1D24. Copyright © 2013 Elsevier B.V. All rights reserved.

Cerebellar peduncle injury predicts motor impairments in preterm infants: A quantitative tractography study at term-equivalent age.

PubMed

Hasegawa, Tatsuji; Yamada, Kei; Tozawa, Takenori; Chiyonobu, Tomohiro; Tokuda, Sachiko; Nishimura, Akira; Hosoi, Hajime; Morimoto, Masafumi

2018-05-15

Cerebellar injury is well established as an important finding in preterm infants with cerebral palsy (CP). In this study, we investigated associations between injury to the cerebellar peduncles and motor impairments in preterm infants using quantitative tractography at term-equivalent age, which represents an early phase before the onset of motor impairments. We studied 64 preterm infants who were born at <33 weeks gestational age. These infants were divided into three groups: CP, Non-CP (defined as infants with periventricular leukomalacia but having normal motor function), and a Normal group. Diffusion tensor imaging was performed at term-equivalent age and motor function was assessed no earlier than a corrected age of 2 years. Using tractography, we measured fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the superior cerebellar peduncles (SCP) and middle cerebellar peduncles (MCP), as well as the motor/sensory tracts. The infants in the CP group had significantly lower FA of the SCP and sensory tract than those in the other groups. There was no significant difference in FA and ADC of the motor tract among the three groups. Severity of CP had a significant correlation with FA of the MCP, but not with the FA of other white matter tracts. Our results suggested that the infants with CP had injuries of the ascending tracts (e.g. the SCP and sensory tract), and that additional MCP injury might increase the severity of CP. Quantitative tractography assessment at term-equivalent age may be useful for screening preterm infants for prediction of future motor impairments. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

A qualitative electron microscopic study of the corticopontine projections after neonatal cerebellar hemispherectomy.

PubMed

Leong, S K

1980-08-04

The present study shows that 3--5 days following lesions of the dentate and interposed nuclei in normal adult rats degenerating axons and axon terminals can be detected in the contralateral pontine gray. The degenerating axon terminals form Gray's type I axo-dendritic contacts with fine and intermediate dendrites measuring between 0.8--2.4 microns. The present study also investigates, by electron microscopy, the synaptic rearrangement of the sensorimotor corticopontine projections following neonatal left cerebellar hemispherectomy. Following neonatal left cerebellar hemispherectomy, the right sensorimotor and adjacent cortex (SMC) presents a very dense ipsilateral and a modest amount of contralateral corticopontine projections in contrast with a predominantly ipsilateral corticopontine projection seen in the normal adult rat. As with the ipsilateral corticopontine projection seen in the normal adult animal, the bilateral corticopontine projections seen in the experimental animals form contacts with dendrites suggestive of Gray's type I synapses. While the corticopontine projections in normal control animals form synapses with fine dendrites measuring 0.2--1.2 micron the corticopontine projections in the experimental animals form synaptic relations with fine dendrites and with intermediate dendrites measuring 0.2--2.4 microns. As the normal cerebellopontine fibers from the dentate and interposed nuclei also form axo-dendritic synapses on fine and intermediate dendrites and the contracts formed are also of Gray's type I synapses, it is possible that some of the newly formed corticopontine fibers in the experimental animals might have replaced the cerebellopontine fibers synapsing on intermediate dendrites. Synaptic rearrangement appears to take place as suggested by the presence of synaptic complexes in which one axon terminal contacts two or more dendrites or two or more axon terminals contact one dendrite. Such complexes are frequently seen to undergo degeneration following the right SMC lesion in the experimental animals. Other complex synaptic structures are also present in both the right and left pontine gray in the experimental animals. They are not seen to undergo degeneration following the right SMC lesions. Occasional features of neuronal reaction could still be seen in both sides of the pontine gray for as long as 3--6 months after the neonatal cerebellar lesions.

Neurodevelopmental Malformations of the Cerebellar Vermis in Genetically Engineered Rats.

PubMed

Ramos, Raddy L; Van Dine, Sarah E; Gilbert, Mary E; Leheste, Joerg R; Torres, German

2015-12-01

The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformations are almost exclusively found along the primary fissure and are indicative of deficits of neuronal migration during cerebellar development. In the present report, we test the prediction that genetically engineered rats on Sprague-Dawley or Long-Evans backgrounds will also exhibit the same cerebellar malformations. Consistent with our hypothesis, we found that three different transgenic lines on two different backgrounds had cerebellar malformations. Heterotopia in transgenic rats had identical cytoarchitecture as that observed in wild-type rats including altered morphology of Bergmann glia. In light of the possibility that heterotopia could affect results from behavioral studies, these data suggest that histological analyses be performed in studies of cerebellar function or development when using genetically engineered rats on these backgrounds in order to have more careful interpretation of experimental findings.

Potential mechanisms of cerebellar hypoplasia in prematurity.

PubMed

Tam, Emily W Y

2013-09-01

The cerebellum undergoes dramatic growth and maturation over the neonatal period after preterm birth and is thus particularly sensitive to impaired development due to various clinical factors. Impairments in growth can occur independent of cerebellar parenchymal damage, such as from local hemorrhage, resulting from reduced expression of sonic hedgehog signaling to trigger the appropriate expansion of the granule precursor cells. The primary risk factors for impaired cerebellar development include postnatal glucocorticoid exposure, which has direct effects on the sonic hedgehog pathway, and supratentorial brain injury, including intraventricular hemorrhage and white matter injury, which may result in crossed cerebellar diaschisis and local toxic effects of blood products on the external granular layer. Other cardiorespiratory and nutritional factors may also exist. Impaired cerebellar development is associated with adverse outcomes in motor and cognitive development. New approaches to care to counteract these risk factors may help improve long-term outcome after preterm birth.

LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bian, Xuting; Zhong, Hongyu; Li, Fen

Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the externalmore » granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects.« less

Correlation Between Cerebellar Retraction and Hearing Loss After Microvascular Decompression for Hemifacial Spasm: A Prospective Study.

PubMed

Li, Ning; Zhao, Wei-Guo; Pu, Chun-Hua; Yang, Wen-Lei

2017-06-01

This study prospectively investigated the relationship between cerebellar retraction factors measured on preoperative magnetic resonance and the development of postoperative hearing loss and evaluated their potential role in predicting the possibility of hearing loss after microvascular decompression (MVD) for hemifacial spasm (HFS). The study included 110 patients clinically diagnosed with primary HFS who underwent MVD in our department. The cerebellar retraction factors were quantitatively measured on preoperative magnetic resonance. Associations of cerebellar retraction and other risk factors with postoperative hearing loss were analyzed. Eleven patients (10%) developed nonserviceable hearing loss after MVD. Compared with the group without hearing loss, the cerebellar retraction distance and depth of the group with hearing loss were significantly greater (P < 0.05). Multivariate logistic regression analysis showed that greater cerebellar retraction depth was significantly associated with the higher incidence of postoperative hearing loss (P < 0.05). The results in this study strongly suggested the correlation between the cerebellar retraction depth and the possibility of hearing loss after MVD for HFS. In addition, cerebellar retraction depth could be considered as a useful tool to predict the risk of post-MVD hearing loss. Copyright © 2017 Elsevier Inc. All rights reserved.

Normal Cerebellar Growth by Using Three-dimensional US in the Preterm Infant from Birth to Term-corrected Age.

PubMed

Benavente-Fernández, Isabel; Rodríguez-Zafra, Enrique; León-Martínez, Jesús; Jiménez-Gómez, Gema; Ruiz-González, Estefanía; Fernández-Colina, Rosalía Campuzano; Lechuga-Sancho, Alfonso M; Lubián-López, Simón P

2018-04-03

Purpose To establish cross-sectional and longitudinal reference values for cerebellar size in preterm infants with normal neuroimaging findings and normal 2-year neurodevelopmental outcome by using cranial ultrasonography (US). Materials and Methods This prospective study consecutively enrolled preterm infants admitted to a neonatal intensive care unit from June 2011 to June 2014 with a birth weight of less than or equal to 1500 g and/or gestational age (GA) of less than or equal to 32 weeks. They underwent weekly cranial US from birth to term-equivalent age and magnetic resonance (MR) imaging at term-equivalent age. The infants underwent neurodevelopmental assessments at age 2 years with Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III). Patients with adverse outcomes (death or abnormal neuroimaging findings and/or BSID-III score of <85) were excluded. The following measurements were performed: vermis height, craniocaudal diameter, superior width, inferior width, vermis area, and transcerebellar diameter. Statistical analyses were conducted by using multilevel analyses. Results A total of 137 infants with a mean GA at birth of 29.4 weeks (range, 25-32 weeks) were included. Transcerebellar diameter increased by 1.04 mm per week on average; vermis height and craniocaudal diameter increased by 0.55 mm and 0.59 mm, respectively. Superior vermian width increased by an average of 0.45 mm, whereas inferior vermian width increased by an average of 0.51 mm per week. Vermis area was found to increase by 0.22 cm 2 per week on average. The sex effect was significant (female lower than male) for vermis height (P < .05), craniocaudal diameter (P < .05), inferior vermian width (P <. 05), and vermis area (P <. 05). Conclusion Cross-sectional and longitudinal reference values were established for cerebellar growth in preterm infants, which may be included in routine cranial US. © RSNA, 2018 Online supplemental material is available for this article.

Cerebellar degeneration-related proteins 2 and 2-like are present in ovarian cancer in patients with and without Yo antibodies.

PubMed

Raspotnig, Margrethe; Haugen, Mette; Thorsteinsdottir, Maria; Stefansson, Ingunn; Salvesen, Helga B; Storstein, Anette; Vedeler, Christian A

2017-11-01

Cerebellar degeneration-related protein 2 (CDR2) has been presumed to be the main antigen for the onconeural antibody Yo, which is strongly associated with ovarian cancer and paraneoplastic cerebellar degeneration (PCD). Recent data show that Yo antibodies also target the CDR2-like protein (CDR2L). We, therefore, examined the expression of CDR2 and CDR2L in ovarian cancer tissue from patients with and without Yo antibodies and from various other cancerous and normal human tissues. Ovarian cancer tissue and serum samples from 16 patients were included in the study (four with anti-Yo and PCD, two with anti-Yo without PCD, five with only CDR2L antibodies, and five without onconeural antibodies). Clinical data were available for all patients. The human tissues were examined by western blot and immunohistochemistry using rabbit CDR2 and CDR2L antibodies. Ovarian cancers from all 16 patients expressed CDR2 and CDR2L proteins. Both proteins were also present in normal and cancer tissue from mammary tissue, kidney, ovary, prostate, and testis. CDR2L is present in ovarian cancers from patients with and without Yo antibodies as was shown previously for CDR2. In addition, both CDR2 and CDR2L proteins are more widely expressed than previously thought, both in normal and cancerous tissues.

[A report of atypical hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum caused by a de novo mutation in tubulin beta 4A (TUBB4A) gene and literature review].

PubMed

Du, Y; Li, C; Guo, J; Guo, P; Li, Z Y; Zhang, W

2017-06-01

Objective: To explore the clinical symptoms and neuroimaging features of a patient with atypical hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum (H-ABC) caused by a novel TUBB4A mutation. Methods: We analyzed the clinical data, imaging features and the result of genetic testing of a case diagnosed as atypical H-ABC. Results: The initial symptoms were progressive spasticity, mild cerebellar ataxia and mild cognitive impairment. MRI showed regional blurring of slight high signal on T(2)-weight and FLAIR image in white matter of the bilateral midbrain ventral, internal capsule, posteior horn of lateral ventricle and centrum semiovale, with normal bilateral cerebellar and caudoputamen nucleus. Compared with normal subjects of the same age and gender, hypometabolism was found by (18)F-FDG-PET in brainstem, cerebellar and caudoputamen nucleus in the patient. Genetic testing revealed a de novo pathogenic exome missense heterozygous mutations c. 70G>A in TUBB4A, which was not reported in the human gene mutation database (HGMDpro) and was assessed to be a pathogenic mutation by pathogenic mutation prediction software. Conclusions: The diversity of TUBB4A gene mutations may cause different functional and/or structural impairment in subcortical white matter, cerebellar and caudoputamen nucleus, leading to atypical symptoms and neuroimaging features. Genetic testing for pathogenic mutation in TUBB 4A gene is a key for the diagnosis of H - ABC .

Quantitative study of the correlation between cerebellar retraction factors and hearing loss following microvascular decompression for hemifacial spasm.

PubMed

Li, Ning; Zhao, Wei-Guo; Pu, Chun-Hua; Yang, Wen-Lei

2018-01-01

This prospective study quantitatively measured the cerebellar retraction factors, including retraction distance, depth and duration, and evaluated their potential relationship to the development of hearing loss after microvascular decompression (MVD) for hemifacial spasm (HFS). One hundred ten patients with primary HFS who underwent MVD in our department were included into this study. The cerebellar retraction factors were quantitatively measured on preoperative MR and timed during MVD. Associations of cerebellar retraction and other factors to postoperative hearing loss were analyzed. Eleven (10%) patients developed hearing loss after MVD. Compared with the group without hearing loss, the cerebellar retraction distance, depth and duration of the group with hearing loss were significantly greater (p < 0.05). Multivariate regression analysis showed that greater cerebellar retraction depth and longer retraction duration were significantly associated with a higher incidence of postoperative hearing impairment (p < 0.05). This study strongly suggested a correlation between the cerebellar retraction factors, especially retraction depth and duration, and possibility of hearing loss following MVD for HFS.

Past, Present and Future Therapeutics for Cerebellar Ataxias

PubMed Central

Marmolino, D; Manto, M

2010-01-01

Cerebellar ataxias are a group of disabling neurological disorders. Patients exhibit a cerebellar syndrome and can also present with extra-cerebellar deficits, namely pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. Recently, deficits in cognitive operations have been unraveled. Cerebellar ataxias are heterogeneous both at the phenotypic and genotypic point of view. Therapeutical trials performed during these last 4 decades have failed in most cases, in particular because drugs were not targeting a deleterious pathway, but were given to counteract putative defects in neurotransmission. The identification of the causative mutations of many hereditary ataxias, the development of relevant animal models and the recent identifications of the molecular mechanisms underlying ataxias are impacting on the development of new drugs. We provide an overview of the pharmacological treatments currently used in the clinical practice and we discuss the drugs under development. PMID:20808545

Discovery of Transcription Factors Novel to Mouse Cerebellar Granule Cell Development Through Laser-Capture Microdissection.

PubMed

Zhang, Peter G Y; Yeung, Joanna; Gupta, Ishita; Ramirez, Miguel; Ha, Thomas; Swanson, Douglas J; Nagao-Sato, Sayaka; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Daub, Carsten O; Arner, Erik; de Hoon, Michiel; Carninci, Piero; Forrest, Alistair R R; Hayashizaki, Yoshihide; Goldowitz, Dan

2018-06-01

Laser-capture microdissection was used to isolate external germinal layer tissue from three developmental periods of mouse cerebellar development: embryonic days 13, 15, and 18. The cerebellar granule cell-enriched mRNA library was generated with next-generation sequencing using the Helicos technology. Our objective was to discover transcriptional regulators that could be important for the development of cerebellar granule cells-the most numerous neuron in the central nervous system. Through differential expression analysis, we have identified 82 differentially expressed transcription factors (TFs) from a total of 1311 differentially expressed genes. In addition, with TF-binding sequence analysis, we have identified 46 TF candidates that could be key regulators responsible for the variation in the granule cell transcriptome between developmental stages. Altogether, we identified 125 potential TFs (82 from differential expression analysis, 46 from motif analysis with 3 overlaps in the two sets). From this gene set, 37 TFs are considered novel due to the lack of previous knowledge about their roles in cerebellar development. The results from transcriptome-wide analyses were validated with existing online databases, qRT-PCR, and in situ hybridization. This study provides an initial insight into the TFs of cerebellar granule cells that might be important for development and provide valuable information for further functional studies on these transcriptional regulators.

Specific cerebellar activation during Braille reading in blind subjects.

PubMed

Gizewski, Elke R; Timmann, Dagmar; Forsting, Michael

2004-07-01

The traditional view that the cerebellum is involved only in the control of movements has been changed recently. It has been suggested that the human cerebellum is involved in cognition and language. Likewise, besides cortical activity in sensorimotor and visual areas, an increased global activation of the cerebellum has been revealed during Braille reading in blind subjects. Our purpose was to investigate whether there is cerebellar activation during Braille reading by blind subjects other than sensorimotor activation related to finger movements. Early blind and normal sighted subjects were studied with functional magnetic resonance imaging (fMRI) during Braille reading, tactile discrimination of nonsense dots, dots forming symbols, and finger tapping. The experiments were done in block design. Echo planar imaging sequences were carried out on a 1.5-T MR scanner. All blind individuals reading Braille showed robust activation of the posterior and lateral aspects of cerebellar hemispheral lobules Crus I bilaterally but more predominately on the right side. Additionally, activation was present in the medial cerebellum within lobules IV, V, and VIIIA, predominantly on the right. Discriminating nonsense dots did not reveal any activation of Crus I, but did reveal activation within the medial part of lobules IV, V, and VIIIA, predominately on the right. Analysis of sighted subjects during reading of printed text revealed activation of the posterolateral cerebellar hemisphere in Crus I bilaterally, predominantly on the right. Tactile analysis of dots representing symbols revealed an activation in lobules IV and VIII and in right Crus II but not in Crus I. In conclusion, parts of cerebellar activation during Braille reading in blind subjects (i.e., within lobules IV, V, and VIII) overlap with the known hand representation within the cerebellum and are likely related to the sensorimotor part of the task. Cerebellar activation during Braille reading within bilateral Crus I may be due to language processes or inner speech similar to those found during text reading in normal sighted subjects. Object recognition did not account for Crus I activation. Copyright 2004 Wiley-Liss, Inc.

Metronome Cueing of Walking Reduces Gait Variability after a Cerebellar Stroke.

PubMed

Wright, Rachel L; Bevins, Joseph W; Pratt, David; Sackley, Catherine M; Wing, Alan M

2016-01-01

Cerebellar stroke typically results in increased variability during walking. Previous research has suggested that auditory cueing reduces excessive variability in conditions such as Parkinson's disease and post-stroke hemiparesis. The aim of this case report was to investigate whether the use of a metronome cue during walking could reduce excessive variability in gait parameters after a cerebellar stroke. An elderly female with a history of cerebellar stroke and recurrent falling undertook three standard gait trials and three gait trials with an auditory metronome. A Vicon system was used to collect 3-D marker trajectory data. The coefficient of variation was calculated for temporal and spatial gait parameters. SDs of the joint angles were calculated and used to give a measure of joint kinematic variability. Step time, stance time, and double support time variability were reduced with metronome cueing. Variability in the sagittal hip, knee, and ankle angles were reduced to normal values when walking to the metronome. In summary, metronome cueing resulted in a decrease in variability for step, stance, and double support times and joint kinematics. Further research is needed to establish whether a metronome may be useful in gait rehabilitation after cerebellar stroke and whether this leads to a decreased risk of falling.

Metronome Cueing of Walking Reduces Gait Variability after a Cerebellar Stroke

PubMed Central

Wright, Rachel L.; Bevins, Joseph W.; Pratt, David; Sackley, Catherine M.; Wing, Alan M.

2016-01-01

Cerebellar stroke typically results in increased variability during walking. Previous research has suggested that auditory cueing reduces excessive variability in conditions such as Parkinson’s disease and post-stroke hemiparesis. The aim of this case report was to investigate whether the use of a metronome cue during walking could reduce excessive variability in gait parameters after a cerebellar stroke. An elderly female with a history of cerebellar stroke and recurrent falling undertook three standard gait trials and three gait trials with an auditory metronome. A Vicon system was used to collect 3-D marker trajectory data. The coefficient of variation was calculated for temporal and spatial gait parameters. SDs of the joint angles were calculated and used to give a measure of joint kinematic variability. Step time, stance time, and double support time variability were reduced with metronome cueing. Variability in the sagittal hip, knee, and ankle angles were reduced to normal values when walking to the metronome. In summary, metronome cueing resulted in a decrease in variability for step, stance, and double support times and joint kinematics. Further research is needed to establish whether a metronome may be useful in gait rehabilitation after cerebellar stroke and whether this leads to a decreased risk of falling. PMID:27313563

Numb deficiency in cerebellar Purkinje cells impairs synaptic expression of metabotropic glutamate receptor and motor coordination.

PubMed

Zhou, Liang; Yang, Dong; Wang, De-Juan; Xie, Ya-Jun; Zhou, Jia-Huan; Zhou, Lin; Huang, Hao; Han, Shuo; Shao, Chong-Yu; Li, Hua-Shun; Zhu, J Julius; Qiu, Meng-Sheng; De Zeeuw, Chris I; Shen, Ying

2015-12-15

Protein Numb, first identified as a cell-fate determinant in Drosophila, has been shown to promote the development of neurites in mammals and to be cotransported with endocytic receptors in clathrin-coated vesicles in vitro. Nevertheless, its function in mature neurons has not yet been elucidated. Here we show that cerebellar Purkinje cells (PCs) express high levels of Numb during adulthood and that conditional deletion of Numb in PCs is sufficient to impair motor coordination despite maintenance of a normal cerebellar cyto-architecture. Numb proved to be critical for internalization and recycling of metabotropic glutamate 1 receptor (mGlu1) in PCs. A significant decrease of mGlu1 and an inhibition of long-term depression at the parallel fiber-PC synapse were observed in conditional Numb knockout mice. Indeed, the trafficking of mGlu1 induced by agonists was inhibited significantly in these mutants, but the expression of ionotropic glutamate receptor subunits and of mGlu1-associated proteins was not affected by the loss of Numb. Moreover, transient and persistent forms of mGlu1 plasticity were robustly induced in mutant PCs, suggesting that they do not require mGlu1 trafficking. Together, our data demonstrate that Numb is a regulator for constitutive expression and dynamic transport of mGlu1.

Late onset GM2 gangliosidosis mimicking spinal muscular atrophy.

PubMed

Jamrozik, Z; Lugowska, A; Gołębiowski, M; Królicki, L; Mączewska, J; Kuźma-Kozakiewicz, M

2013-09-25

A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18)F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally. © 2013 Elsevier B.V. All rights reserved.

Development of the cerebellar afferent system in the shark Scyliorhinus canicula: insights into the basal organization of precerebellar nuclei in gnathostomes.

PubMed

Pose-Méndez, Sol; Candal, Eva; Adrio, Fátima; Rodríguez-Moldes, Isabel

2014-01-01

The cerebellum is recognized as an evolutionary innovation of jawed vertebrates, whose most primitive group is represented by the chondrichthyans, or cartilaginous fishes. A comprehensive knowledge of cerebellar connections in these fishes might shed light on the basal organization of the cerebellar system. Although the organization of the precerebellar system is known in adults, developmental studies are essential for understanding the origin and evolution of precerebellar nuclei. In the present work we performed a developmental study of cerebellar connections in embryos and juveniles of an advanced shark species, Scyliorhinus canicula, by application of tract tracing in combination with immunohistochemical techniques. Main precerebellar cell populations were located in the diencephalon (pretectum and thalamus), mesencephalon (reticular formation and nucleus ruber), rhombencephalon (cerebellar nucleus, reticular formation, and inferior olive), and spinal cord (ventral horn). The order of arrival of cerebellar afferent projections throughout development revealed a common pattern with other jawed vertebrates, which was helpful for comparison of stages of cerebellar development. The neurochemical study of the inferior olive and other precerebellar nuclei revealed many shared features with other gnathostomes. Furthermore, because many precerebellar nuclei originate from rhombic lips, the first analysis of neuronal migrations from these lips was performed with markers of neuroblasts. The shared features of development and organization of precerebellar connections observed between sharks and amniotes suggest that their basic pattern was established early in gnathostome evolution. Copyright © 2013 Wiley Periodicals, Inc.

A multicohort, longitudinal study of cerebellar development in attention deficit hyperactivity disorder.

PubMed

Shaw, Philip; Ishii-Takahashi, Ayaka; Park, Min Tae; Devenyi, Gabriel A; Zibman, Chava; Kasparek, Steven; Sudre, Gustavo; Mangalmurti, Aman; Hoogman, Martine; Tiemeier, Henning; von Polier, Georg; Shook, Devon; Muetzel, Ryan; Chakravarty, M Mallar; Konrad, Kerstin; Durston, Sarah; White, Tonya

2018-04-25

The cerebellum supports many cognitive functions disrupted in attention deficit hyperactivity disorder (ADHD). Prior neuroanatomic studies have been often limited by small sample sizes, inconsistent findings, and a reliance on cross-sectional data, limiting inferences about cerebellar development. Here, we conduct a multicohort study using longitudinal data, to characterize cerebellar development. Growth trajectories of the cerebellar vermis, hemispheres and white matter were estimated using piecewise linear regression from 1,656 youth; of whom 63% had longitudinal data, totaling 2,914 scans. Four cohorts participated, all contained childhood data (age 4-12 years); two had adolescent data (12-25 years). Growth parameters were combined using random-effects meta-analysis. Diagnostic differences in growth were confined to the corpus medullare (cerebellar white matter). Here, the ADHD group showed slower growth in early childhood compared to the typically developing group (left corpus medullare z = 2.49, p = .01; right z = 2.03, p = .04). This reversed in late childhood, with faster growth in ADHD in the left corpus medullare (z = 2.06, p = .04). Findings held when gender, intelligence, comorbidity, and psychostimulant medication were considered. Across four independent cohorts, containing predominately longitudinal data, we found diagnostic differences in the growth of cerebellar white matter. In ADHD, slower white matter growth in early childhood was followed by faster growth in late childhood. The findings are consistent with the concept of ADHD as a disorder of the brain's structural connections, formed partly by developing cortico-cerebellar white matter tracts. © 2018 Association for Child and Adolescent Mental Health.

Reference Charts for Fetal Cerebellar Vermis Height: A Prospective Cross-Sectional Study of 10605 Fetuses

PubMed Central

Cignini, Pietro; Giorlandino, Maurizio; Brutti, Pierpaolo; Mangiafico, Lucia; Aloisi, Alessia; Giorlandino, Claudio

2016-01-01

Objective To establish reference charts for fetal cerebellar vermis height in an unselected population. Methods A prospective cross-sectional study between September 2009 and December 2014 was carried out at ALTAMEDICA Fetal–Maternal Medical Centre, Rome, Italy. Of 25203 fetal biometric measurements, 12167 (48%) measurements of the cerebellar vermis were available. After excluding 1562 (12.8%) measurements, a total of 10605 (87.2%) fetuses were considered and analyzed once only. Parametric and nonparametric quantile regression models were used for the statistical analysis. In order to evaluate the robustness of the proposed reference charts regarding various distributional assumptions on the ultrasound measurements at hand, we compared the gestational age-specific reference curves we produced through the statistical methods used. Normal mean height based on parametric and nonparametric methods were defined for each week of gestation and the regression equation expressing the height of the cerebellar vermis as a function of gestational age was calculated. Finally the correlation between dimension/gestation was measured. Results The mean height of the cerebellar vermis was 12.7mm (SD, 1.6mm; 95% confidence interval, 12.7–12.8mm). The regression equation expressing the height of the CV as a function of the gestational age was: height (mm) = -4.85+0.78 x gestational age. The correlation between dimension/gestation was expressed by the coefficient r = 0.87. Conclusion This is the first prospective cross-sectional study on fetal cerebellar vermis biometry with such a large sample size reported in literature. It is a detailed statistical survey and contains new centile-based reference charts for fetal height of cerebellar vermis measurements. PMID:26812238

Medulloblastoma with Atypical Dynamic Imaging Changes: Case Report with Literature Review.

PubMed

Song, Shuang-Shuang; Wang, Jian-Hong; Fu, Wei-Wei; Li, Ying; Sui, Qing-Lan; Liu, Xue-Jun

2017-09-01

We analyzed a case of medulloblastoma with atypical dynamic imaging changes retrospectively to summarize the atypical magnetic resonance imaging (MRI) features of medulloblastoma by reviewing the literature. An atypical case of medulloblastoma in the cerebellar hemisphere confirmed by pathology was analyzed retrospectively, and the literature about it was reviewed. The radiologic findings of the patient were based on 3 examinations. The first examination showed that the cortex of the bilateral cerebellar hemisphere had diffuse nodular thickening, with a high signal on diffusion-weighted imaging and significant enhancement. Contrast enhancement MRI 1 year later showed the signal of cerebellar hemisphere returned to normal but revealed an enhanced nodule. A reexamination 6 months later showed an irregular mass with a high-density shadow in the cerebellar vermis on CT scan. The T2-weighted image revealed multiple degenerative cysts, and the mass had significant enhancement. The radiologic characteristics of atypical medulloblastomas vary in adults and children. Understanding the radiologic characteristics of medulloblastomas, such as MRI features, age of onset, and location of atypical medulloblastomas, can help improve the diagnosis of medulloblastomas. Copyright © 2017. Published by Elsevier Inc.

Voltage-gated calcium channel autoimmune cerebellar degeneration

PubMed Central

McKasson, Marilyn; Clawson, Susan A.; Hill, Kenneth E.; Wood, Blair; Carlson, Noel; Bromberg, Mark; Greenlee, John E.

2016-01-01

Objectives: To describe response to treatment in a patient with autoantibodies against voltage-gated calcium channels (VGCCs) who presented with autoimmune cerebellar degeneration and subsequently developed Lambert-Eaton myasthenic syndrome (LEMS), and to study the effect of the patient's autoantibodies on Purkinje cells in rat cerebellar slice cultures. Methods: Case report and study of rat cerebellar slice cultures incubated with patient VGCC autoantibodies. Results: A 53-year-old man developed progressive incoordination with ataxic speech. Laboratory evaluation revealed VGCC autoantibodies without other antineuronal autoantibodies. Whole-body PET scans 6 and 12 months after presentation detected no malignancy. The patient improved significantly with IV immunoglobulin G (IgG), prednisone, and mycophenolate mofetil, but worsened after IV IgG was halted secondary to aseptic meningitis. He subsequently developed weakness with electrodiagnostic evidence of LEMS. The patient's IgG bound to Purkinje cells in rat cerebellar slice cultures, followed by neuronal death. Reactivity of the patient's autoantibodies with VGCCs was confirmed by blocking studies with defined VGCC antibodies. Conclusions: Autoimmune cerebellar degeneration associated with VGCC autoantibodies may precede onset of LEMS and may improve with immunosuppressive treatment. Binding of anti-VGCC antibodies to Purkinje cells in cerebellar slice cultures may be followed by cell death. Patients with anti-VGCC autoantibodies may be at risk of irreversible neurologic injury over time, and treatment should be initiated early. PMID:27088118

Structural and Functional Magnetic Resonance Imaging of the Cerebellum: Considerations for Assessing Cerebellar Ataxias.

PubMed

Deistung, Andreas; Stefanescu, Maria R; Ernst, Thomas M; Schlamann, Marc; Ladd, Mark E; Reichenbach, Jürgen R; Timmann, Dagmar

2016-02-01

Magnetic resonance imaging (MRI) of the brain is of high interest for diagnosing and understanding degenerative ataxias. Here, we present state-of-the-art MRI methods to characterize structural alterations of the cerebellum and introduce initial experiments to show abnormalities in the cerebellar nuclei. Clinically, T1-weighted MR images are used to assess atrophy of the cerebellar cortex, the brainstem, and the spinal cord, whereas T2-weighted and PD-weighted images are typically employed to depict potential white matter lesions that may be associated with certain types of ataxias. More recently, attention has also focused on the characterization of the cerebellar nuclei, which are discernible on spatially highly resolved iron-sensitive MR images due to their relatively high iron content, including T2 (*)-weighted images, susceptibility-weighted images (SWI), effective transverse relaxation rate (R2 (*)) maps, and quantitative susceptibility maps (QSM). Among these iron-sensitive techniques, QSM reveals the best contrast between cerebellar nuclei and their surroundings. In particular, the gyrification of the dentate nuclei is prominently depicted, even at the clinically widely available field strength of 3 T. The linear relationship between magnetic susceptibility and local iron content allows for determination of iron deposition in cerebellar nuclei non-invasively. The increased signal-to-noise ratio of ultrahigh-field MRI (B0 ≥ 7 T) and advances in spatial normalization methods enable functional MRI (fMRI) at the level of the cerebellar cortex and cerebellar nuclei. Data from initial fMRI studies are presented in three common forms of hereditary ataxias (Friedreich's ataxia, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6). Characteristic changes in the fMRI signal are discussed in the light of histopathological data and current knowledge of the underlying physiology of the fMRI signal in the cerebellum.

LKB1 Regulates Cerebellar Development by Controlling Sonic Hedgehog-mediated Granule Cell Precursor Proliferation and Granule Cell Migration.

PubMed

Men, Yuqin; Zhang, Aizhen; Li, Haixiang; Jin, Yecheng; Sun, Xiaoyang; Li, Huashun; Gao, Jiangang

2015-11-09

The Liver Kinase B1 (LKB1) gene plays crucial roles in cell differentiation, proliferation and the establishment of cell polarity. We created LKB1 conditional knockout mice (LKB1(Atoh1) CKO) to investigate the function of LKB1 in cerebellar development. The LKB1(Atoh1) CKO mice displayed motor dysfunction. In the LKB1(Atoh1) CKO cerebellum, the overall structure had a larger volume and more lobules. LKB1 inactivation led to an increased proliferation of granule cell precursors (GCPs), aberrant granule cell migration and overproduction of unipolar brush cells. To investigate the mechanism underlying the abnormal foliation, we examined sonic hedgehog signalling (Shh) by testing its transcriptional mediators, the Gli proteins, which regulate the GCPs proliferation and cerebellar foliation during cerebellar development. The expression levels of Gli genes were significantly increased in the mutant cerebellum. In vitro assays showed that the proliferation of cultured GCPs from mutant cerebellum significantly increased, whereas the proliferation of mutant GCPs significantly decreased in the presence of a Shh inhibitor GDC-0049. Thus, LKB1 deficiency in the LKB1(Atoh1) CKO mice enhanced Shh signalling, leading to the excessive GCP proliferation and the formation of extra lobules. We proposed that LKB1 regulates cerebellar development by controlling GCPs proliferation through Shh signalling during cerebellar development.

LKB1 Regulates Cerebellar Development by Controlling Sonic Hedgehog-mediated Granule Cell Precursor Proliferation and Granule Cell Migration

PubMed Central

Men, Yuqin; Zhang, Aizhen; Li, Haixiang; Jin, Yecheng; Sun, Xiaoyang; Li, Huashun; Gao, Jiangang

2015-01-01

The Liver Kinase B1 (LKB1) gene plays crucial roles in cell differentiation, proliferation and the establishment of cell polarity. We created LKB1 conditional knockout mice (LKB1Atoh1 CKO) to investigate the function of LKB1 in cerebellar development. The LKB1Atoh1 CKO mice displayed motor dysfunction. In the LKB1Atoh1 CKO cerebellum, the overall structure had a larger volume and morelobules. LKB1 inactivationled to an increased proliferation of granule cell precursors (GCPs), aberrant granule cell migration and overproduction of unipolar brush cells. To investigate the mechanism underlying the abnormal foliation, we examined sonic hedgehog signalling (Shh) by testing its transcriptional mediators, the Gli proteins, which regulate the GCPs proliferation and cerebellar foliation during cerebellar development. The expression levels of Gli genes were significantly increased in the mutant cerebellum. In vitro assays showed that the proliferation of cultured GCPs from mutant cerebellum significantly increased, whereas the proliferation of mutant GCPs significantly decreased in the presence of a Shh inhibitor GDC-0049. Thus, LKB1 deficiency in the LKB1Atoh1 CKO mice enhanced Shh signalling, leading to the excessive GCP proliferation and the formation of extra lobules. We proposed that LKB1 regulates cerebellar development by controlling GCPs proliferation through Shh signalling during cerebellar development. PMID:26549569

Late radiation side-effects in three patients undergoing parotid irradiation for benign disease.

PubMed

Armour, A; Ghanna, P; O'Rielly, B; Habeshaw, T; Symonds, P

2000-01-01

We report three patients in whom standard radiation therapy was given and serious late radiation damage was seen. The first patient suffered recurrent parotiditis and a parotid fistula. He was treated initially with 20 Gy in ten fractions via a 300 kV field. Further irradiation was required 1 year later and 40 Gy was given in 2 Gy fractions by an oblique anterior and posterior wedged photon pair. Ten years later he developed localized temporal bone necrosis. The second patient, with pleomorphic salivary adenoma, developed localized temporal bone necrosis 6 years after 60 Gy had been given using standard fractionation and technique. The third patient received 55 Gy in 25 fractions for a pleomorphic salivary adenoma and after 3 years developed temporal bone necrosis. Sixteen years later the same patient developed cerebellar and brainstem necrosis. All patients developed chronic persistent infection during or shortly after the radiation therapy, which increased local tissue sensitivity to late radiation damage. As a result, severe bone, cerebellar and brainstem necrosis was observed at doses that are normally considered safe. We therefore strongly recommend that any infection in a proposed irradiated area should be treated aggressively, with surgical debridement if necessary, before radiotherapy is administered, or that infection developing during or after irradiation is treated promptly.

Common pediatric cerebellar tumors: correlation between cell densities and apparent diffusion coefficient metrics.

PubMed

Koral, Korgün; Mathis, Derek; Gimi, Barjor; Gargan, Lynn; Weprin, Bradley; Bowers, Daniel C; Margraf, Linda

2013-08-01

To test whether there is correlation between cell densities and apparent diffusion coefficient (ADC) metrics of common pediatric cerebellar tumors. This study was reviewed for issues of patient safety and confidentiality and was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center and was compliant with HIPAA. The need for informed consent was waived. Ninety-five patients who had preoperative magnetic resonance imaging and surgical pathologic findings available between January 2003 and June 2011 were included. There were 37 pilocytic astrocytomas, 34 medulloblastomas (23 classic, eight desmoplastic-nodular, two large cell, one anaplastic), 17 ependymomas (13 World Health Organization [WHO] grade II, four WHO grade III), and seven atypical teratoid rhabdoid tumors. ADCs of solid tumor components and normal cerebellum were measured. Tumor-to-normal brain ADC ratios (hereafter, ADC ratio) were calculated. The medulloblastomas and ependymomas were subcategorized according to the latest WHO classification, and tumor cellularity was calculated. Correlation was sought between cell densities and mean tumor ADCs, minimum tumor ADCs, and ADC ratio. When all tumors were considered together, negative correlation was found between cellularity and mean tumor ADCs (ρ = -0.737, P < .05) and minimum tumor ADCs (ρ = -0.736, P < .05) of common pediatric cerebellar tumors. There was no correlation between cellularity and ADC ratio. Negative correlation was found between cellularity and minimum tumor ADC in atypical teratoid rhabdoid tumors (ρ = -0.786, P < .05). In atypical teratoid rhabdoid tumors, no correlation was found between cellularity and mean tumor ADC and ADC ratio. There was no correlation between the ADC metrics and cellularity of the pilocytic astrocytomas, medulloblastomas, and ependymomas. Negative correlation was found between cellularity and ADC metrics of common pediatric cerebellar tumors. Although ADC metrics are useful in the preoperative diagnosis of common pediatric cerebellar tumors and this utility is generally attributed to differences in cellularity of tumors, tumor cellularity may not be the sole determinant of the differences in diffusivity.

Cerebro-cerebellar circuits in autism spectrum disorder.

PubMed

D'Mello, Anila M; Stoodley, Catherine J

2015-01-01

The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD.

Cerebro-cerebellar circuits in autism spectrum disorder

PubMed Central

D'Mello, Anila M.; Stoodley, Catherine J.

2015-01-01

The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD. PMID:26594140

Preterm birth disrupts cerebellar development by affecting granule cell proliferation program and Bergmann glia.

PubMed

Iskusnykh, Igor Y; Buddington, Randal K; Chizhikov, Victor V

2018-08-01

Preterm birth is a leading cause of long-term motor and cognitive deficits. Clinical studies suggest that some of these deficits result from disruption of cerebellar development, but the mechanisms that mediate cerebellar abnormalities in preterm infants are largely unknown. Furthermore, it remains unclear whether preterm birth and precocious exposure to the ex-utero environment directly disrupt cerebellar development or indirectly by increasing the probability of cerebellar injury, including that resulting from clinical interventions and protocols associated with the care of preterm infants. In this study, we analyzed the cerebellum of preterm pigs delivered via c-section at 91% term and raised for 10 days, until term-equivalent age. The pigs did not receive any treatments known or suspected to affect cerebellar development and had no evidence of brain damage. Term pigs sacrificed at birth were used as controls. Immunohistochemical analysis revealed that preterm birth did not affect either size or numbers of Purkinje cells or molecular layer interneurons at term-equivalent age. The number of granule cell precursors and Bergmann glial fibers, however, were reduced in preterm pigs. Preterm pigs had reduced proliferation but not differentiation of granule cells. qRT-PCR analysis of laser capture microdissected external granule cell layer showed that preterm pigs had a reduced expression of Ccnd1 (Cyclin D1), Ccnb1 (Cyclin B1), granule cell master regulatory transcription factor Atoh1, and signaling molecule Jag1. In vitro rescue experiments identified Jag1 as a central granule cell gene affected by preterm birth. Thus, preterm birth and precocious exposure to the ex-utero environment disrupt cerebellum by modulating expression of key cerebellar developmental genes, predominantly affecting development of granule precursors and Bergmann glia. Copyright © 2018 Elsevier Inc. All rights reserved.

Differential Effects of Intraventricular Hemorrhage and White Matter Injury on Preterm Cerebellar Growth

PubMed Central

Tam, Emily W.Y.; Miller, Steven P.; Studholme, Colin; Chau, Vann; Glidden, David; Poskitt, Kenneth J.; Ferriero, Donna M.; Barkovich, A. James

2010-01-01

Objective To hypothesize that detailed examination of early cerebellar volumes over time would distinguish differences in cerebellar growth associated with intraventricular hemorrhage (IVH) and white matter injury (WMI) in preterm infants. Study design Preterm newborns at the University of California San Francisco (n=57) and the University of British Columbia (n=115) were studied using serial MRI scans near birth and again at near term-equivalent age. Interactive semi-automated tools were used to determine volumes of the cerebellar hemispheres. Results Adjusting for supratentorial brain injury, cerebellar hemorrhage, and study site, cerebellar volume increased 1.7cm3/week postmenstrual age (95% CI 1.6–1.7, P<0.001). More severe supratentorial IVH was associated with slower growth of cerebellar volumes (P<0.001). Volumes by 40 weeks were 1.4 cm3 lower in premature infants with grade 1–2 IVH and 5.4 cm3 lower with grade 3–4 IVH. The same magnitude of decrease was found between ipsilateral and contralateral IVH. No association was found with severity of WMI (P=0.3). Conclusions Early effects of decreased cerebellar volume associated with supratentorial IVH in either hemisphere may be a result of concurrent cerebellar injury or direct effects of subarachnoid blood on cerebellar development. PMID:20961562

Familial Hemiplegic Migraine Type 1 Associated with Parkinsonism: A Case Report

PubMed Central

Bruun, Marie; Hjermind, Lena Elisabeth; Thomsen, Carsten; Danielsen, Else; Thomsen, Lise Lykke; Pinborg, Lars Hageman; Khabbazbavani, Nastaran; Nielsen, Joergen Erik

2015-01-01

Familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) are allelic disorders caused by mutations in the CACNA1A gene on chromosome 19p13. It is well described that FHM1 can present with cerebellar signs, but parkinsonism has not previously been reported in FHM1 or EA2 even though parkinsonism has been described in SCA6. We report a 63-year-old woman with FHM1 caused by an R583Q mutation in the CACNA1A gene, clinically presenting with migraine and permanent cerebellar ataxia. Since the age of 60 years, the patient also developed parkinsonism with rigidity, bradykinesia and a resting tremor. An MRI showed a normal substantia nigra, but a bilateral loss of substance in the basal ganglia, which is in contrast to the typically normal MRI in idiopathic Parkinson's disease. Dopamine transporter (DAT) imaging with single-photon emission computed tomography demonstrated a decreased DAT-binding potential in the putamen. We wish to draw attention to FHM1 associated with parkinsonism; however, whether the reported case is a consequence of FHM1 being allelic to SCA6, unknown modifiers to the specific R583Q CACNA1A mutation or idiopathic Parkinson's disease remains unanswered. PMID:25969684

Cerebellar damage diminishes long-latency responses to multijoint perturbations

PubMed Central

Trautman, Paxson; Rasquinha, Russell J.; Bhanpuri, Nasir H.; Scott, Stephen H.; Bastian, Amy J.

2013-01-01

Damage to the cerebellum can cause significant problems in the coordination of voluntary arm movements. One prominent idea is that incoordination stems from an inability to predictively account for the complex mechanical interactions between the arm's several joints. Motivated by growing evidence that corrective feedback control shares important capabilities and neural substrates with feedforward control, we asked whether cerebellar damage impacts feedback stabilization of the multijoint arm appropriate for the arm's intersegmental dynamics. Specifically, we tested whether cerebellar dysfunction impacts the ability of posterior deltoid to incorporate elbow motion in its long-latency response (R2 = 45–75 ms and R3 = 75–100 ms after perturbation) to an unexpected torque perturbation. Healthy and cerebellar-damaged subjects were exposed to a selected pattern of shoulder-elbow displacements to probe the response pattern from this shoulder extensor muscle. The healthy elderly subjects expressed a long-latency response linked to both shoulder and elbow motion, including an increase/decrease in shoulder extensor activity with elbow flexion/extension. Critically, cerebellar-damaged subjects displayed the normal pattern of activity in the R3 period indicating an intact ability to rapidly integrate multijoint motion appropriate to the arm's intersegmental dynamics. However, cerebellar-damaged subjects had a lower magnitude of activity that was specific to the long-latency period (both R2 and R3) and a slightly delayed onset of multijoint sensitivity. Taken together, our results suggest that the basic motor pattern of the long-latency response is housed outside the cerebellum and is scaled by processes within the cerebellum. PMID:23390311

[Reversible neurotoxicity secondary to metronidazole: report of one case].

PubMed

Retamal-Riquelme, Eva; Soto-San Martín, Hernán; Vallejos-Castro, José; Galdames-Poblete, Daniel

2014-03-01

Metronidazole can cause adverse effects both in the central and peripheral nervous system. We report a 34-year-old female who presented a reversible cerebellar syndrome and peripheral neuropathy as an adverse effect associated with the use of metronidazole. Brain magnetic resonance imaging (MRI) showed hyperintense T2 and FLAIR bilateral symmetrical cerebellar lesions, without contrast enhancement or mass effect, isointense in diffusion-weighted imaging and hypointense in apparent diffusion coefficient sequences. Also, electrophysiological evaluation was consistent with axonal polyneuropathy. She had received metronidazole for a liver abscess during 49 days. After discontinuation of metronidazole, she had rapid regression of cerebellar symptoms and normalization of MRI, with subsequent disappearance of peripheral symptoms. The brain MRI, electromyography and nerve conduction studies performed at 35 months later showed complete resolution of the lesions. Although metronidazole neurotoxicity is a rare event, it must be borne in mind because the prognosis is usually favorable after stopping the drug.

Crossed cerebellar and uncrossed basal ganglia and thalamic diaschisis in Alzheimer's disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akiyama, H.; Harrop, R.; McGeer, P.L.

1989-04-01

We detected crossed cerebellar as well as uncrossed basal ganglia and thalamic diaschisis in Alzheimer's disease by positron emission tomography (PET) using /sup 18/F-fluorodeoxyglucose. We studied a series of 26 consecutive, clinically diagnosed Alzheimer cases, including 6 proven by later autopsy, and compared them with 9 age-matched controls. We calculated asymmetry indices (AIs) of cerebral metabolic rate for matched left-right regions of interest (ROIs) and determined the extent of diaschisis by correlative analyses. For the Alzheimer group, we found cerebellar AIs correlated negatively, and thalamic AIs positively, with those of the cerebral hemisphere and frontal, temporal, parietal, and angular cortices,more » while basal ganglia AIs correlated positively with frontal cortical AIs. The only significant correlation of AIs for normal subjects was between the thalamus and cerebral hemisphere. These data indicate that PET is a sensitive technique for detecting diaschisis.« less

Adult onset of the Dandy-Walker syndrome.

PubMed

Lipton, H L; Preziosi, T J; Moses, H

1978-10-01

Two patients with the Dandy-Walker malformation first developed neurologic symptoms in adult life. In both patients there was normal motor and intellectual development during childhood, but as adults they had gradual evolution of brain stem and cerebellar signs and obstructive hydrocephalus. Following resection of the fourth ventricular cyst, both patients recovered. A review of the literature disclosed seven additional patients in whom the Dandy-Walker syndrome was first diagnosed in adult life. These cases illustrate that this congenital brain malformation may not only first become symptomatic later in life, but that it is possible for patients to remain asymptomatic.

The chromatin remodeling factor CHD7 controls cerebellar development by regulating reelin expression

PubMed Central

Whittaker, Danielle E.; Riegman, Kimberley L.H.; Kasah, Sahrunizam; Mohan, Conor; Yu, Tian; Sala, Blanca Pijuan; Hebaishi, Husam; Caruso, Angela; Marques, Ana Claudia; Michetti, Caterina; Smachetti, María Eugenia Sanz; Shah, Apar; Sabbioni, Mara; Kulhanci, Omer; Tee, Wee-Wei; Reinberg, Danny; Scattoni, Maria Luisa; McGonnell, Imelda; Wardle, Fiona C.; Fernandes, Cathy

2017-01-01

The mechanisms underlying the neurodevelopmental deficits associated with CHARGE syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems, and autistic features, have not been identified. CHARGE syndrome has been associated with mutations in the gene encoding the ATP-dependent chromatin remodeler CHD7. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we have shown that deletion of Chd7 from cerebellar granule cell progenitors (GCps) results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay, and motor deficits in mice. Genome-wide expression profiling revealed downregulated expression of the gene encoding the glycoprotein reelin (Reln) in Chd7-deficient GCps. Recessive RELN mutations have been associated with severe cerebellar hypoplasia in humans. We found molecular and genetic evidence that reductions in Reln expression contribute to GCp proliferative defects and cerebellar hypoplasia in GCp-specific Chd7 mouse mutants. Finally, we showed that CHD7 is necessary for maintaining an open, accessible chromatin state at the Reln locus. Taken together, this study shows that Reln gene expression is regulated by chromatin remodeling, identifies CHD7 as a previously unrecognized upstream regulator of Reln, and provides direct in vivo evidence that a mammalian CHD protein can control brain development by modulating chromatin accessibility in neuronal progenitors. PMID:28165338

Intra- and interobserver agreement for fetal cerebral measurements in 3D-ultrasonography.

PubMed

Albers, Maria E W A; Buisman, Erato T I A; Kahn, René S; Franx, Arie; Onland-Moret, N Charlotte; de Heus, Roel

2018-04-10

The aim of this study is to evaluate intra- and interobserver agreement for measurement of intracranial, cerebellar, and thalamic volume with the Virtual Organ Computer-aided AnaLysis (VOCAL) technique in three-dimensional ultrasound images, in comparison to two-dimensional measurements of these brain structures. Three-dimensional ultrasound images of the brains of 80 fetuses at 20-24 weeks' gestational age were obtained from YOUth, a Dutch prospective cohort study. Two observers performed offline measurement of the occipitofrontal diameter, intracranial volume, transcerebellar diameter, cerebellar volume, and thalamic width, area, and volume, independently. VOCAL was used for calculation of the volumes. The two-way random, single measures intraclass correlation coefficient (ICC) was used for analysis of agreement and Bland-Altman plots were configured. Intra- and interobserver agreement was almost perfect for occipitofrontal diameter (intra ICC 0.88, 95% CI 0.82-0.92; inter ICC 0.91, 95% CI 0.85-0.94), intracranial volume (intra ICC 0.96, 95% CI 0.91-0.98; inter ICC 0.97, 95% CI 0.96-0.98) and transcerebellar diameter (intra ICC 0.91, 95% CI 0.86-0.94; inter ICC 0.86, 95% CI 0.78-0.910). For cerebellar volume, the intraobserver agreement was almost perfect (0.85, 95% CI 0.76-0.90), whereas the interobserver agreement was substantial (0.75, 95% CI 0.44-0.88). Agreement was only moderate for thalamic measurements. Bland-Altman plots for the volume measurements are normally distributed with acceptable mean differences and 95% limits of agreement. The intra- and interobserver agreement of the measurement of intracranial and cerebellar volume with VOCAL was almost perfect. These measurements are therefore reliable, and can be used to investigate fetal brain development. Thalamic measurements are not reliable enough. © 2018 Wiley Periodicals, Inc.

Brain morphology in children with nevoid basal cell carcinoma syndrome.

PubMed

Shiohama, Tadashi; Fujii, Katsunori; Miyashita, Toshiyuki; Mizuochi, Hiromi; Uchikawa, Hideki; Shimojo, Naoki

2017-04-01

Brain morphology is tightly regulated by diverse signaling pathways. Hedgehog signaling is a candidate pathway considered responsible for regulating brain morphology. Nevoid basal cell carcinoma syndrome (NBCCS), caused by a PTCH1 mutation in the hedgehog signaling pathway, occasionally exhibits macrocephaly and medulloblastoma. Although cerebellar enlargement occurs in ptch1 heterozygous-deficient mice, its impact on human brain development remains unknown. We investigated the brain morphological characteristics of children with NBCCS. We evaluated brain T1-weighted images from nine children with NBCCS and 15 age-matched normal control (NC) children (mean [standard deviation], 12.2 [2.8] vs. 11.6 [2.3] years old). The diameters of the cerebrum, corpus callosum, and brain stem and the cerebellar volume were compared using two-tailed t-tests with Welch's correction. The transverse diameters (150.4 [9.9] vs. 136.0 [5.5] mm, P = 0.002) and longitudinal diameters (165.4 [8.0] vs. 151.3 [8.7] mm, P = 0.0007) of the cerebrum, cross-sectional area of the cerebellar vermis (18.7 [2.6] vs. 11.8 [1.7] cm 2 , P = 0.0001), and total volume of the cerebellar hemispheres (185.1 [13.0] vs. 131.9 [10.4] cm 3 , P = 0.0001) were significantly larger in the children with NBCCS than in NC children. Thinning of the corpus callosum and ventricular enlargement were also confirmed in children with NBCCS. We demonstrate that, on examination of the brain morphology, an increase in the size of the cerebrum, cerebellum, and cerebral ventricles is revealed in children with NBCCS compared to NC children. This suggests that constitutively active hedgehog signaling affects human brain morphology and the PI3K/AKT and RAS/MAPK pathways. © 2017 Wiley Periodicals, Inc.

Cerebellum: links between development, developmental disorders and motor learning

PubMed Central

Manto, Mario U.; Jissendi, Patrice

2012-01-01

The study of the links and interactions between development and motor learning has noticeable implications for the understanding and management of neurodevelopmental disorders. This is particularly relevant for the cerebellum which is critical for sensorimotor learning. The olivocerebellar pathway is a key pathway contributing to learning of motor skills. Its developmental maturation and remodeling are being unraveled. Advances in genetics have led to major improvements in our appraisal of the genes involved in cerebellar development, especially studies in mutant mice. Cerebellar neurogenesis is compartmentalized in relationship with neurotransmitter fate. The Engrailed-2 gene is a major actor of the specification of cerebellar cell types and late embryogenic morphogenesis. Math1, expressed by the rhombic lip, is required for the genesis of glutamatergic neurons. Mutants deficient for the transcription factor Ptf1a display a lack of Purkinje cells and gabaergic interneurons. Rora gene contributes to the developmental signaling between granule cells and Purkinje neurons. The expression profile of sonic hedgehog in postnatal stages determines the final size/shape of the cerebellum. Genes affecting the development impact upon the physiological properties of the cerebellar circuits. For instance, receptors are developmentally regulated and their action interferes directly with developmental processes. Another field of research which is expanding relates to very preterm neonates. They are at risk for cerebellar lesions, which may themselves impair the developmental events. Very preterm neonates often show sensori-motor deficits, highlighting another major link between impaired developments and learning deficiencies. Pathways playing a critical role in cerebellar development are likely to become therapeutical targets for several neurodevelopmental disorders. PMID:22291620

The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration

PubMed Central

Elsen, Gina E.; Choi, Louis Y.; Prince, Victoria E.; Ho, Robert K.

2009-01-01

During development, Met signaling regulates a range of cellular processes including growth, differentiation, survival and migration. The Met gene encodes a tyrosine kinase receptor, which is activated by Hgf (hepatocyte growth factor) ligand. Altered regulation of human MET expression has been implicated in autism. In mouse, Met signaling has been shown to regulate cerebellum development. Since abnormalities in cerebellar structure have been reported in some autistic patients, we have used the zebrafish to address the role of Met signaling during cerebellar development and thus further our understanding of the molecular basis of autism. We find that zebrafish met is expressed in the cerebellar primordium, later localizing to the ventricular zone (VZ), with the hgf1 and hgf2 ligand genes expressed in surrounding tissues. Morpholino knockdown of either Met or its Hgf ligands leads to a significant reduction in the size of the cerebellum, primarily as a consequence of reduced proliferation. Met signaling knockdown disrupts specification of VZ-derived cell types, and also reduces granule cell numbers, due to an early effect on cerebellar proliferation and/or as an indirect consequence of loss of signals from VZ-derived cells later in development. These patterning defects preclude analysis of cerebellar neuronal migration, but we have found that Met signaling is necessary for migration of hindbrain facial motor neurons. In summary, we have described roles for Met signaling in coordinating growth and cell type specification within the developing cerebellum, and in migration of hindbrain neurons. These functions may underlie the correlation between altered MET regulation and Autism Spectrum Disorders. PMID:19732764

Maternal Postsecondary Education Associated With Improved Cerebellar Growth After Preterm Birth.

PubMed

Stiver, Mikaela L; Kamino, Daphne; Guo, Ting; Thompson, Angela; Duerden, Emma G; Taylor, Margot J; Tam, Emily W Y

2015-10-01

The preterm cerebellum is vulnerable to impaired development impacting long-term outcome. Preterm newborns (<32 weeks) underwent serial magnetic resonance imaging (MRI) scans. The association between parental education and cerebellar volume at each time point was assessed, adjusting for age at scan. In 26 infants, cerebellar volumes at term (P = .001), but not birth (P = .4), were associated with 2-year volumes. For 1 cm(3) smaller cerebellar volume (4% total volume) at term, the cerebellum was 3.18 cm(3) smaller (3% total volume) by 2 years. Maternal postsecondary education was not associated with cerebellar volume at term (P = .16). Maternal postsecondary education was a significant confounder in the relationship between term and 2-year cerebellar volumes (P = .016), with higher education associated with improved volumes by 2 years. Although preterm birth has been found to be associated with smaller cerebellar volumes at term, maternal postsecondary education is associated with improved growth detectable by 2 years. © The Author(s) 2015.

Early childhood obesity is associated with compromised cerebellar development.

PubMed

Miller, Jennifer L; Couch, Jessica; Schwenk, Krista; Long, Michelle; Towler, Stephen; Theriaque, Douglas W; He, Guojun; Liu, Yijun; Driscoll, Daniel J; Leonard, Christiana M

2009-01-01

As part of a study investigating commonalities between Prader-Willi syndrome (PWS-a genetic imprinting disorder) and early-onset obesity of unknown etiology (EMO) we measured total cerebral and cerebellar volume on volumetric magnetic resonance imaging (MRI) images. Individuals with PWS (N = 16) and EMO (N = 12) had smaller cerebellar volumes than a control group of 15 siblings (p = .02 control vs. EMO; p = .0005 control vs. PWS), although there was no difference among the groups in cerebral volume. Individuals with PWS and EMO also had impaired cognitive function: general intellectual ability (GIA): PWS 65 +/- 25; EMO 81 +/- 19; and Controls 112 +/- 13 (p < .0001 controls vs. PWS and controls vs. EMO). As both conditions are characterized by early-onset obesity and slowed cognitive development, these results raise the possibility that early childhood obesity retards both cerebellar and cognitive development.

Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1.

PubMed

Edamakanti, Chandrakanth Reddy; Do, Jeehaeh; Didonna, Alessandro; Martina, Marco; Opal, Puneet

2018-06-01

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the protein ATXN1, which is involved in transcriptional regulation. Although symptoms appear relatively late in life, primarily from cerebellar dysfunction, pathogenesis begins early, with transcriptional changes detectable as early as a week after birth in SCA1-knockin mice. Given the importance of this postnatal period for cerebellar development, we asked whether this region might be developmentally altered by mutant ATXN1. We found that expanded ATXN1 stimulates the proliferation of postnatal cerebellar stem cells in SCA1 mice. These hyperproliferating stem cells tended to differentiate into GABAergic inhibitory interneurons rather than astrocytes; this significantly increased the GABAergic inhibitory interneuron synaptic connections, disrupting cerebellar Purkinje cell function in a non-cell autonomous manner. We confirmed the increased basket cell-Purkinje cell connectivity in human SCA1 patients. Mutant ATXN1 thus alters the neural circuitry of the developing cerebellum, setting the stage for the later vulnerability of Purkinje cells to SCA1. We propose that other late-onset degenerative diseases may also be rooted in subtle developmental derailments.

Inferior Cerebellar Hypoplasia Resembling a Dandy-Walker-Like Malformation in Purebred Eurasier Dogs with Familial Non-Progressive Ataxia: A Retrospective and Prospective Clinical Cohort Study

PubMed Central

Bernardino, Filipa; Rentmeister, Kai; Schmidt, Martin J.; Bruehschwein, Andreas; Matiasek, Kaspar; Matiasek, Lara A.; Lauda, Alexander; Schoon, Heinz A.; Fischer, Andrea

2015-01-01

Cerebellar malformations can be inherited or caused by insults during cerebellar development. To date, only sporadic cases of cerebellar malformations have been reported in dogs, and the genetic background has remained obscure. Therefore, this study`s objective was to describe the clinical characteristics, imaging features and pedigree data of a familial cerebellar hypoplasia in purebred Eurasier dogs. A uniform cerebellar malformation characterized by consistent absence of the caudal portions of the cerebellar vermis and, to a lesser degree, the caudal portions of the cerebellar hemispheres in association with large retrocerebellar fluid accumulations was recognized in 14 closely related Eurasier dogs. Hydrocephalus was an additional feature in some dogs. All dogs displayed non-progressive ataxia, which had already been noted when the dogs were 5 – 6 weeks old. The severity of the ataxia varied between dogs, from mild truncal sway, subtle dysmetric gait, dysequilibrium and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Follow-up examinations in adult dogs showed improvement of the cerebellar ataxia and a still absent menace response. Epileptic seizures occurred in some dogs. The association of partial vermis agenesis with an enlarged fourth ventricle and an enlarged caudal (posterior) fossa resembled a Dandy-Walker-like malformation in some dogs. Pedigree analyses were consistent with autosomal recessive inheritance. PMID:25668516

Amelioration of cerebellar dysfunction in rats following postnatal ethanol exposure using low-intensity pulsed ultrasound.

PubMed

Bolbanabad, Hiva Mohammadi; Anvari, Enayat; Rezai, Mohammad Jafar; Moayeri, Ardashir; Kaffashian, Mohammad Reza

2017-04-01

The neonatal development stage of the cerebellum in rats is equivalent to a human foetus in the third trimester of pregnancy. In this stage, cell proliferation, migration, differentiation, and synaptogenesis occur. Clinical and experimental findings have shown that ethanol exposure during brain development causes a variety of disruptions to the brain, including neurogenesis depression, delayed neuronal migration, changes in neurotransmitter synthesis, and neuronal depletion.During postnatal cerebellar development, neurons are more vulnerable to the destructive effects of ethanol. The effects of low-intensity pulsed ultrasound (LIPUS) on the number of cells and thickness of the cell layers within the cerebellar cortex were examined during the first two postnatal weeks in rats following postnatal ethanol exposure. Postpartum rats were distributed randomly into six groups. Normal saline was injected intraperitoneally into control animals and ethanol (20%) was injected into the intervention groups for three consecutive days. Intervention groups received LIPUS at different frequencies (3 or 5MHz), after administration of ethanol. After transcardial perfusion, the rat's brain was removed, and a complete series of sagittal cerebellum sections were obtained by systematic random manner. Photomicrographs were made with Motic digital cameras and analysed using Nikon digital software. The numbers of granular cells decreased in ethanol-treated rats compared to the control group. LIPUS, administered at (3 or 5MHz), combined with ethanol administration resulted in a reduction of ethanol's effects. Using 5MHz LIPUS resulted in significantly higher numbers of granular cells in the internal layer compared to the control rats. Using 3 or 5MHz LIPUS alone resulted in a significant enhancement in the granular cells of the molecular layer. A significant reduction was seen in the thickness of the external granular layer in ethanol-treated rats. This study showed that exposure to LIPUS can affect the number of granular cells and thickness of the cell layer within the cerebellar cortex in neonatal rats. LIPUS also could attenuate ethanol toxicity effects on the cerebellum. Copyright © 2017 Elsevier B.V. All rights reserved.

Hypothyroidism alters the expression of Bcl-2 family genes to induce enhanced apoptosis in the developing cerebellum.

PubMed

Singh, R; Upadhyay, G; Kumar, S; Kapoor, A; Kumar, A; Tiwari, M; Godbole, M M

2003-01-01

Thyroid hormone (TH) deficiency results in delayed proliferation and migration of cerebellar granule cells. Although extensive cell loss during the development of the cerebellum under hypothyroid conditions is known, its nature and its mechanism are poorly understood. Bcl-2 family gene expression is known to determine the fate of cells to undergo apoptosis. We evaluated the effect of hypothyroidism on Bcl-2 family gene expression in the developing rat cerebellum. Electrophoresis and Western blotting were used to analyze DNA fragmentation and expression of DNA fragmentation factor (DFF-45), Bcl-2, Bcl-xL and Bax genes respectively. In the hypothyroid condition, extensive DNA fragmentation and enhanced cleavage of DFF-45 were seen throughout development (postnatal day 0 to day 24) and adulthood whereas they were absent in the euthyroid state. The anti-apoptotic genes Bcl-2 and Bcl-xL were down-regulated and the pro-apoptotic gene Bax was expressed at higher levels compared with the euthyroid state. These results suggest that normal levels of TH prevent cerebellar apoptosis to a large extent, whereas hypothyroidism not only increases the extent but also the duration of apoptosis by down-regulating the anti-apoptotic genes and maintaining a high level of the pro-apoptotic gene Bax.

Intrauterine Growth Restriction Affects Cerebellar Granule Cells in the Developing Guinea Pig Brain.

PubMed

Tolcos, Mary; McDougall, Annie; Shields, Amy; Chung, Yoonyoung; O'Dowd, Rachael; Turnley, Ann; Wallace, Megan; Rees, Sandra

2018-01-01

Intrauterine growth restriction (IUGR) can lead to adverse neurodevelopmental sequelae in postnatal life. However, the effects of IUGR on the cerebellum are still to be fully elucidated. A major determinant of growth and development of the cerebellum is proliferation and subsequent migration of cerebellar granule cells. Our objective was to determine whether IUGR, induced by chronic placental insufficiency (CPI) in guinea pigs, results in abnormal cerebellar development due to deficits suggestive of impaired granule cell proliferation and/or migration. CPI was induced by unilateral ligation of the uterine artery at mid-gestation, producing growth-restricted (GR) foetuses at 52 and 60 days of gestation (dg), and neonates at 1 week postnatal age (term approx. 67 dg). Controls were from sham-operated animals. In GR foetuses compared with controls at 52 dg, the external granular layer (EGL) width and internal granular layer (IGL) area were similar. In GR foetuses compared with controls at 60 dg: (a) the EGL width was greater (p < 0.005); (b) the IGL area was smaller (p < 0.005); (c) the density of Ki67-negative (postmitotic) granule cells in the EGL was greater (p < 0.01); (d) the somal area of Purkinje cells was reduced (p < 0.005), and (e) the linear density of Bergmann glia was similar. The EGL width in GR foetuses at 60 dg was comparable to that of 52 dg control and GR foetuses. The pattern of p27-immunoreactivity in the EGL was the inverse of Ki67-immunoreactivity at both foetal ages; there was no difference between control and GR foetuses at either age in the width of p27-immunoreactivity, or in the percentage of the EGL width that it occupied. In the molecular layer of GR neonates compared with controls there was an increase in the areal density of granule cells (p < 0.05) and in the percentage of migrating to total number of granule cells (p < 0.01) at 1 week but not at 60 dg (p > 0.05). Thus, we found no specific evidence that IUGR affects granule cell proliferation, but it alters the normal program of migration to the IGL and, in addition, the development of Purkinje cells. Such alterations will likely affect the development of appropriate circuitry and have implications for cerebellar function. © 2018 S. Karger AG, Basel.

A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies.

PubMed

Geminiani, Alice; Casellato, Claudia; Antonietti, Alberto; D'Angelo, Egidio; Pedrocchi, Alessandra

2018-06-01

The cerebellum plays a crucial role in sensorimotor control and cerebellar disorders compromise adaptation and learning of motor responses. However, the link between alterations at network level and cerebellar dysfunction is still unclear. In principle, this understanding would benefit of the development of an artificial system embedding the salient neuronal and plastic properties of the cerebellum and operating in closed-loop. To this aim, we have exploited a realistic spiking computational model of the cerebellum to analyze the network correlates of cerebellar impairment. The model was modified to reproduce three different damages of the cerebellar cortex: (i) a loss of the main output neurons (Purkinje Cells), (ii) a lesion to the main cerebellar afferents (Mossy Fibers), and (iii) a damage to a major mechanism of synaptic plasticity (Long Term Depression). The modified network models were challenged with an Eye-Blink Classical Conditioning test, a standard learning paradigm used to evaluate cerebellar impairment, in which the outcome was compared to reference results obtained in human or animal experiments. In all cases, the model reproduced the partial and delayed conditioning typical of the pathologies, indicating that an intact cerebellar cortex functionality is required to accelerate learning by transferring acquired information to the cerebellar nuclei. Interestingly, depending on the type of lesion, the redistribution of synaptic plasticity and response timing varied greatly generating specific adaptation patterns. Thus, not only the present work extends the generalization capabilities of the cerebellar spiking model to pathological cases, but also predicts how changes at the neuronal level are distributed across the network, making it usable to infer cerebellar circuit alterations occurring in cerebellar pathologies.

Role of cerebral ultrasound and magnetic resonance imaging in newborns with congenital cytomegalovirus infection.

PubMed

Capretti, Maria Grazia; Lanari, Marcello; Tani, Giovanni; Ancora, Gina; Sciutti, Rita; Marsico, Concetta; Lazzarotto, Tiziana; Gabrielli, Liliana; Guerra, Brunella; Corvaglia, Luigi; Faldella, Giacomo

2014-03-01

To assess the diagnostic and prognostic value of cerebral magnetic resonance imaging (cMRI) in comparison with that of cerebral ultrasound (cUS) in predicting neurodevelopmental outcome in newborns with congenital cytomegalovirus (CMV) infection. Forty CMV-congenitally infected newborns underwent cUS and cMRI within the first month of life. Clinical course, laboratory findings, visual/hearing function and neurodevelopmental outcome were documented. Thirty newborns showed normal cMRI, cUS and hearing/visual function in the first month of life; none showed CMV-related abnormalities at follow-up. Six newborns showed pathological cMRI and cUS findings (pseudocystis, ventriculomegaly, calcifications, cerebellar hypoplasia) but cMRI provided additional information (white matter abnormalities in three cases, lissencephaly/polymicrogyria in one and a cyst of the temporal lobe in another one); cerebral calcifications were detected in 3/6 infants by cUS but only in 2/6 by cMRI. Four of these 6 infants showed severe neurodevelopmental impairment and five showed deafness during follow-up. Three newborns had a normal cUS, but cMRI documented white matter abnormalities and in one case also cerebellar hypoplasia; all showed neurodevelopmental impairment and two were deaf at follow-up. One more newborn showed normal cUS and cMRI, but brainstem auditory evoked responses were abnormal; psychomotor development was normal at follow-up. Compared with cUS, cMRI disclosed additional pathological findings in CMV-congenitally infected newborns. cUS is a readily available screening tool useful in the identification of infected newborns with major cerebral involvement. Further studies with a larger sample size are needed to determine the prognostic role of MRI, particularly regarding isolated white matter lesions. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Cerebellar ataxia and epilepsy with anti-GAD antibodies: treatment with IVIG and plasmapheresis

PubMed Central

Georgieva, Zoya; Parton, Matthew

2014-01-01

Glutamic acid decarboxylase autoantibody (GAD-65) catalyses glutamate conversion into γ-aminobutyric acid (GABA) in the central nervous system and in the pancreatic β cells. Antibodies targeting GAD-65 are of uncertain pathogenic significance and occur in stiff person syndrome, cerebellar ataxia, epilepsy, limbic encephalitis and combinations thereof and diabetes mellitus. A 45-year-old man with a cerebellar gait ataxia, dysmetria, nystagmus and mild cerebellar dysarthria was diagnosed with insulin-dependent diabetes mellitus a year after the onset of neurological symptoms. He also developed complex and tonic-clonic seizures, resistant to anticonvulsant medication and deteriorated cognitively. Blood and cerebrospinal fluid serology, and imaging supported the diagnosis of GAD-65 cerebellar ataxia and epilepsy. He was treated with intravenous immunoglobulin and subsequently plasmapheresis. We report the outcome of 3 years of treatment, which resulted in the improvement of cerebellar signs (particularly gait), with some ultimate decline of efficacy. PMID:24419643

Reorganization of the cerebro-cerebellar network of language production in patients with congenital left-hemispheric brain lesions.

PubMed

Lidzba, K; Wilke, M; Staudt, M; Krägeloh-Mann, I; Grodd, W

2008-09-01

Patients with congenital lesions of the left cerebral hemisphere may reorganize language functions into the right hemisphere. In these patients, language production is represented homotopically to the left-hemispheric language areas. We studied cerebellar activation in five patients with congenital lesions of the left cerebral hemisphere to assess if the language network is reorganized completely in these patients, i.e. including also cerebellar language functions. As compared to a group of controls matched for age, sex, and verbal IQ, the patients recruited an area not in the right but in the left cerebellar hemisphere. The extent of laterality of the cerebellar activation correlated significantly with the laterality of the frontal activation. We suggest that the developing brain reacts to early focal lesions in the left hemisphere with a mirror-image organization of the entire cerebro-cerebellar network engaged in speech production.

Misdiagnosis of cerebellar hemorrhage - features of 'pseudo-gastroenteritis' clinical presentations to the ED and primary care.

PubMed

Lee, Seung-Han; Stanton, Victoria; Rothman, Richard E; Crain, Barbara; Wityk, Robert; Wang, Zheyu; Newman-Toker, David E

2017-03-01

Early-stage cerebellar hemorrhage can present with nausea or vomiting absent other neurological symptoms or signs, potentially leading to an incorrect diagnosis of gastroenteritis. We sought to determine the frequency of gastroenteritis-like presentations and delayed or missed diagnoses among patients with spontaneous cerebellar hemorrhage. This is a retrospective, case-control analysis of atraumatic, primary cerebellar hemorrhages derived from a systematic search of surgical pathology and autopsy databases at two large urban, academic medical centers from 1984 to 2006. Hospital visit and clinical symptom data were abstracted from electronic and paper medical records for included patients. Delayed or missed diagnoses were defined as those at least one previous visit for relevant clinical symptoms in the 7 days prior to the correct diagnosis being confirmed. Among 254 records captured by our search filter, we identified 35 cases of pathologically proven primary cerebellar hemorrhage. Four patients (11%) were misdiagnosed initially - three with "gastroenteritis" and one with "hypertension". In this small sample, misdiagnosed patients presented more often with normal mental state (100% vs. 35%, p=0.07) and nausea/vomiting (100% vs. 58%, p=0.22). Although patients deteriorated clinically after the initial misdiagnosis, and potentially dangerous diagnostic tests and treatment strategies were instituted as a result of misdiagnosis, none of the misdiagnosed patients died or suffered major permanent harms due to diagnostic delay. Our study is limited by the small number of identified cases. Nevertheless, it appears that patients with cerebellar hemorrhages can present with relatively unimpressive clinical findings without obvious neurological manifestations. Such individuals are sometimes misdiagnosed with gastroenteritis or other benign disorders initially, possibly when neurologic examination, particularly gait testing, is omitted or abridged. A careful search for subtle cerebellar signs, including dysarthria, limb ataxia, nystagmus or tandem gait instability, absent in true gastroenteritis cases, could potentially reduce misdiagnosis.

The Cerebellar Dysplasia of Chiari II Malformation as Revealed by Eye Movements

PubMed Central

Salman, Michael S.; Dennis, Maureen; Sharpe, James A.

2011-01-01

Introduction Chiari type II malformation (CII) is a developmental deformity of the hindbrain. We have previously reported that many patients with CII have impaired smooth pursuit, while few make inaccurate saccades or have an abnormal vestibulo-ocular reflex. In contrast, saccadic adaptation and visual fixation are normal. In this report, we correlate results from several eye movement studies with neuroimaging in CII. We present a model for structural changes within the cerebellum in CII. Methods Saccades, smooth pursuit, the vestibulo-ocular reflex, and visual fixation were recorded in 21 patients with CII, aged 8–19 years and 39 age-matched controls, using an infrared eye tracker. Qualitative and quantitative MRI data were correlated with eye movements in 19 CII patients and 28 controls. Results Nine patients with CII had abnormal eye movements. Smooth pursuit gain was subnormal in eight, saccadic accuracy abnormal in four, and vestibulo-ocular reflex gain abnormal in three. None had fixation instability. Patients with CII had a significantly smaller cerebellar volume than controls, and those with normal eye motion had an expanded midsagittal vermis compared to controls. However, patients with abnormal eye movements had a smaller (non-expanded) midsagittal vermis area, posterior fossa area and medial cerebellar volumes than CII patients with normal eye movements. Conclusions The deformity of CII affects the structure and function of the cerebellum selectively and differently in those with abnormal eye movements. We propose that the vermis can expand when compressed within a small posterior fossa in some CII patients, thus sparing its ocular motor functions. PMID:19960749

Neurotoxicological effects of nicotine on the embryonic development of cerebellar cortex of chick embryo during various stages of incubation.

PubMed

El-Beltagy, Abd El-Fattah B M; Abou-El-Naga, Amoura M; Sabry, Dalia M

2015-10-01

Long-acting nicotine is known to exert pathological effects on almost all tissues including the cerebellar cortex. The present work was designed to elucidate the effect of nicotine on the development of cerebellar cortex of chick embryo during incubation period. The fertilized eggs of hen (Gallus gallus domesticus) were injected into the air space by a single dose of long acting nicotine (1.6 mg/kg/egg) at the 4th day of incubation. The embryos were taken out of the eggs on days 8, 12 and 16 of incubation. The cerebellum of the control and treated embryos at above ages were processed for histopathological examination. The TEM were examined at 16th day of incubation. The results of the present study revealed that, exposure to long-acting nicotine markedly influence the histogenesis of cerebellar cortex of chick embryo during the incubation period. At 8th day of incubation, nicotine delayed the differentiation of the cerebellar analge; especially the external granular layer (EGL) and inner cortical layer (ICL). Furthermore, at 12th day of incubation, the cerebellar foliation was irregular and the Purkinje cells not recognized. By 16th day of incubation, the cerebellar foliations were irregular with interrupted cerebellar cortex and irregular arrangement of Purkinje cells. Immunohistochemical analysis for antibody P53 protein revealed that the cerebellar cortex in all stages of nicotine treated groups possessed a moderate to weak reaction for P53 protein however; this reaction was markedly stronger in the cerebellar cortex of control groups. Moreover, the flow cytometric analysis confirmed that the percentage of apoptosis in control group was significantly higher compared with that of nicotine treated group. At the TEM level, the cerebellar Purkinje cells of 16th day of treated groups showed multiple subcellular alterations in compared with those of the corresponding control group. Such changes represented by appearing of vacuolated mitochondria, cisternal fragmentation of RER, irregular grooves of Golgi tubules. Also, multiple cytoplasmic vacuoles and aggregation of Nissl granules were recorded around pyknotic nucleus. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cerebellar gray matter and lobular volumes correlate with core autism symptoms

PubMed Central

D'Mello, Anila M.; Crocetti, Deana; Mostofsky, Stewart H.; Stoodley, Catherine J.

2015-01-01

Neuroanatomical differences in the cerebellum are among the most consistent findings in autism spectrum disorder (ASD), but little is known about the relationship between cerebellar dysfunction and core ASD symptoms. The newly-emerging existence of cerebellar sensorimotor and cognitive subregions provides a new framework for interpreting the functional significance of cerebellar findings in ASD. Here we use two complementary analyses — whole-brain voxel-based morphometry (VBM) and the SUIT cerebellar atlas — to investigate cerebellar regional gray matter (GM) and volumetric lobular measurements in 35 children with ASD and 35 typically-developing (TD) children (mean age 10.4 ± 1.6 years; range 8–13 years). To examine the relationships between cerebellar structure and core ASD symptoms, correlations were calculated between scores on the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview (ADI) and the VBM and volumetric data. Both VBM and the SUIT analyses revealed reduced GM in ASD children in cerebellar lobule VII (Crus I/II). The degree of regional and lobular gray matter reductions in different cerebellar subregions correlated with the severity of symptoms in social interaction, communication, and repetitive behaviors. Structural differences and behavioral correlations converged on right cerebellar Crus I/II, a region which shows structural and functional connectivity with fronto-parietal and default mode networks. These results emphasize the importance of the location within the cerebellum to the potential functional impact of structural differences in ASD, and suggest that GM differences in cerebellar right Crus I/II are associated with the core ASD profile. PMID:25844317

Homolateral ataxia and crural paresis: a crossed cerebral-cerebellar diaschisis.

PubMed Central

Giroud, M; Creisson, E; Fayolle, H; Gras, P; Vion, P; Brunotte, F; Dumas, R

1994-01-01

A patient developed weakness of the right leg and homolateral ataxia of the arm, caused by a subcortical infarct in the area supplied by the anterior cerebral artery in the left paracentral region, demonstrated by CT and MRI. Cerebral blood flow studied by technetium-labelled hexamethyl-propylene-amine oxime using single photon emission computed tomography showed decreased blood flow in the left lateral frontal cortex and in the right cerebellar hemisphere ("crossed cerebral-cerebellar diaschisis"). The homolateral ataxia of the arm may be caused by decreased function of the right cerebellar hemisphere, because of a lesion of the corticopontine-cerebellar tracts, whereas crural hemiparesis is caused by a lesion of the upper part of the corona radiata. Images PMID:8126511

Dyslexic Children Show Atypical Cerebellar Activation and Cerebro-Cerebellar Functional Connectivity in Orthographic and Phonological Processing.

PubMed

Feng, Xiaoxia; Li, Le; Zhang, Manli; Yang, Xiujie; Tian, Mengyu; Xie, Weiyi; Lu, Yao; Liu, Li; Bélanger, Nathalie N; Meng, Xiangzhi; Ding, Guosheng

2017-04-01

Previous neuroimaging studies have found atypical cerebellar activation in individuals with dyslexia in either motor-related tasks or language tasks. However, studies investigating atypical cerebellar activation in individuals with dyslexia have mostly used tasks tapping phonological processing. A question that is yet unanswered is whether the cerebellum in individuals with dyslexia functions properly during orthographic processing of words, as growing evidence shows that the cerebellum is also involved in visual and spatial processing. Here, we investigated cerebellar activation and cerebro-cerebellar functional connectivity during word processing in dyslexic readers and typically developing readers using tasks that tap orthographic and phonological codes. In children with dyslexia, we observed an abnormally higher engagement of the bilateral cerebellum for the orthographic task, which was negatively correlated with literacy measures. The greater the reading impairment was for young dyslexic readers, the stronger the cerebellar activation was. This suggests a compensatory role of the cerebellum in reading for children with dyslexia. In addition, a tendency for higher cerebellar activation in dyslexic readers was found in the phonological task. Moreover, the functional connectivity was stronger for dyslexic readers relative to typically developing readers between the lobule VI of the right cerebellum and the left fusiform gyrus during the orthographic task and between the lobule VI of the left cerebellum and the left supramarginal gyrus during the phonological task. This pattern of results suggests that the cerebellum compensates for reading impairment through the connections with specific brain regions responsible for the ongoing reading task. These findings enhance our understanding of the cerebellum's involvement in reading and reading impairment.

[A case of early onset cerebellar ataxia with hearing loss, mental disturbance and primary hypogonadism].

PubMed

Ikezoe, K; Yamada, A; Takeuchi, H; Miki, H; Katanaka, J

1992-09-01

A 14-year-old girl, whose birth and developmental history were normal till the age of 7, was admitted to our hospital because of slowly progressive difficulties in walking, speaking and hearing. She also complained of absence of menstruation. She showed poor school records since the age of 7. On neurological examination, she showed limb and truncal ataxia. There was no nystagmus but slurred speech was found. Muscular power was good and her sensory system was normal. Tendon reflexes were equally present, and plantar reflexes were flexor. Bilateral moderate nerve deafness was also present. Mental deficiency was diagnosed on an intelligence test. Brain CT and MRI showed cerebellar atrophy. Gynecological examination revealed scanty pubic hair and small uterus. Karyotype was 46XX. Endocrinological studies demonstrated high level of FSH, low level of E2, and the normal response to pituitary stimulation with LHRH, indicating the existence of primary hypogonadism. Although the etiology of this multisystem disorder is unknown, it is possible that both nervous and endocrine disorders were genetically determined.

The cell adhesion molecule CHL1 interacts with patched-1 to regulate apoptosis during postnatal cerebellar development.

PubMed

Katic, Jelena; Loers, Gabriele; Tosic, Jelena; Schachner, Melitta; Kleene, Ralf

2017-08-01

The immunoglobulin superfamily adhesion molecule close homolog of L1 (CHL1) plays important roles during nervous system development. Here, we identified the hedgehog receptor patched-1 (PTCH1) as a novel CHL1-binding protein and showed that CHL1 interacts with the first extracellular loop of PTCH1 via its extracellular domain. Colocalization and co-immunoprecipitation of CHL1 with PTCH1 suggest an association of CHL1 with this major component of the hedgehog signaling pathway. The trans -interaction of CHL1 with PTCH1 promotes neuronal survival in cultures of dissociated cerebellar granule cells and of organotypic cerebellar slices. An inhibitor of the PTCH1-regulated hedgehog signal transducer, smoothened (SMO), and inhibitors of RhoA and Rho-associated kinase (ROCK) 1 and 2 prevent CHL1-dependent survival of cultured cerebellar granule cells and survival of cerebellar granule and Purkinje cells in organotypic cultures. In histological sections from 10- and 14-day-old CHL1-deficient mice, enhanced apoptosis of granule, but not Purkinje, cells was observed. The results of the present study indicate that CHL1 triggers PTCH1-, SMO-, RhoA- and ROCK-dependent signal transduction pathways to promote neuronal survival after cessation of the major morphogenetic events during mouse cerebellar development. © 2017. Published by The Company of Biologists Ltd.

Cerebellar ataxia: abnormal control of interaction torques across multiple joints.

PubMed

Bastian, A J; Martin, T A; Keating, J G; Thach, W T

1996-07-01

1. We studied seven subjects with cerebellar lesions and seven control subjects as they made reaching movements in the sagittal plane to a target directly in front of them. Reaches were made under three different conditions: 1) "slow-accurate," 2) "fast-accurate," and 3) "fast as possible." All subjects were videotaped moving in a sagittal plane with markers on the index finger, wrist, elbow, and shoulder. Marker positions were digitized and then used to calculate joint angles. For each of the shoulder, elbow and wrist joints, inverse dynamics equations based on a three-segment limb model were used to estimate the net torque (sum of components) and each of the component torques. The component torques consisted of the torque due to gravity, the dynamic interaction torques induced passively by the movement of the adjacent joint, and the torque produced by the muscles and passive tissue elements (sometimes called "residual" torque). 2. A kinematic analysis of the movement trajectory and the change in joint angles showed that the reaches of subjects with cerebellar lesions were abnormal compared with reaches of control subjects. In both the slow-accurate and fast-accurate conditions the cerebellar subjects made abnormally curved wrist paths; the curvature was greater in the slow-accurate condition. During the slow-accurate condition, cerebellar subjects showed target undershoot and tended to move one joint at a time (decomposition). During the fast-accurate reaches, the cerebellar subjects showed target overshoot. Additionally, in the fast-accurate condition, cerebellar subjects moved the joints at abnormal rates relative to one another, but the movements were less decomposed. Only three subjects were tested in the fast as possible condition; this condition was analyzed only to determine maximal reaching speeds of subjects with cerebellar lesions. Cerebellar subjects moved more slowly than controls in all three conditions. 3. A kinetic analysis of torques generated at each joint during the slow-accurate reaches and the fast-accurate reaches revealed that subjects with cerebellar lesions produced very different torque profiles compared with control subjects. In the slow-accurate condition, the cerebellar subjects produced abnormal elbow muscle torques that prevented the normal elbow extension early in the reach. In the fast-accurate condition, the cerebellar subjects produced inappropriate levels of shoulder muscle torque and also produced elbow muscle torques that did not very appropriately with the dynamic interaction torques that occurred at the elbow. Lack of appropriate muscle torque resulted in excessive contributions of the dynamic interaction torque during the fast-accurate reaches. 4. The inability to produce muscle torques that predict, accommodate, and compensate for the dynamic interaction torques appears to be an important cause of the classic kinematic deficits shown by cerebellar subjects during attempted reaching. These kinematic deficits include incoordination of the shoulder and the elbow joints, a curved trajectory, and overshoot. In the fast-accurate condition, cerebellar subjects often made inappropriate muscle torques relative to the dynamic interaction torques. Because of this, interaction torques often determined the pattern of incoordination of the elbow and shoulder that produced the curved trajectory and target overshoot. In the slow-accurate condition, we reason that the cerebellar subjects may use a decomposition strategy so as to simplify the movement and not have to control both joints simultaneously. From these results, we suggest that a major role of the cerebellum is in generating muscle torques at a joint that will predict the interaction torques being generated by other moving joints and compensate for them as they occur.

Volumetric Analysis of Regional Variability in the Cerebellum of Children with Dyslexia

PubMed Central

Stuebing, Karla; Juranek, Jenifer; Fletcher, Jack M.

2013-01-01

Cerebellar deficits and subsequent impairment in procedural learning may contribute to both motor difficulties and reading impairment in dyslexia. We used quantitative magnetic resonance imaging to investigate the role of regional variation in cerebellar anatomy in children with single-word decoding impairments (N=23), children with impairment in fluency alone (N=8), and typically developing children (N=16). Children with decoding impairments (dyslexia) demonstrated no statistically significant differences in overall grey and white matter volumes or cerebellar asymmetry; however, reduced volume in the anterior lobe of the cerebellum relative to typically developing children was observed. These results implicate cerebellar involvement in dyslexia and establish an important foundation for future research on the connectivity of the cerebellum and cortical regions typically associated with reading impairment. PMID:23828023

Volumetric analysis of regional variability in the cerebellum of children with dyslexia.

PubMed

Fernandez, Vindia G; Stuebing, Karla; Juranek, Jenifer; Fletcher, Jack M

2013-12-01

Cerebellar deficits and subsequent impairment in procedural learning may contribute to both motor difficulties and reading impairment in dyslexia. We used quantitative magnetic resonance imaging to investigate the role of regional variation in cerebellar anatomy in children with single-word decoding impairments (N = 23), children with impairment in fluency alone (N = 8), and typically developing children (N = 16). Children with decoding impairments (dyslexia) demonstrated no statistically significant differences in overall grey and white matter volumes or cerebellar asymmetry; however, reduced volume in the anterior lobe of the cerebellum relative to typically developing children was observed. These results implicate cerebellar involvement in dyslexia and establish an important foundation for future research on the connectivity of the cerebellum and cortical regions typically associated with reading impairment.

Oculomotor evidence for neocortical systems but not cerebellar dysfunction in autism

PubMed Central

Minshew, Nancy J.; Luna, Beatriz; Sweeney, John A.

2010-01-01

Objective To investigate the functional integrity of cerebellar and frontal system in autism using oculomotor paradigms. Background Cerebellar and neocortical systems models of autism have been proposed. Courchesne and colleagues have argued that cognitive deficits such as shifting attention disturbances result from dysfunction of vermal lobules VI and VII. Such a vermal deficit should be associated with dysmetric saccadic eye movements because of the major role these areas play in guiding the motor precision of saccades. In contrast, neocortical models of autism predict intact saccade metrics, but impairments on tasks requiring the higher cognitive control of saccades. Methods A total of 26 rigorously diagnosed nonmentally retarded autistic subjects and 26 matched healthy control subjects were assessed with a visually guided saccade task and two volitional saccade tasks, the oculomotor delayed-response task and the antisaccade task. Results Metrics and dynamic of the visually guided saccades were normal in autistic subjects, documenting the absence of disturbances in cerebellar vermal lobules VI and VII and in automatic shifts of visual attention. Deficits were demonstrated on both volitional saccade tasks, indicating dysfunction in the circuitry of prefrontal cortex and its connections with the parietal cortex, and associated cognitive impairments in spatial working memory and in the ability to voluntarily suppress context-inappropriate responses. Conclusions These findings demonstrate intrinsic neocortical, not cerebellar, dysfunction in autism, and parallel deficits in higher order cognitive mechanisms and not in elementary attentional and sensorimotor systems in autism. PMID:10102406

Nos2 inactivation promotes the development of medulloblastoma in Ptch1(+/-) mice by deregulation of Gap43-dependent granule cell precursor migration.

PubMed

Haag, Daniel; Zipper, Petra; Westrich, Viola; Karra, Daniela; Pfleger, Karin; Toedt, Grischa; Blond, Frederik; Delhomme, Nicolas; Hahn, Meinhard; Reifenberger, Julia; Reifenberger, Guido; Lichter, Peter

2012-01-01

Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptch1(+/-) mice. As nitric oxide may regulate GCP proliferation and differentiation, we crossed Ptch1(+/-) mice with mice lacking inducible nitric oxide synthase (Nos2) to investigate a possible influence on tumorigenesis. We observed a two-fold higher medulloblastoma rate in Ptch1(+/-) Nos2(-/-) mice compared to Ptch1(+/-) Nos2(+/+) mice. To identify the molecular mechanisms underlying this finding, we performed gene expression profiling of medulloblastomas from both genotypes, as well as normal cerebellar tissue samples of different developmental stages and genotypes. Downregulation of hedgehog target genes was observed in postnatal cerebellum from Ptch1(+/+) Nos2(-/-) mice but not from Ptch1(+/-) Nos2(-/-) mice. The most consistent effect of Nos2 deficiency was downregulation of growth-associated protein 43 (Gap43). Functional studies in neuronal progenitor cells demonstrated nitric oxide dependence of Gap43 expression and impaired migration upon Gap43 knock-down. Both effects were confirmed in situ by immunofluorescence analyses on tissue sections of the developing cerebellum. Finally, the number of proliferating GCPs at the cerebellar periphery was decreased in Ptch1(+/+) Nos2(-/-) mice but increased in Ptch1(+/-) Nos2(-/) (-) mice relative to Ptch1(+/-) Nos2(+/+) mice. Taken together, these results indicate that Nos2 deficiency promotes medulloblastoma development in Ptch1(+/-) mice through retention of proliferating GCPs in the external granular layer due to reduced Gap43 expression. This study illustrates a new role of nitric oxide signaling in cerebellar development and demonstrates that the localization of pre-neoplastic cells during morphogenesis is crucial for their malignant progression.

Consensus Paper: Roles of the Cerebellum in Motor Control—The Diversity of Ideas on Cerebellar Involvement in Movement

PubMed Central

Bower, James M.; Conforto, Adriana Bastos; Delgado-García, José M.; da Guarda, Suzete Nascimento Farias; Gerwig, Marcus; Habas, Christophe; Hagura, Nobuhiro; Ivry, Richard B.; Mariën, Peter; Molinari, Marco; Naito, Eiichi; Nowak, Dennis A.; Ben Taib, Nordeyn Oulad; Pelisson, Denis; Tesche, Claudia D.; Tilikete, Caroline; Timmann, Dagmar

2015-01-01

Considerable progress has been made in developing models of cerebellar function in sensorimotor control, as well as in identifying key problems that are the focus of current investigation. In this consensus paper, we discuss the literature on the role of the cerebellar circuitry in motor control, bringing together a range of different viewpoints. The following topics are covered: oculomotor control, classical conditioning (evidence in animals and in humans), cerebellar control of motor speech, control of grip forces, control of voluntary limb movements, timing, sensorimotor synchronization, control of corticomotor excitability, control of movement-related sensory data acquisition, cerebro-cerebellar interaction in visuokinesthetic perception of hand movement, functional neuroimaging studies, and magnetoencephalographic mapping of cortico-cerebellar dynamics. While the field has yet to reach a consensus on the precise role played by the cerebellum in movement control, the literature has witnessed the emergence of broad proposals that address cerebellar function at multiple levels of analysis. This paper highlights the diversity of current opinion, providing a framework for debate and discussion on the role of this quintessential vertebrate structure. PMID:22161499

Rapid Eye Movement Sleep Behavior Disorder in Paraneoplastic Cerebellar Degeneration: Improvement with Immunotherapy.

PubMed

Vale, Thiago Cardoso; Fernandes do Prado, Lucila Bizari; do Prado, Gilmar Fernandes; Povoas Barsottini, Orlando Graziani; Pedroso, José Luiz

2016-01-01

To report two female patients with paraneoplastic cerebellar degeneration (PCD) related to breast cancer that presented with rapid eye movement-sleep behavior disorder (RBD) and improved sleep symptoms with immunotherapy. The two patients were evaluated through clinical scale and polysomnography before and after therapy with intravenous immunoglobulin. RBD was successfully treated with immunotherapy in both patients. Score on the RBD screening questionnaire dropped from 10 to 1 or 0, allied with the normalization of polysomnographic findings. A marked improvement in RBD after immunotherapy in PCD raises the hypothesis that secondary RBD may be an immune-mediated sleep disorder. © 2016 Associated Professional Sleep Societies, LLC.

Paraneoplastic downbeat nystagmus associated with cerebellar hypermetabolism especially in the nodulus.

PubMed

Choi, Seo Young; Park, Seong-Ho; Kim, Hyo-Jung; Kim, Ji-Soo

2014-08-15

A 52-year-old man with vertigo and imbalance for two weeks showed spontaneous downbeat (DBN), horizontal gaze-evoked, and positional apogeotropic nystagmus along with severe limb and truncal ataxia. Gadolinium-enhanced brain MRI was normal, but whole body and brain 2-deoxy-2-[F18]fluoro-d-glucose-positron emission tomography revealed hypermetabolism in the right lower lobe of the lung and the cerebellum, especially in the nodulus. The lesion in the lung was confirmed as mixed cell carcinoma. Paraneoplastic DBN may be associated with cerebellar hypermetabolism, especially in the nodulus. Copyright © 2014 Elsevier B.V. All rights reserved.

The Binding Problem for Syntax, Semantics, and Prosody: H.M.'s Selective Sentence-Reading Deficits under the Theoretical-Syndrome Approach.

ERIC Educational Resources Information Center

MacKay, Donald G.; James, Lori E.

2001-01-01

A "hippocampal amnesiac" (H.M.) and memory-normal controls of similar age, background, intelligence, and education read novel sentences aloud in tasks where fast and accurate reading was or was not the primary goal. H.M produced more misreadings than normal and cerebellar controls, usually without self-correction. Results support a theoretical…

The Long Adventurous Journey of Rhombic Lip Cells in Jawed Vertebrates: A Comparative Developmental Analysis

PubMed Central

Wullimann, Mario F.; Mueller, Thomas; Distel, Martin; Babaryka, Andreas; Grothe, Benedikt; Köster, Reinhard W.

2011-01-01

This review summarizes vertebrate rhombic lip and early cerebellar development covering classic approaches up to modern developmental genetics which identifies the relevant differential gene expression domains and their progeny. Most of this information is derived from amniotes. However, progress in anamniotes, particularly in the zebrafish, has recently been made. The current picture suggests that rhombic lip and cerebellar development in jawed vertebrates (gnathostomes) share many characteristics. Regarding cerebellar development, these include a ptf1a expressing ventral cerebellar proliferation (VCP) giving rise to Purkinje cells and other inhibitory cerebellar cell types, and an atoh1 expressing upper rhombic lip giving rise to an external granular layer (EGL, i.e., excitatory granule cells) and an early ventral migration into the anterior rhombencephalon (cholinergic nuclei). As for the lower rhombic lip (LRL), gnathostome commonalities likely include the formation of precerebellar nuclei (mossy fiber origins) and partially primary auditory nuclei (likely convergently evolved) from the atoh1 expressing dorsal zone. The fate of the ptf1a expressing ventral LRL zone which gives rise to (excitatory cells of) the inferior olive (climbing fiber origin) and (inhibitory cells of ) cochlear nuclei in amniotes, has not been determined in anamniotes. Special for the zebrafish in comparison to amniotes is the predominant origin of anamniote excitatory deep cerebellar nuclei homologs (i.e., eurydendroid cells) from ptf1a expressing VCP cells, the sequential activity of various atoh1 paralogs and the incomplete coverage of the subpial cerebellar plate with proliferative EGL cells. Nevertheless, the conclusion that a rhombic lip and its major derivatives evolved with gnathostome vertebrates only and are thus not an ancestral craniate character complex is supported by the absence of a cerebellum (and likely absence of its afferent and efferent nuclei) in jawless fishes PMID:21559349

Hydroxyurea Treatment and Development of the Rat Cerebellum: Effects on the Neurogenetic Profiles and Settled Patterns of Purkinje Cells and Deep Cerebellar Nuclei Neurons.

PubMed

Martí, Joaquín; Santa-Cruz, M C; Serra, Roger; Hervás, José P

2016-11-01

The current paper analyzes the development of the male and female rat cerebellum exposed to hydroxyurea (HU) (300 or 600 mg/kg) as embryo and collected at postnatal day 90. Our study reveals that the administration of this drug compromises neither the cytoarchitecture of the cerebellar cortex nor deep nuclei (DCN). However, in comparison with the saline group, we observed that several cerebellar parameters were lower in the HU injected groups. These parameters included area of the cerebellum, cerebellar cortex length, molecular layer area, Purkinje cell number, granule cell counts, internal granular layer, white matter and cerebellar nuclei areas, and number of deep cerebellar nuclei neurons. These features were larger in the rats injected with saline, smaller in those exposed to 300 mg/kg of HU and smallest in the group receiving 600 mg/kg of this agent. No sex differences in the effect of the HU were observed. In addition, we infer the neurogenetic timetables and the neurogenetic gradients of PCs and DCN neurons in rats exposed to either saline or HU as embryos. For this purpose, 5-bromo-2'-deoxyuridine was injected into pregnant rats previously administered with saline or HU. This thymidine analog was administered following a progressively delayed cumulative labeling method. The data presented here show that systematic differences exist in the pattern of neurogenesis and in the spatial location of cerebellar neurons between rats injected with saline or HU. No sex differences in the effect of the HU were observed. These findings have implications for the administration of this compound to women in gestation as the effects of HU on the development of the cerebellum might persist throughout their offsprings' life.

Histone Deacetylase 3 Is Necessary for Proper Brain Development*

PubMed Central

Norwood, Jordan; Franklin, Jade M.; Sharma, Dharmendra; D'Mello, Santosh R.

2014-01-01

The functional role of histone deacetylase 3 (HDAC3) in the developing brain has yet to be elucidated. We show that mice lacking HDAC3 in neurons and glia of the central nervous system, Nes-Cre/HDAC3 conditional KO mice, show major abnormalities in the cytoarchitecture of the neocortex and cerebellum and die within 24 h of birth. Later-born neurons do not localize properly in the cortex. A similar mislocalization is observed with cerebellar Purkinje neurons. Although the proportion of astrocytes is higher than normal, the numbers of oligodendrocytes are reduced. In contrast, conditional knockout of HDAC3 in neurons of the forebrain and certain other brain regions, using Thy1-Cre and calcium/calmodulin dependent protein kinase II α-Cre for ablation, produces no overt abnormalities in the organization of cells within the cortex or of cerebellar Purkinje neurons at birth. However, both lines of conditional knockout mice suffer from progressive hind limb paralysis and ataxia and die around 6 weeks after birth. The mice display an increase in overall numbers of cells, higher numbers of astrocytes, and Purkinje neuron degeneration. Taken together, our results demonstrate that HDAC3 plays an essential role in regulating brain development, with effects on both neurons and glia in different brain regions. PMID:25339172

Postoperative cerebellar mutism and autistic spectrum disorder.

PubMed

Tasdemiroğlu, Erol; Kaya, Miktat; Yildirim, Can Hakan; Firat, Levent

2011-06-01

I read the article "An Inside View of Autism" written by a 44-year-old autistic woman who had a successful international career designing livestock equipment. In this article, she wrote about her life, disease, and experiences as an autistic individual. She stated that "It is interesting that my speech resembled the stressed speech in young children who have had tumors removed from the cerebellum". In this article, we intend to review and extensively document both postoperative cerebellar mutism and autistic spectrum disorder. We reviewed the clinical and neurological findings, etio-pathogenesis, neuroanatomy, mechanisms of development, and similarities between the etio-pathogenesis of both diseases. Cerebellar lesions can produce mutism and dysarthria, symptoms sometimes seen in autistic spectrum disorder. In mammals, cerebellar lesions disturb motivated behavior and reduce social interactions, functions that are disturbed in autistic spectrum disorder and cerebellar mutism. The cerebellum and two regions within the frontal lobes are active in certain language tasks. Language is abnormal in autistic spectrum disorder and cerebellar mutism.

Neuro-Behcet disease presenting as a solitary cerebellar hemorrhagic lesion: a case report and review of the literature.

PubMed

Yeo, Minju; Lee, Hye-Lim; Cha, Minju; Kim, Ji Seon; Han, Ho-Seong; Lee, Sung-Hyun; Lee, Sang-Soo; Shin, Dong-Ick

2016-12-20

Behcet's disease is a heterogeneous, multisystem, inflammatory disorder of unknown etiology. The classic triad of oral and genital ulcerations in conjunction with uveitis was originally described by the Turkish dermatologist Hulusi Behcet in 1937, but associated symptoms of the cardiovascular, central nervous, pulmonary, and gastrointestinal systems were later identified. In fact, Behcet's disease with neurological involvement (neuro-Behcet's disease) is not uncommon. Patients with neuro-Behcet's disease typically exhibit a diverse array of symptoms, most commonly in the brainstem and diencephalic regions. Herein, we report an unusual case of neuro-Behcet's disease in a patient who presented with a solitary cerebellar hemorrhage. A 39-year-old Asian woman was admitted to our hospital with complaints of a sudden speech difficulty that had manifested the same morning, and dizziness and mild vomiting experienced over the previous 3 days. Magnetic resonance images revealed target-like hemorrhagic lesions in the right hemisphere of the cerebellum. Risk factors that may result in cerebellar hemorrhage, such as high blood pressure or bleeding diathesis, were ruled out, and subsequent brain angiograms were normal. These findings suggest that the patient's cerebellar hemorrhage could have been due to intracranial vasculitis in a rare, if not unique, complication of neuro-Behcet's disease.

Overexpression of Lin28b in Neural Stem Cells is Insufficient for Brain Tumor Formation, but Induces Pathological Lobulation of the Developing Cerebellum.

PubMed

Wefers, Annika K; Lindner, Sven; Schulte, Johannes H; Schüller, Ulrich

2017-02-01

LIN28B is a homologue of the RNA-binding protein LIN28A and regulates gene expression during development and carcinogenesis. It is strongly upregulated in a variety of brain tumors, such as medulloblastoma, embryonal tumor with multilayered rosettes (ETMR), atypical teratoid/rhabdoid tumor (AT/RT), or glioblastoma, but the effect of an in vivo overexpression of LIN28B on the developing central nervous system is unknown. We generated transgenic mice that either overexpressed Lin28b in Math1-positive cerebellar granule neuron precursors or in a broad range of Nestin-positive neural precursors. Sections of the cerebellar vermis from adult Math1-Cre::lsl-Lin28b mice had an additional subfissure in lobule IV. Vermes from p0 and p7 Nestin-Cre::lsl-Lin28b mice appeared normal, but we found a pronounced vermal hypersublobulation at p15 and p21 in these mice. Also, the external granule cell layer (EGL) was thicker at p15 than in controls, contained more proliferating cells, and persisted up to p21. Consistently, some Pax6- and NeuN-positive cells were present in the EGL of Nestin-Cre::lsl-Lin28b mice even at p21, and we detected more NeuN-positive granule neuron precursors in the molecular layer (ML) as compared to control. Finally, we found some residual Pax2-positive precursors of inhibitory interneurons in the ML of Nestin-Cre::lsl-Lin28b mice at p21, which have already disappeared in controls. We conclude that while overexpression of LIN28B in Nestin-positive cells does not lead to tumor formation, it results in a protracted development of granule cells and inhibitory interneurons and leads to a hypersublobulation of the cerebellar vermis.

A simple and clinically relevant combination of neuroimaging and functional indexes for the identification of those at highest risk of Alzheimer's disease.

PubMed

Tabatabaei-Jafari, Hossein; Walsh, Erin; Shaw, Marnie E; Cherbuin, Nicolas

2018-06-01

The current challenge in clinical practice is to identify those with mild cognitive impairment (MCI), who are at greater risk of Alzheimer's disease (AD) conversion in the near future. The aim of this study was to assess a clinically practical new hippocampal index-hippocampal volume normalized by cerebellar volume (hippocampus to cerebellum volume ratio) used alone or in combination with scores on the Mini-Mental State Examination, as a predictor of conversion from MCI to AD. The predictive value of the HCCR was also contrasted to that of the hippocampal volume to intracranial volume ratio. The findings revealed that the performance of the combination of measures was significantly better than that of each measure used individually. The combination of Mini-Mental State Examination and hippocampal volume, normalized by the cerebellum or by intracranial volume, accurately discriminated individuals with MCI who progress to AD within 5 years from other MCI types (stable, reverters) and those with intact cognition (area under receiver operating curve of 0.88 and 0.89, respectively). Normalization by cerebellar volume was as accurate as normalization by intracranial volume with the advantage of being more practical, particularly for serial assessments. Copyright © 2018 Elsevier Inc. All rights reserved.

Neuroimmune regulation of neurophysiology in the cerebellum.

PubMed

Gruol, Donna L

2013-06-01

Recent studies have established the existence of an innate immune system in the central nervous system (CNS) and implicated a critical role for this system in both normal and pathological processes. Astrocytes and microglia, normal components of the CNS, are the primary cell types that comprise the innate immune system of the CNS. Basic to their role during normal and adverse conditions is the production of neuroimmune factors such as cytokines and chemokines, which are signaling molecules that initiate or coordinate downstream cellular actions. During adverse conditions, cytokines and chemokines function in defensive and repair. However, if expression of these factors becomes dysregulated, abnormal CNS function can result. Both neurons and glial cells of the CNS express receptors for cytokines and chemokines, but the biological consequence of receptor activation has yet to be fully resolved. Our studies show that neuroadaptive changes are produced in primary cultures of rat cerebellar cells chronically treated with the cytokine interleukin-6 (IL-6) and in the cerebellum of transgenic mice that chronically express elevated levels of IL-6 in the CNS. In the cerebellum in culture and in vivo, the neuroadaptive changes included alterations in the level of expression of proteins involved in gene expression, signal transduction, and synaptic transmission. Associated with these changes were alterations in neuronal function. A comparison of results from the cultured cerebellar cells and cerebellum of the transgenic mice indicated that the effects of IL-6 can vary across neuronal types. However, alterations in mechanisms involved in Ca(2+) homeostasis were observed in all cell types studied. These results indicate that modifications in cerebellar function are likely to occur in disorders associated with elevated levels of IL-6 in the cerebellum.

Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development.

PubMed

Lise, Stefano; Clarkson, Yvonne; Perkins, Emma; Kwasniewska, Alexandra; Sadighi Akha, Elham; Schnekenberg, Ricardo Parolin; Suminaite, Daumante; Hope, Jilly; Baker, Ian; Gregory, Lorna; Green, Angie; Allan, Chris; Lamble, Sarah; Jayawant, Sandeep; Quaghebeur, Gerardine; Cader, M Zameel; Hughes, Sarah; Armstrong, Richard J E; Kanapin, Alexander; Rimmer, Andrew; Lunter, Gerton; Mathieson, Iain; Cazier, Jean-Baptiste; Buck, David; Taylor, Jenny C; Bentley, David; McVean, Gilean; Donnelly, Peter; Knight, Samantha J L; Jackson, Mandy; Ragoussis, Jiannis; Németh, Andrea H

2012-01-01

β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.

Cerebello-cortical heterotopia in dentate nucleus, and other microdysgeneses in trisomy D1 (Patau) syndrome.

PubMed

Hori, A; Peiffer, J; Pfeiffer, R A; Iizuka, R

1980-01-01

Several new histological findings in six cases of the trisomy D1 syndrome are described: hyperplasia of fetal structures (indusium griseum, median raphe of the medulla oblongata) and completely developed cerebellar cortical heterotopia in the dentate nucleus. In one case, a heterotopic pontine nucleus was found within the cerebellar white matter. The coexistence of overdeveloped and remaining fetal structures is emphasized. Several hypotheses regarding cerebellar dysgenesis are discussed.

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

PubMed Central

2012-01-01

Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma. PMID:22236771

[Presentation of Niemann-Pick type C disease with psychiatric disturbance in an adult].

PubMed

Tyvaert, L; Stojkovic, T; Cuisset, J-M; Vanier, M-T; Turpin, J-C; De Sèze, J; Vermersch, P

2005-03-01

Niemann-Pick Type C disease (NPC) is an autosomal recessive neurovisceral lysosomal lipid storage disorder. A 31-year-old right-handed woman had suffered from schizophrenia for 13 years. At 25 years of age, she developed a gait disorder with a static and kinetic cerebellar syndrome, dysarthria, vertical supranuclear gaze palsy and cognitive impairment. Brain MRI was normal. Abdominal ultrasonography was performed because of hypercholesterolemia and elevated transaminases and revealed hepatosplenomegaly, which in conjunction with other signs and symptoms, suggested the diagnosis of NPC. The diagnosis was confirmed by demonstration of lysosomal storage of unesterified cholesterol (filipin staining) and of a reduced rate of LDL-induced cholesterol esterification. Implication of the NPC1 gene was assessed by genetic complementation analysis. The phenotypic presentation of NPC is remarkably variable. The rarer adult-onset form has a slowly progressive course. Psychotic manifestations are often prominent and may precede neurologic symptoms. Exposure to neuroleptics delays the diagnosis of NPC. Psychotic manifestations associated with cerebellar syndrome, vertical supranuclear gaze palsy, and splenomegaly are very suggestive of NPC disease which can be reliably diagnosed on cultured skin fibroblasts by filipin staining.

Memory Consolidation within the Central Amygdala Is Not Necessary for Modulation of Cerebellar Learning

ERIC Educational Resources Information Center

Steinmetz, Adam B.; Ng, Ka H.; Freeman, John H.

2017-01-01

Amygdala lesions impair, but do not prevent, acquisition of cerebellum-dependent eyeblink conditioning suggesting that the amygdala modulates cerebellar learning. Two-factor theories of eyeblink conditioning posit that a fast-developing memory within the amygdala facilitates slower-developing memory within the cerebellum. The current study tested…

Cellular and genetic regulation of the development of the cerebellar system.

PubMed

Sotelo, Constantino

2004-04-01

Recent advances in molecular biology have drastically changed our vision on the development of the nervous system, the cerebellum in particular. After a classical descriptive period, we are now in a modern mechanistic epoch as we begin to answer crucial questions in our quest to understand the mechanisms underlying the emergence of brain complexity. This review begins with an analysis of the role of the "isthmic organizer" in the induction and specification of the cerebellar territory and progresses through cerebellar development to the formation of cerebellar maps. It gathers information about the control of the proliferation of granule cell precursors by Purkinje cells and the role of Shh/Gli-patched signaling. The migratory routes for cerebellar and precerebellar neurons, together with the long-range and short-range cues guiding gliophilic and, particularly, neurophilic migrations, are also discussed. Because these cues are similar to those involved in axon guidance, both processes are under the same molecular constraints. Finally, using primarily the olivocerebellar projection as a model, the cellular and molecular mechanisms involved in the formation of cerebellar maps are discussed. During embryonic development, Purkinje cells in the cerebellum and neurons in the inferior olive follow a simultaneous, but independent, process of intrinsic parcellation, giving rise to subsets of biochemically different cortical compartments. The occurrence of positional information shared between olivary axons and their postsynaptic targets, the Purkinje cells, provides a molecular code for the formation of coarse-grained maps. Activity-dependent mechanisms are required for the transition from crude to fine-grained maps. This important refinement, which confers ultimate specificity to the maps, is under the regulation of parallel fiber-Purkinje cell synaptic activity.

Fucosidosis in a domestic shorthair cat.

PubMed

Arrol, Lorna P; Kerrins, Annette M; Yamakawa, Yoshika; Smith, Peter M

2011-02-01

This paper documents the first reported case of fucosidosis in a cat. The cat presented with signs of forebrain and cerebellar dysfunction and a magnetic resonance imaging scan of the brain suggested a degenerative or metabolic disease process. A fine needle aspirate of grossly normal lymph nodes revealed vacuolated lymphocytes and a renal biopsy of an irregular shaped kidney identified vacuolated tubular epithelial cells. A white cell lysosomal enzyme screen revealed negligible α-fucosidase activity. Fucosidosis should be considered in the differential diagnosis of young cats with cerebellar dysfunction and must be added to the list of lysosomal storage diseases affecting the cat. Copyright © 2010 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

Abnormal cerebellar morphometry in abstinent adolescent marijuana users

PubMed Central

Medina, Krista Lisdahl; Nagel, Bonnie J.; Tapert, Susan F.

2010-01-01

Background Functional neuroimaging data from adults have, in general, found frontocerebellar dysfunction associated with acute and chronic marijuana (MJ) use (Loeber & Yurgelun-Todd, 1999). One structural neuroimaging study found reduced cerebellar vermis volume in young adult MJ users with a history of heavy polysubstance use (Aasly et al., 1993). The goal of this study was to characterize cerebellar volume in adolescent chronic MJ users following one month of monitored abstinence. Method Participants were MJ users (n=16) and controls (n=16) aged 16-18 years. Extensive exclusionary criteria included history of psychiatric or neurologic disorders. Drug use history, neuropsychological data, and structural brain scans were collected after 28 days of monitored abstinence. Trained research staff defined cerebellar volumes (including three cerebellar vermis lobes and both cerebellar hemispheres) on high-resolution T1-weighted magnetic resonance images. Results Adolescent MJ users demonstrated significantly larger inferior posterior (lobules VIII-X) vermis volume (p<.009) than controls, above and beyond effects of lifetime alcohol and other drug use, gender, and intracranial volume. Larger vermis volumes were associated with poorer executive functioning (p’s<.05). Conclusions Following one month of abstinence, adolescent MJ users had significantly larger posterior cerebellar vermis volumes than non-using controls. These greater volumes are suggested to be pathological based on linkage to poorer executive functioning. Longitudinal studies are needed to examine typical cerebellar development during adolescence and the influence of marijuana use. PMID:20413277

Development of motor coordination and cerebellar structure in male and female rat neonates exposed to hypergravity

NASA Astrophysics Data System (ADS)

Nguon, K.; Ladd, B.; Baxter, M. G.; Sajdel-Sulkowska, E. M.

2006-01-01

We previously reported that the developing rat cerebellum is affected by exposure to hypergravity. In the present study, we explored the hypothesis that the changes in cerebellar structure in hypergravity-exposed rat neonates may affect their motor coordination. Furthermore, we hypothesized that the changes observed at 1.5G will be magnified at higher gravitational loading. To test this hypothesis, we compared motor behavior, cerebellar structure, and protein expression in rat neonates exposed to 1.5 1.75G on a 24-ft centrifuge daily for 22.5 h starting on gestational day (G) 10, through birth on G22/G23 and through postnatal day (P) 21. Exposure to hypergravity impacted the neurodevelopmental process as indicated by: (1) impaired righting response on P3, more than doubling the righting time at 1.75G, and (2) delayed onset of the startle response by one day, from P9 in controls to P10 in hypergravity-exposed pups. Hypergravity exposure resulted in impaired motor functions as evidenced by performance on a rotarod on P21; the duration of the stay on the rotarod recorded for 1.75G pups of both sexes was one tenth that of the stationary control (SC) pups. These changes in motor behavior were associated with cerebellar changes: (1) cerebellar mass on P6 was decreased by 7.5% in 1.5G-exposed male pups, 27.5% in 1.75G-exposed male pups, 17.5% in 1.5G-exposed female pups, and 22.5% in 1.75G female pups and (2) changes in the expression of glial and neuronal proteins. The results of this study suggest that perinatal exposure to hypergravity affects cerebellar development as evidenced by decreased cerebellar mass and altered cerebellar protein expression; cerebellar changes observed in hypergravity-exposed rat neonates are associated with impaired motor behavior. Furthermore, the response to hypergravity appears to be different in male and female neonates. If one accepts that the hypergravity paradigm is a useful animal model with which to predict those biological processes in the CNS affected by microgravity, and because males and females were shown to respond differently to hypergravity, it can be surmised that males and females may respond differently to the microgravity encountered in space.

Genome sequencing reveals a splice donor site mutation in the SNX14 gene associated with a novel cerebellar cortical degeneration in the Hungarian Vizsla dog breed.

PubMed

Fenn, Joe; Boursnell, Mike; Hitti, Rebekkah J; Jenkins, Christopher A; Terry, Rebecca L; Priestnall, Simon L; Kenny, Patrick J; Mellersh, Cathryn S; Forman, Oliver P

2016-08-26

Cerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many dog breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several breeds, allowing screening for selective breeding to reduce the prevalence of these conditions. There have been no previous reports of CCD in Hungarian Vizslas. Two full-sibling Hungarian Vizsla puppies from a litter of nine presented with a history of progressive ataxia, starting around three months of age. Clinical signs included marked hypermetric and dysmetric ataxia, truncal sway, intention tremors and absent menace responses, with positional horizontal nystagmus in one dog. Routine diagnostic investigations were unremarkable, and magnetic resonance imaging performed in one dog revealed mild craniodorsal cerebellar sulci widening, supportive of cerebellar atrophy. Owners of both dogs elected for euthanasia shortly after the onset of signs. Histopathological examination revealed primary Purkinje neuron loss consistent with CCD. Whole genome sequencing was used to successfully identify a disease-associated splice donor site variant in the sorting nexin 14 gene (SNX14) as a strong causative candidate. An altered SNX14 splicing pattern for a CCD case was demonstrated by RNA analysis, and no SNX14 protein could be detected in CCD case cerebellum by western blotting. SNX14 is involved in maintaining normal neuronal excitability and synaptic transmission, and a mutation has recently been found to cause autosomal recessive cerebellar ataxia and intellectual disability syndrome in humans. Genetic screening of 133 unaffected Hungarian Vizslas revealed the presence of three heterozygotes, supporting the presence of carriers in the wider population. This is the first report of CCD in Hungarian Vizsla dogs and identifies a highly associated splice donor site mutation in SNX14, with an autosomal recessive mode of inheritance suspected.

Effective reinforcement learning following cerebellar damage requires a balance between exploration and motor noise.

PubMed

Therrien, Amanda S; Wolpert, Daniel M; Bastian, Amy J

2016-01-01

Reinforcement and error-based processes are essential for motor learning, with the cerebellum thought to be required only for the error-based mechanism. Here we examined learning and retention of a reaching skill under both processes. Control subjects learned similarly from reinforcement and error-based feedback, but showed much better retention under reinforcement. To apply reinforcement to cerebellar patients, we developed a closed-loop reinforcement schedule in which task difficulty was controlled based on recent performance. This schedule produced substantial learning in cerebellar patients and controls. Cerebellar patients varied in their learning under reinforcement but fully retained what was learned. In contrast, they showed complete lack of retention in error-based learning. We developed a mechanistic model of the reinforcement task and found that learning depended on a balance between exploration variability and motor noise. While the cerebellar and control groups had similar exploration variability, the patients had greater motor noise and hence learned less. Our results suggest that cerebellar damage indirectly impairs reinforcement learning by increasing motor noise, but does not interfere with the reinforcement mechanism itself. Therefore, reinforcement can be used to learn and retain novel skills, but optimal reinforcement learning requires a balance between exploration variability and motor noise. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

Effective reinforcement learning following cerebellar damage requires a balance between exploration and motor noise

PubMed Central

Therrien, Amanda S.; Wolpert, Daniel M.

2016-01-01

Abstract See Miall and Galea (doi: 10.1093/awv343 ) for a scientific commentary on this article. Reinforcement and error-based processes are essential for motor learning, with the cerebellum thought to be required only for the error-based mechanism. Here we examined learning and retention of a reaching skill under both processes. Control subjects learned similarly from reinforcement and error-based feedback, but showed much better retention under reinforcement. To apply reinforcement to cerebellar patients, we developed a closed-loop reinforcement schedule in which task difficulty was controlled based on recent performance. This schedule produced substantial learning in cerebellar patients and controls. Cerebellar patients varied in their learning under reinforcement but fully retained what was learned. In contrast, they showed complete lack of retention in error-based learning. We developed a mechanistic model of the reinforcement task and found that learning depended on a balance between exploration variability and motor noise. While the cerebellar and control groups had similar exploration variability, the patients had greater motor noise and hence learned less. Our results suggest that cerebellar damage indirectly impairs reinforcement learning by increasing motor noise, but does not interfere with the reinforcement mechanism itself. Therefore, reinforcement can be used to learn and retain novel skills, but optimal reinforcement learning requires a balance between exploration variability and motor noise. PMID:26626368

Altered microstructural connectivity of the superior cerebellar peduncle is related to motor dysfunction in children with autistic spectrum disorders.

PubMed

Hanaie, Ryuzo; Mohri, Ikuko; Kagitani-Shimono, Kuriko; Tachibana, Masaya; Azuma, Junji; Matsuzaki, Junko; Watanabe, Yoshiyuki; Fujita, Norihiko; Taniike, Masako

2013-10-01

Many studies have reported motor impairments in autistic spectrum disorders (ASD). However, the brain mechanism underlying motor impairment in ASD remains unclear. Recent neuroimaging studies have suggested that underconnectivity between the cerebellum and other brain regions contributes to the features of ASD. In this study, we investigated the microstructural integrity of the cerebellar pathways, including the superior, middle, and inferior cerebellar peduncles, of children with and without ASD by using diffusion tensor imaging (DTI) tractography to determine whether the microstructural integrity of the cerebellar pathways is related to motor function in children with ASD. Thirteen children with ASD and 11 age-, gender-, handedness-, and IQ-matched typically developing (TD) controls were enrolled in this study. DTI outcome measurements, such as fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), for the cerebellar pathways were calculated. The Movement Assessment Battery for Children 2 (M-ABC 2) was used for assessing motor functions. There were no significant differences between the two groups in RD. However, compared to the TD subjects, patients with ASD had a significantly lower FA in the right superior cerebellar peduncle and lower AD in the left superior cerebellar peduncle, in addition to a significantly lower score in ball skills and the total test score of M-ABC 2. There was a significant positive correlation between the total test score of M-ABC 2 and FA in the right superior cerebellar peduncle in the ASD group. These findings suggest that the altered microstructural integrity of the superior cerebellar peduncle may be related to motor impairment in ASD.

The Cerebellar-Cerebral Microstructure Is Disrupted at Multiple Sites in Very Preterm Infants with Cerebellar Haemorrhage.

PubMed

Neubauer, Vera; Djurdjevic, Tanja; Griesmaier, Elke; Biermayr, Marlene; Gizewski, Elke Ruth; Kiechl-Kohlendorfer, Ursula

2018-01-01

Recent advances in magnetic resonance imaging (MRI) techniques have prompted reconsideration of the anatomical correlates of adverse outcomes in preterm infants. The importance of the contribution made by the cerebellum is now increasingly appreciated. The effect of cerebellar haemorrhage (CBH) on the microstructure of the cerebellar-cerebral circuit is largely unexplored. To investigate the effect of CBH on the microstructure of cerebellar-cerebral connections in preterm infants aged <32 gestational weeks. Infants underwent diffusion tensor MRI at term-equivalent age. MRI was evaluated for CBH and additional supratentorial brain injury using a validated scoring system. Region of interest-based measures of brain microstructure (fractional anisotropy [FA] and apparent diffusion coefficient) were quantified in 5 vulnerable regions (the centrum semiovale, posterior limb of the internal capsule, corpus callosum, and superior and middle cerebellar peduncles). Group differences between infants with CBH and infants without CBH were assessed. There were 267 infants included in the study. Infants with CBH (isolated and combined) had significantly lower FA values in all regions investigated. Infants with isolated CBH showed lower FA in the middle and superior cerebellar peduncles and in the posterior limb of the internal capsule. This study provides evidence that CBH causes alterations in localised and remote WM pathways in the developing brain. The disruption of the cerebellar-cerebral microstructure at multiple sites adds further support for the concept of developmental diaschisis, which is propagated as an explanation for the consequences of early cerebellar injury on cognitive and affective domains. © 2017 S. Karger AG, Basel.

Infarcts presenting with a combination of medial medullary and posterior inferior cerebellar artery syndromes.

PubMed

Lee, Hyung; Baik, Seung Kug

2004-09-15

Cerebellar and medial medullary infarctions are well-known vertebrobasilar stroke syndromes. However, their development in a patient with distal vertebral artery occlusion has not been previously reported. A 49-year-old man with longstanding hypertension suddenly developed vertigo, right-sided Horner syndrome, and left-sided weakness. An MRI of the brain showed acute infarcts in the right inferior cerebellum (posterior inferior cerebellar artery territory) and the right upper medial medulla (direct penetrating branches of vertebral artery). Magnetic resonance angiogram showed occlusion of the distal vertebral artery on the right side. Atherothrombotic occlusion of the distal vertebral artery may cause this unusual combination of vertebrobasilar stroke.

The Role of BRCA1 in Normal Mammary Epithelial Development and Tumorigenesis.

DTIC Science & Technology

1999-06-01

addition, a hemangiosarcoma was found in one of the Brcal’’~p53~’~ mice. Cell lines were generated from each of these tumors. Generation and...19 10 45.2 23.8 2/9 0/5 Hemangiosarcoma Cerebellar developmental defect Adenocarcinoma of the Hardarian gland 3 2 1 5.9 3.9 2.0 2 4.8...17.4 0/2 Hemangiosarcoma 2 8.7 Squamous cell carcinoma 1 4.3 Benign spindle cell tumor 1 4.3 No visible or metastatic tumors at death 3 15.8 3 13.0

Purkinje Cell Compartmentation in the Cerebellum of the Lysosomal Acid Phosphatase 2 Mutant Mouse (Nax - Naked-Ataxia Mutant Mouse)

PubMed Central

Bailey, Karen; Rahimi Balaei, Maryam; Mannan, Ashraf; Del Bigio, Marc R.; Marzban, Hassan

2014-01-01

The Acp2 gene encodes the beta subunit of lysosomal acid phosphatase, which is an isoenzyme that hydrolyzes orthophosphoric monoesters. In mice, a spontaneous mutation in Acp2 results in severe cerebellar defects. These include a reduced size, abnormal lobulation, and an apparent anterior cerebellar disorder with an absent or hypoplastic vermis. Based on differential gene expression in the cerebellum, the mouse cerebellar cortex can normally be compartmentalized anteroposteriorly into four transverse zones and mediolaterally into parasagittal stripes. In this study, immunohistochemistry was performed using various Purkinje cell compartmentation markers to examine their expression patterns in the Acp2 mutant. Despite the abnormal lobulation and anterior cerebellar defects, zebrin II and PLCβ4 showed similar expression patterns in the nax mutant and wild type cerebellum. However, fewer stripes were found in the anterior zone of the nax mutant, which could be due to a lack of Purkinje cells or altered expression of the stripe markers. HSP25 expression was uniform in the central zone of the nax mutant cerebellum at around postnatal day (P) 18–19, suggesting that HSP25 immunonegative Purkinje cells are absent or delayed in stripe pattern expression compared to the wild type. HSP25 expression became heterogeneous around P22–23, with twice the number of parasagittal stripes in the nax mutant compared to the wild type. Aside from reduced size and cortical disorganization, both the posterior zone and nodular zone in the nax mutant appeared less abnormal than the rest of the cerebellum. From these results, it is evident that the anterior zone of the nax mutant cerebellum is the most severely affected, and this extends beyond the primary fissure into the rostral central zone/vermis. This suggests that ACP2 has critical roles in the development of the anterior cerebellum and it may regulate anterior and central zone compartmentation. PMID:24722417

Quantitative evaluation of human cerebellum-dependent motor learning through prism adaptation of hand-reaching movement.

PubMed

Hashimoto, Yuji; Honda, Takeru; Matsumura, Ken; Nakao, Makoto; Soga, Kazumasa; Katano, Kazuhiko; Yokota, Takanori; Mizusawa, Hidehiro; Nagao, Soichi; Ishikawa, Kinya

2015-01-01

The cerebellum plays important roles in motor coordination and learning. However, motor learning has not been quantitatively evaluated clinically. It thus remains unclear how motor learning is influenced by cerebellar diseases or aging, and is related with incoordination. Here, we present a new application for testing human cerebellum-dependent motor learning using prism adaptation. In our paradigm, the participant wearing prism-equipped goggles touches their index finger to the target presented on a touchscreen in every trial. The whole test consisted of three consecutive sessions: (1) 50 trials with normal vision (BASELINE), (2) 100 trials wearing the prism that shifts the visual field 25° rightward (PRISM), and (3) 50 trials without the prism (REMOVAL). In healthy subjects, the prism-induced finger-touch error, i.e., the distance between touch and target positions, was decreased gradually by motor learning through repetition of trials. We found that such motor learning could be quantified using the "adaptability index (AI)", which was calculated by multiplying each probability of [acquisition in the last 10 trials of PRISM], [retention in the initial five trials of REMOVAL], and [extinction in the last 10 trials of REMOVAL]. The AI of cerebellar patients less than 70 years old (mean, 0.227; n = 62) was lower than that of age-matched healthy subjects (0.867, n = 21; p < 0.0001). While AI did not correlate with the magnitude of dysmetria in ataxic patients, it declined in parallel with disease progression, suggesting a close correlation between the impaired cerebellar motor leaning and the dysmetria. Furthermore, AI decreased with aging in the healthy subjects over 70 years old compared with that in the healthy subjects less than 70 years old. We suggest that our paradigm of prism adaptation may allow us to quantitatively assess cerebellar motor learning in both normal and diseased conditions.

Quantitative Evaluation of Human Cerebellum-Dependent Motor Learning through Prism Adaptation of Hand-Reaching Movement

PubMed Central

Hashimoto, Yuji; Honda, Takeru; Matsumura, Ken; Nakao, Makoto; Soga, Kazumasa; Katano, Kazuhiko; Yokota, Takanori; Mizusawa, Hidehiro; Nagao, Soichi; Ishikawa, Kinya

2015-01-01

The cerebellum plays important roles in motor coordination and learning. However, motor learning has not been quantitatively evaluated clinically. It thus remains unclear how motor learning is influenced by cerebellar diseases or aging, and is related with incoordination. Here, we present a new application for testing human cerebellum-dependent motor learning using prism adaptation. In our paradigm, the participant wearing prism-equipped goggles touches their index finger to the target presented on a touchscreen in every trial. The whole test consisted of three consecutive sessions: (1) 50 trials with normal vision (BASELINE), (2) 100 trials wearing the prism that shifts the visual field 25° rightward (PRISM), and (3) 50 trials without the prism (REMOVAL). In healthy subjects, the prism-induced finger-touch error, i.e., the distance between touch and target positions, was decreased gradually by motor learning through repetition of trials. We found that such motor learning could be quantified using the “adaptability index (AI)”, which was calculated by multiplying each probability of [acquisition in the last 10 trials of PRISM], [retention in the initial five trials of REMOVAL], and [extinction in the last 10 trials of REMOVAL]. The AI of cerebellar patients less than 70 years old (mean, 0.227; n = 62) was lower than that of age-matched healthy subjects (0.867, n = 21; p < 0.0001). While AI did not correlate with the magnitude of dysmetria in ataxic patients, it declined in parallel with disease progression, suggesting a close correlation between the impaired cerebellar motor leaning and the dysmetria. Furthermore, AI decreased with aging in the healthy subjects over 70 years old compared with that in the healthy subjects less than 70 years old. We suggest that our paradigm of prism adaptation may allow us to quantitatively assess cerebellar motor learning in both normal and diseased conditions. PMID:25785588

Cerebellar Volume in Children With Attention-Deficit Hyperactivity Disorder (ADHD).

PubMed

Wyciszkiewicz, Aleksandra; Pawlak, Mikolaj A; Krawiec, Krzysztof

2017-02-01

Attention Deficit Hyperactivity Disorder (ADHD) is associated with altered cerebellar volume and cerebellum is associated with cognitive performance. However there are mixed results regarding the cerebellar volume in young patients with ADHD. To clarify the size and direction of this effect, we conducted the analysis on the large public database of brain images. The aim of this study was to confirm that cerebellar volume in ADHD is smaller than in control subjects in currently the largest publicly available cohort of ADHD subjects.We applied cross-sectional case control study design by comparing 286 ADHD patients (61 female) with age and gender matched control subjects. Volumetric measurements of cerebellum were obtained using automated segmentation with FreeSurfer 5.1. Statistical analysis was performed in R-CRAN statistical environment. Patients with ADHD had significantly smaller total cerebellar volumes (134.5±17.11cm 3 vs.138.90±15.32 cm 3 ). The effect was present in both females and males (males 136.9±14.37 cm 3 vs. 141.20±14.75 cm 3 ; females 125.7±12.34 cm 3 vs. 131.20±15.03 cm 3 ). Age was positively and significantly associated with the cerebellar volumes. These results indicate either delayed or disrupted cerebellar development possibly contributing to ADHD pathophysiology.

Ultastructural analysis on acetylcholinesterase localization in the cerebellar cortex of teleosts.

PubMed

Contestabile, A; Villani, L; Ciani, F

1977-12-28

The histochemical localization of acetylcholinesterase (AChE) was studied by electron microscopy in the cerebellar cortex of the goldfish and the catfish. The patterns of enzyme distribution show noticeable differences in the two teleost species at the level of the corresponding cerebellar structures. Among the most distinctive features is the prevailing intracellular localization of enzyme activity in the goldfish and the prevailing extracellular localization in the catfish in the molecular layer and, to a lesser extent, the granular layer. Only quantitative differences in the ability to synthesize AChE can be recorded among the different cerebellar neurons in the two species, since all these neurons exhibit different amounts of enzyme activity linked to their cytoplasmic structures. Comparing the results obtained with those of previous histochemical, experimental and developmental researches, the hypothesis seems well founded that the embryonic pool of cerebellar neurons is made up of AChE-synthesizing nruroblasts which, during development, loss or maintain to a different the mechanisms for AChE synthesis. In addition the light and electron microscope histochemistry reveals at different levels of resolution that the final pattern of AChE distribution in the cerebellar cortex is the sum of different degress of AChE synthesis by cerebellar neurons and different degrees of enzyme release in extracellular spaces.

Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis.

PubMed

Martí, Joaquín; Santa-Cruz, María C; Hervás, José P; Bayer, Shirley A; Villegas, Sandra

2016-01-01

Ataxias are neurological disorders associated with the degeneration of Purkinje cells (PCs). Homozygous weaver mice (wv/wv) have been proposed as a model for hereditary cerebellar ataxia because they present motor abnormalities and PC loss. To ascertain the physiopathology of the weaver condition, the development of the cerebellar cortex lobes was examined at postnatal day (P): P8, P20 and P90. Three approaches were used: 1) quantitative determination of several cerebellar features; 2) qualitative evaluation of the developmental changes occurring in the cortical lobes; and 3) autoradiographic analyses of PC generation and placement. Our results revealed a reduction in the size of the wv/wv cerebellum as a whole, confirming previous results. However, as distinguished from these reports, we observed that quantified parameters contribute differently to the abnormal growth of the wv/wv cerebellar lobes. Qualitative analysis showed anomalies in wv/wv cerebellar cytoarchitecture, depending on the age and lobe analyzed. Such abnormalities included the presence of the external granular layer after P20 and, at P90, ectopic cells located in the molecular layer following several placement patterns. Finally, we obtained autoradiographic evidence that wild-type and wv/wv PCs presented similar neurogenetic timetables, as reported. However, the innovative character of this current work lies in the fact that the neurogenetic gradients of wv/wv PCs were not modified from P8 to P90. A tendency for the accumulation of late-formed PCs in the anterior and posterior lobes was found, whereas early-generated PCs were concentrated in the central and inferior lobes. These data suggested that wv/wv PCs may migrate properly to their final destinations. The extrapolation of our results to patients affected with cerebellar ataxias suggests that all cerebellar cortex lobes are affected with several age-dependent alterations in cytoarchitectonics. We also propose that PC loss may be regionally variable and not related to their neurogenetic timetables.

Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts, unlinked to the LAMA2, FCMD, MEB and CMD1B loci, in three Tunisian patients.

PubMed

Triki, Chahnez; Louhichi, Nacim; Méziou, Mériam; Choyakh, Fakher; Kéchaou, Mohamed Salah; Jlidi, Rachid; Mhiri, Chokri; Fakhfakh, Faiza; Ayadi, Hamadi

2003-01-01

We report three Tunisian patients affected by congenital muscular dystrophy with mental retardation and cerebellar cysts on cranial magnetic resonance imaging. The clinical features were characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absence of speech, inability to walk in three patients, but calf hypertrophy was noted only in two patients. Brain magnetic resonance imaging showed several cerebellar cysts and vermis hypoplasia in all of the patients. Abnormality of the white matter was present in two patients. The pattern of gyration was normal in all cases. Serum creatine kinase was elevated in all three cases and their muscle biopsy showed dystrophic changes compatible with congenital muscular dystrophy. The immunohistochemical analysis of the skeletal muscle revealed partial merosin deficiency, more pronounced for the N-terminal antibody. Linkage analysis excluded congenital muscular dystrophy loci on chromosomes 6q22, 9q31, 1p32 and 1q42. These patients constituted a particular form of congenital muscular dystrophy with a combination of severe motor delay, mental retardation, partial merosin deficiency and cerebellar cysts. Two patients showed white matter abnormalities on magnetic resonance imaging and hypertrophy of the calves. These cases, in addition to those reported previously, confirmed the large phenotypic variability in the group of secondary merosin deficiency congenital muscular dystrophy.

Dengue fever presenting with acute cerebellitis: a case report.

PubMed

Withana, Milinda; Rodrigo, Chaturaka; Chang, Thashi; Karunanayake, Panduka; Rajapakse, Senaka

2014-03-05

The incidence of dengue fever is on the rise in tropical countries. In Sri Lanka, nearly 45,000 patients were reported in 2012. With the increasing numbers, rare manifestations of dengue are occasionally encountered. We report a patient who presented with bilateral cerebellar signs as the presenting feature of dengue. A 45-year-old previously healthy female from the suburbs of Colombo, Sri Lanka presented with an acute febrile illness associated with unsteadiness of gait. Clinical examination revealed a scanning dysarthria and marked horizontal nystagmus with bilateral dysmetria, dysdiadokokinesia and incordination more prominent on the right. Her gait was wide-based and ataxic with a tendency to fall to the right more than to the left. Dengue nonstructural protein antigen 1 test and IgM antibody testing both became positive indicating acute dengue infection. She recovered from the febrile episode within 9 days since the onset of fever but cerebellar symptoms outlasted the fever by one week. The magnetic resonance imaging of brain was normal and cerebellar signs resolved spontaneously by day 17 of the illness. Cerebellar syndrome in association with dengue fever has been reported in only four instances and our patient is the first reported case of dengue fever presenting with cerebellitis as the first manifestation of disease. This case report is intended to highlight the occurrence of acute cerebellitis as a presenting syndrome of the expanding list of unusual neurological manifestations of dengue infection.

Memory consolidation within the central amygdala is not necessary for modulation of cerebellar learning.

PubMed

Steinmetz, Adam B; Ng, Ka H; Freeman, John H

2017-06-01

Amygdala lesions impair, but do not prevent, acquisition of cerebellum-dependent eyeblink conditioning suggesting that the amygdala modulates cerebellar learning. Two-factor theories of eyeblink conditioning posit that a fast-developing memory within the amygdala facilitates slower-developing memory within the cerebellum. The current study tested this hypothesis by impairing memory consolidation within the amygdala with inhibition of protein synthesis, transcription, and NMDA receptors in rats. Rats given infusions of anisomycin or DRB into the central amygdala (CeA) immediately after each eyeblink conditioning session were severely impaired in contextual and cued fear conditioning, but were completely unimpaired in eyeblink conditioning. Rats given the NMDA antagonist ifenprodil into the CeA before each eyeblink conditioning session also showed impaired fear conditioning, but no deficit in eyeblink conditioning. The results indicate that memory formation within the CeA is not necessary for its modulation of cerebellar learning mechanisms. The CeA may modulate cerebellar learning and retention through an attentional mechanism that develops within the training sessions. © 2017 Steinmetz et al.; Published by Cold Spring Harbor Laboratory Press.

Cerebellar malformations alter regional cerebral development.

PubMed

Bolduc, Marie-Eve; Du Plessis, Adre J; Evans, Alan; Guizard, Nicolas; Zhang, Xun; Robertson, Richard L; Limperopoulos, Catherine

2011-12-01

The aim of this study was to compare total and regional cerebral volumes in children with isolated cerebellar malformations (CBMs) with those in typically developing children, and to examine the extent to which cerebellar volumetric reductions are associated with total and regional cerebral volumes. This is a case-control study of children diagnosed with isolated CBMs. Each child was matched on age and sex to two typically developing children. Using advanced three-dimensional volumetric magnetic resonance imaging, the cerebrum was segmented into tissue classes and partitioned into eight regions. Analysis of variance was used to compare cerebral volumes between children with CBMs and control children, and linear regressions to examine the impact of cerebellar volume reduction on cerebral volumes. Magnetic resonance imaging was performed at a mean age of 27 months in 20 children (10 males, 10 females) with CBMs and 40 typically developing children. Children with CBMs showed significantly smaller deep grey matter nuclei (p < 0.001), subgenual white matter (p = 0.03), midtemporal white matter (p = 0.02), and inferior occipital grey matter (p = 0.03) volumes than typically developing children. Greater cerebellar volumetric reduction in children with CBMs was associated with decreased total cerebral volume and deep grey matter nuclei (p = 0.02), subgenual white/grey matter (p = 0.001), midtemporal white (p = 0.02) and grey matter (p = 0.01), and parieto-occipital grey matter (p = 0.004). CBMs are associated with impaired regional cerebral growth, suggesting deactivation of principal cerebello-cerebral pathways. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

Procaspase-activating compound 1 induces a caspase-3-dependent cell death in cerebellar granule neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aziz, Gulzeb; Akselsen, Oyvind W.; Hansen, Trond V.

2010-09-15

Procaspase-activating compound 1, PAC-1, has been introduced as a direct activator of procaspase-3 and has been suggested as a therapeutic agent against cancer. Its activation of procaspase-3 is dependent on the chelation of zinc. We have tested PAC-1 and an analogue of PAC-1 as zinc chelators in vitro as well as their ability to activate caspase-3 and induce cell death in chicken cerebellar granule neuron cultures. These neurons are non-dividing, primary cells with normal caspase-3. The results reported herein show that PAC-1 chelates zinc, activates procaspase-3, and leads to caspase-3-dependent cell death in neurons, as the specific caspase-3-inhibitor Ac-DEVD-cmk inhibitedmore » both the caspase-3 activity and cell death. Thus, chicken cerebellar granule neurons is a suitable model to study mechanisms of interference with apoptosis of PAC-1 and similar compounds. Furthermore, the present study also raises concern about potential neurotoxicity of PAC-1 if used in cancer therapy.« less

Network-targeted cerebellar transcranial magnetic stimulation improves attentional control

PubMed Central

Esterman, Michael; Thai, Michelle; Okabe, Hidefusa; DeGutis, Joseph; Saad, Elyana; Laganiere, Simon E.; Halko, Mark A.

2018-01-01

Developing non-invasive brain stimulation interventions to improve attentional control is extremely relevant to a variety of neurologic and psychiatric populations, yet few studies have identified reliable biomarkers that can be readily modified to improve attentional control. One potential biomarker of attention is functional connectivity in the core cortical network supporting attention - the dorsal attention network (DAN). We used a network-targeted cerebellar transcranial magnetic stimulation (TMS) procedure, intended to enhance cortical functional connectivity in the DAN. Specifically, in healthy young adults we administered intermittent theta burst TMS (iTBS) to the midline cerebellar node of the DAN and, as a control, the right cerebellar node of the default mode network (DMN). These cerebellar targets were localized using individual resting-state fMRI scans. Participants completed assessments of both sustained (gradual onset continuous performance task, gradCPT) and transient attentional control (attentional blink) immediately before and after stimulation, in two sessions (cerebellar DAN and DMN). Following cerebellar DAN stimulation, participants had significantly fewer attentional lapses (lower commission error rates) on the gradCPT. In contrast, stimulation to the cerebellar DMN did not affect gradCPT performance. Further, in the DAN condition, individuals with worse baseline gradCPT performance showed the greatest enhancement in gradCPT performance. These results suggest that temporarily increasing functional connectivity in the DAN via network-targeted cerebellar stimulation can enhance sustained attention, particularly in those with poor baseline performance. With regard to transient attention, TMS stimulation improved attentional blink performance across both stimulation sites, suggesting increasing functional connectivity in both networks can enhance this aspect of attention. These findings have important implications for intervention applications of TMS and theoretical models of functional connectivity. PMID:28495634

Magnetic resonance imaging and brainstem auditory evoked responses in the diagnosis of cerebellar cortical degeneration in american staffordshire terriers.

PubMed

Kwiatkowska, Miłosława; Pomianowski, Andrzej; Adamiak, Zbigniew; Bocheńska, Aneta

2013-03-01

The aim of the study was to determine the diagnostic usefulness of magnetic resonance imaging (MRI) and brainstem auditory evoked responses (BAER) in dogs suspected of having cerebellar cortical degeneration (CCD). In the years 2009-2011, six dogs with suspected CCD were examined. Both MRI and BAER examinations revealed abnormalities in all dogs (100%). By MRI, T2-weighted midsagittal images revealed an increased amount of cerebrospinal fluid (CSF) surrounding the cerebellum within the sulci of the folia in all dogs (100%). In 4 out of the 6 dogs (66.66%), cerebellar hypoplasia was more visible in the region of the dorsal cerebellar lobules. In 5 out of the 6 dogs (83.33%), the fourth ventricle was enlarged. In our studies, the brain to cerebellum ratio evaluated on the midsagittal image was 11.93%, in comparison to 14.9% in normal dogs. By BAER examination, the amplitude of the first and second waves was diminished and III-V interlatency was prolonged in 5 out of the 6 dogs (83.33%). In one out of the 6 dogs (16.67%), only the III-V interlatency was prolonged. In one dog (16.67%), somato-nervous deafness in the left ear was detected, whereas in the right ear the III-V interlatency was prolonged. MRI of the cerebellum is a reliable method for the antemortem diagnosis of CCD in American Staffordshire terriers, as is BAER examination. BAER is an objective diagnostic tool, which - along with other diagnostic modalities - can be helpful in the assessment, management and follow-up of dogs with cerebellar abiotrophy. It proved to be useful in determining the severity of neurological lesions in comparison to MRI findings, as well as in assessing the prognosis.

Moringa oleifera phytochemicals protect the brain against experimental nicotine-induced neurobehavioral disturbances and cerebellar degeneration.

PubMed

Omotoso, Gabriel Olaiya; Gbadamosi, Ismail Temitayo; Olajide, Olayemi Joseph; Dada-Habeeb, Shakirat Opeyemi; Arogundade, Tolulope Timothy; Yawson, Emmanuel Olusola

2018-03-01

Nicotine is a neuro-stimulant that has been implicated in the pathophysiology of many brain diseases. The need to prevent or alleviate the resulting dysfunction is therefore paramount, which has also given way to the use of medicinal plants in the management of brain conditions. This study was designed to determine the histomorphological and neurobehavioural changes in the cerebellum of Wistar rats following nicotine insult and how such injuries respond to Moringa intervention. Twenty-four adult male Wistar rats were divided into 4 groups. Group A and B were orally treated with normal saline and Moringa oleifera respectively for twenty-eight days; Group C was treated with nicotine while group D was treated orally with Moringa oleifera and intraperitoneally with nicotine for twenty-eight days. Animals were subjected to the open field test on the last day of treatment. 24 h after last day treatment, the animals were anesthetized and perfusion fixation was carried out. The cerebellum was excised and post-fixed in 4% paraformaldehyde and thereafter put through routine histological procedures. Results revealed cytoarchitectural distortion and extreme chromatolysis in neuronal cells of the cerebellar cortical layers in the nicotine-treated group. The Purkinje cells of the cerebellum of animals in this group were degenerated. There were also reduced locomotor activities in the group. Moringa was able to prevent the chromatolysis, distortion of the cerebellar cortical cells and neurobehavioural deficit. Our result suggests that Moringa oleifera could prevent nicotine-induced cerebellar injury in Wistar rats, with the possibility of ameliorating the clinical features presented in associated cerebellar pathology. Copyright © 2018 Elsevier B.V. All rights reserved.

The Cellular State Determines the Effect of Melatonin on the Survival of Mixed Cerebellar Cell Culture

PubMed Central

Franco, Daiane Gil; Markus, Regina P.

2014-01-01

The constitutive activation of nuclear factor-κB (NF-κB), a key transcription factor involved in neuroinflammation, is essential for the survival of neurons in situ and of cerebellar granule cells in culture. Melatonin is known to inhibit the activation of NF-κB and has a cytoprotective function. In this study, we evaluated whether the cytoprotective effect of melatonin depends on the state of activation of a mixed cerebellar culture that is composed predominantly of granule cells; we tested the effect of melatonin on cultured rat cerebellar cells stimulated or not with lipopolysaccharide (LPS). The addition of melatonin (0.1 nM–1 µM) reduced the survival of naïve cells while inhibiting LPS-induced cell death. Melatonin (100 nM) transiently (15 min) inhibited the nuclear translocation of both NF-κB dimers (p50/p50, p50/RelA) and, after 60 min, increased the activation of p50/RelA. Melatonin-induced p50/RelA activity in naïve cells resulted in the transcription of inducible nitric oxide synthase (iNOS) and the production of NO. Otherwise, in cultures treated with LPS, melatonin blocked the LPS-induced activation of p50/RelA and the reduction in p50/p50 levels and inhibited iNOS expression and NO synthesis. Therefore, melatonin in vehicle-treated cells induces cell death, while it protects against LPS-induced cytotoxicity. In summary, we confirmed that melatonin is a neuroprotective drug when cerebellar cells are challenged; however, melatonin can also lead to cell death when the normal balance of the NF-κB pathway is disturbed. Our data provide a mechanistic basis for understanding the influence of cell context on the final output response of melatonin. PMID:25184316

Global and regional brain mean diffusivity changes in patients with heart failure.

PubMed

Woo, Mary A; Palomares, Jose A; Macey, Paul M; Fonarow, Gregg C; Harper, Ronald M; Kumar, Rajesh

2015-04-01

Heart failure (HF) patients show gray and white matter changes in multiple brain sites, including autonomic and motor coordination areas. It is unclear whether the changes represent acute or chronic tissue pathology, a distinction necessary for understanding pathological processes that can be resolved with diffusion tensor imaging (DTI)-based mean diffusivity (MD) procedures. We collected four DTI series from 16 HF (age 55.1 ± 7.8 years, 12 male) and 26 control (49.7 ± 10.8 years, 17 male) subjects with a 3.0-Tesla magnetic resonance imaging scanner. MD maps were realigned, averaged, normalized, and smoothed. Global and regional MD values from autonomic and motor coordination sites were calculated by using normalized MD maps and brain masks; group MD values and whole-brain smoothed MD maps were compared by analysis of covariance (covariates; age and gender). Global brain MD (HF vs. controls, units × 10(-6) mm(2) /sec, 1103.8 ± 76.6 vs. 1035.9 ± 69.4, P = 0.038) and regional autonomic and motor control site values (left insula, 1,085.4 ± 95.7 vs. 975.7 ± 65.4, P = 0.001; right insula, 1,050.2 ± 100.6 vs. 965.7 ± 58.4, P = 0.004; left hypothalamus, 1,419.6 ± 165.2 vs. 1,234.9 ± 136.3, P = 0.002; right hypothalamus, 1,446.5 ± 178.8 vs. 1,273.3 ± 136.9, P = 0.004; left cerebellar cortex, 889.1 ± 81.9 vs. 796.6 ± 46.8, P < 0.001; right cerebellar cortex, 797.8 ± 50.8 vs. 750.3 ± 27.5, P = 0.001; cerebellar deep nuclei, 1,236.1 ± 193.8 vs. 1,071.7 ± 107.1, P = 0.002) were significantly higher in HF vs. control subjects, indicating chronic tissue changes. Whole-brain comparisons showed increased MD values in HF subjects, including limbic, basal-ganglia, thalamic, solitary tract nucleus, frontal, and cerebellar regions. Brain injury occurs in autonomic and motor control areas, which may contribute to deficient function in HF patients. The chronic tissue changes likely result from processes that develop over a prolonged period. © 2014 Wiley Periodicals, Inc.

Cerebellar Expression of Copper Chaperone for Superoxide, Cytosolic Cu/Zn-Superoxide Dismutase, 4-Hydroxy-2-Nonenal, Acrolein and Heat Shock Protein 32 in Patients with Menkes Kinky Hair Disease: Immunohistochemical Study

PubMed Central

Yokoyama, Atsushi; Ohno, Kousaku; Hirano, Asao; Shintaku, Masayuki; Kato, Masako; Hayashi, Kazuhiko; Kato, Shinsuke

2014-01-01

Background To clarify the pathogenesis of cerebellar Purkinje cell death in patients with Menkes kinky hair disease (MD), a disorder of copper absorption, we investigated the morphological and functional abnormalities of residual Purkinje cells in MD patients and the mechanism of cell death. Methods Seven MD patients and 39 neurologically normal autopsy cases were studied. We performed histopathological and quantitative analyses of the Purkinje cells. In addition, we used immunohistochemistry to detect copper-dependent enzymes [cytosolic Cu/Zn-superoxide dismutase (SOD1) and copper chaperone for superoxide dismutase (CCS)], oxidative stress markers [4-hydroxy-2-nonenal (HNE) and acrolein] and heat shock protein 32 (hsp 32). Results The surviving MD Purkinje cells showed abnormal development, such as somatic sprouts and heterotopic location. Due to maldevelopment and degeneration, dendrites showed the cactus and weeping willow patterns. Axonal degeneration led to the formation of torpedoes. Quantitative analysis revealed loss of approximately 50% of the Purkinje cells in MD patients. Almost all of the normal Purkinje cells were positive for immunostaining by anti-CCS and anti-SOD1 antibodies, with staining of the cell bodies, dendrites and axons. Normal Purkinje cells were not stained by antibodies for HNE, acrolein or hsp 32. In MD patients, the majority of Purkinje cells were positive for CCS, but the positive rate for SOD1 was only about 23%. Approximately 56%, 42% and 40% of the Purkinje cells of MD patients were positive for HNE, acrolein and hsp 32, respectively. Conclusion In MD patients, about 50% of the Purkinje cells have been lost due to maldevelopment and degeneration. In the residual Purkinje cells, CCS expression seems to be nearly normal as a protective response to decreased SOD1 activity due to copper deficiency. Because oxidative stress is elevated secondary to decreased SOD1 activity, hsp 32 is induced as another protective mechanism. PMID:25067875

Cerebellar expression of copper chaperone for superoxide, cytosolic cu/zn-superoxide dismutase, 4-hydroxy-2-nonenal, acrolein and heat shock protein 32 in patients with menkes kinky hair disease: immunohistochemical study.

PubMed

Yokoyama, Atsushi; Ohno, Kousaku; Hirano, Asao; Shintaku, Masayuki; Kato, Masako; Hayashi, Kazuhiko; Kato, Shinsuke

2014-03-01

To clarify the pathogenesis of cerebellar Purkinje cell death in patients with Menkes kinky hair disease (MD), a disorder of copper absorption, we investigated the morphological and functional abnormalities of residual Purkinje cells in MD patients and the mechanism of cell death. Seven MD patients and 39 neurologically normal autopsy cases were studied. We performed histopathological and quantitative analyses of the Purkinje cells. In addition, we used immunohistochemistry to detect copper-dependent enzymes [cytosolic Cu/Zn-superoxide dismutase (SOD1) and copper chaperone for superoxide dismutase (CCS)], oxidative stress markers [4-hydroxy-2-nonenal (HNE) and acrolein] and heat shock protein 32 (hsp 32). The surviving MD Purkinje cells showed abnormal development, such as somatic sprouts and heterotopic location. Due to maldevelopment and degeneration, dendrites showed the cactus and weeping willow patterns. Axonal degeneration led to the formation of torpedoes. Quantitative analysis revealed loss of approximately 50% of the Purkinje cells in MD patients. Almost all of the normal Purkinje cells were positive for immunostaining by anti-CCS and anti-SOD1 antibodies, with staining of the cell bodies, dendrites and axons. Normal Purkinje cells were not stained by antibodies for HNE, acrolein or hsp 32. In MD patients, the majority of Purkinje cells were positive for CCS, but the positive rate for SOD1 was only about 23%. Approximately 56%, 42% and 40% of the Purkinje cells of MD patients were positive for HNE, acrolein and hsp 32, respectively. In MD patients, about 50% of the Purkinje cells have been lost due to maldevelopment and degeneration. In the residual Purkinje cells, CCS expression seems to be nearly normal as a protective response to decreased SOD1 activity due to copper deficiency. Because oxidative stress is elevated secondary to decreased SOD1 activity, hsp 32 is induced as another protective mechanism.

Functional recovery after cerebellar damage is related to GAP-43-mediated reactive responses of pre-cerebellar and deep cerebellar nuclei.

PubMed

Burello, Lorena; De Bartolo, Paola; Gelfo, Francesca; Foti, Francesca; Angelucci, Francesco; Petrosini, Laura

2012-01-01

Since brain injuries in adulthood are a leading cause of long-term disabilities, the development of rehabilitative strategies able to impact on functional outcomes requires detailing adaptive neurobiological responses. Functional recovery following brain insult is mainly ascribed to brain neuroplastic properties although the close linkage between neuronal plasticity and functional recovery is not yet fully clarified. The present study analyzed the reactive responses of pre-cerebellar (inferior olive, lateral reticular nucleus and pontine nuclei) and deep cerebellar nuclei after a hemicerebellectomy, considering the great plastic potential of the cerebellar system in physiological and pathological conditions. The time course of the plastic reorganization following cerebellar lesion was investigated by monitoring the Growth Associated Protein-43 (GAP-43) immunoreactivity. The time course of recovery from cerebellar symptoms was also assessed to parallel behavioral and neurobiological parameters. A key role of GAP-43 in neuronal reactive responses was evidenced. Neurons that underwent an axotomy as consequence of the right hemicerebellectomy (neurons of left inferior olive, right lateral reticular nucleus and left pontine nuclei) exhibited enhanced GAP-43 immunoreactivity and cell death. As for the not-axotomized neurons, we found enhanced GAP-43 immunoreactivity only in right pontine nuclei projecting to the spared (left) hemicerebellum. GAP-43 levels augmented also in the three deep cerebellar nuclei of the spared hemicerebellum, indicating the ponto-cerebellar circuit as crucially involved in functional recovery. Interestingly, each nucleus showed a distinct time course in GAP-43 immunoreactivity. GAP-43 levels peaked during the first post-operative week in the fastigial and interposed nuclei and after one month in the dentate nucleus. These results suggest that the earlier plastic events of the fastigial and interposed nuclei were driving compensation of the elementary features of posture and locomotion, while the later plastic events of the dentate nucleus were mediating the recovered ability to flexibly adjust the locomotor plan. Copyright © 2011. Published by Elsevier Inc.

Endovascular Treatment of AICA Flow Dependent Aneurysms

PubMed Central

Mahmoud, M.; El Serwi, A.; Alaa Habib, M.; Abou Gamrah, S.

2012-01-01

Summary Peripheral anterior inferior cerebellar artery (AICA) aneurysms are rare, accounting for less than 1% of all cerebral aneurysms. To our knowledge 34 flow-related cases including the present study have been reported in the literature. Three patients harbouring four flow dependent aneurysms were referred to our institution. Two patients presented with subarachnoid hemorrhage, one presented with cerebellar manifestations. They were all treated by endovascular embolization of the aneurysm as well as the parent artery using liquid embolic material. Two cases were embolized using NBCA, Onyx was used in the third case. No bleeding or rebleeding were encountered during the follow-up period which ranged from five to nine months. One patient developed facial palsy, cerebellar symptoms and sensorineural hearing loss. The remaining two cases did not develop any post treatment neurological complications. Endovascular management of flow-dependent AICA aneurysms by parent artery occlusion is feasible and efficient in terms of rebleeding prevention. Post embolization neurological complications are unpredictable. This depends upon the adequacy of collaterals from other cerebellar arteries. PMID:23217640

Three families with mild PMM2-CDG and normal cognitive development.

PubMed

Vals, Mari-Anne; Morava, Eva; Teeäär, Kai; Zordania, Riina; Pajusalu, Sander; Lefeber, Dirk J; Õunap, Katrin

2017-06-01

Congenital disorders of glycosylation (CDG) are caused by defective glycosylation of proteins and lipids. PMM2-CDG is the most common subtype among the CDG. The severity of PMM2-CDG is variable. Patients often have a recognizable phenotype with neurological and multisystem symptoms that might cause early death. We report six patients from three families who are diagnosed with a clinically mild PMM2-CDG and have normal cognitive development. All these patients had delayed gross motor skills with mild-to-moderate neurological findings. Cerebellar hypoplasia was detected in all siblings for whom brain MRI was performed. In 5/6 children the Wechsler Intelligence Scale for Children (WISC) showed normal cognitive development with full scale IQ scores ranging from borderline to average. Four patients were diagnosed with PMM2-CDG at the age of 8 years or later as their neurological symptoms were quite mild and they had been able to participate in regular school programs. We report patients with p.Val231Met/p.Arg239Trp and p.Ile120Thr/p.Gly228Cys genotypes which may cause milder variants of PMM2-CDG. © 2017 Wiley Periodicals, Inc.

Regional infant brain development: an MRI-based morphometric analysis in 3 to 13 month olds.

PubMed

Choe, Myong-Sun; Ortiz-Mantilla, Silvia; Makris, Nikos; Gregas, Matt; Bacic, Janine; Haehn, Daniel; Kennedy, David; Pienaar, Rudolph; Caviness, Verne S; Benasich, April A; Grant, P Ellen

2013-09-01

Elucidation of infant brain development is a critically important goal given the enduring impact of these early processes on various domains including later cognition and language. Although infants' whole-brain growth rates have long been available, regional growth rates have not been reported systematically. Accordingly, relatively less is known about the dynamics and organization of typically developing infant brains. Here we report global and regional volumetric growth of cerebrum, cerebellum, and brainstem with gender dimorphism, in 33 cross-sectional scans, over 3 to 13 months, using T1-weighted 3-dimensional spoiled gradient echo images and detailed semi-automated brain segmentation. Except for the midbrain and lateral ventricles, all absolute volumes of brain regions showed significant growth, with 6 different patterns of volumetric change. When normalized to the whole brain, the regional increase was characterized by 5 differential patterns. The putamen, cerebellar hemispheres, and total cerebellum were the only regions that showed positive growth in the normalized brain. Our results show region-specific patterns of volumetric change and contribute to the systematic understanding of infant brain development. This study greatly expands our knowledge of normal development and in future may provide a basis for identifying early deviation above and beyond normative variation that might signal higher risk for neurological disorders.

Regional Infant Brain Development: An MRI-Based Morphometric Analysis in 3 to 13 Month Olds

PubMed Central

Choe, Myong-sun; Ortiz-Mantilla, Silvia; Makris, Nikos; Gregas, Matt; Bacic, Janine; Haehn, Daniel; Kennedy, David; Pienaar, Rudolph; Caviness, Verne S.; Benasich, April A.; Grant, P. Ellen

2013-01-01

Elucidation of infant brain development is a critically important goal given the enduring impact of these early processes on various domains including later cognition and language. Although infants’ whole-brain growth rates have long been available, regional growth rates have not been reported systematically. Accordingly, relatively less is known about the dynamics and organization of typically developing infant brains. Here we report global and regional volumetric growth of cerebrum, cerebellum, and brainstem with gender dimorphism, in 33 cross-sectional scans, over 3 to 13 months, using T1-weighted 3-dimensional spoiled gradient echo images and detailed semi-automated brain segmentation. Except for the midbrain and lateral ventricles, all absolute volumes of brain regions showed significant growth, with 6 different patterns of volumetric change. When normalized to the whole brain, the regional increase was characterized by 5 differential patterns. The putamen, cerebellar hemispheres, and total cerebellum were the only regions that showed positive growth in the normalized brain. Our results show region-specific patterns of volumetric change and contribute to the systematic understanding of infant brain development. This study greatly expands our knowledge of normal development and in future may provide a basis for identifying early deviation above and beyond normative variation that might signal higher risk for neurological disorders. PMID:22772652

Auditory-perceptual speech analysis in children with cerebellar tumours: a long-term follow-up study.

PubMed

De Smet, Hyo Jung; Catsman-Berrevoets, Coriene; Aarsen, Femke; Verhoeven, Jo; Mariën, Peter; Paquier, Philippe F

2012-09-01

Mutism and Subsequent Dysarthria (MSD) and the Posterior Fossa Syndrome (PFS) have become well-recognized clinical entities which may develop after resection of cerebellar tumours. However, speech characteristics following a period of mutism have not been documented in much detail. This study carried out a perceptual speech analysis in 24 children and adolescents (of whom 12 became mute in the immediate postoperative phase) 1-12.2 years after cerebellar tumour resection. The most prominent speech deficits in this study were distorted vowels, slow rate, voice tremor, and monopitch. Factors influencing long-term speech disturbances are presence or absence of postoperative PFS, the localisation of the surgical lesion and the type of adjuvant treatment. Long-term speech deficits may be present up to 12 years post-surgery. The speech deficits found in children and adolescents with cerebellar lesions following cerebellar tumour surgery do not necessarily resemble adult speech characteristics of ataxic dysarthria. Copyright © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Altered fronto-cerebellar connectivity in alcohol-naïve youth with a family history of alcoholism

PubMed Central

Herting, Megan M.; Fair, Damien; Nagel, Bonnie J.

2011-01-01

Fronto-cerebellar connections are thought to be involved in higher-order cognitive functioning. It is suspected that damage to this network may contribute to cognitive deficits in chronic alcoholics. However, it remains to be elucidated if fronto-cerebellar circuitry is altered in high-risk individuals even prior to alcohol use onset. The current study used functional connectivity MRI (fcMRI) to examine fronto-cerebellar circuitry in 13 alcohol-naïve, at-risk youth with a family history of alcoholism (FH+) and 14 age-matched controls. In addition, we examined how white matter microstructure, as evidenced by fractional anisotropy (FA) related to fcMRI. FH+ youth showed significantly reduced functional connectivity between bilateral anterior prefrontal cortices and contralateral cerebellar seed regions compared to controls. We found that this reduction in connectivity significantly correlated with reduced FA in the anterior limb of the internal capsule and the superior longitudinal fasciculus. Taken together, our findings reflect associated aberrant functional and structural connectivity in substance-naïve FH+ adolescents, perhaps suggesting an identifiable neurophenotypic precursor to substance use. Given the role of frontal and cerebellar brain regions in subserving executive functioning, the presence of premorbid abnormalities in fronto-cerebellar circuitry may heighten the risk for developing an alcohol use disorder in FH+ youth through atypical control processing. PMID:20970506

Genome-Wide Search Reveals the Existence of a Limited Number of Thyroid Hormone Receptor Alpha Target Genes in Cerebellar Neurons

PubMed Central

Chatonnet, Fabrice; Guyot, Romain; Picou, Frédéric; Bondesson, Maria; Flamant, Frederic

2012-01-01

Thyroid hormone (T3) has a major influence on cerebellum post-natal development. The major phenotypic landmark of exposure to low levels of T3 during development (hypothyroidism) in the cerebellum is the retarded inward migration of the most numerous cell type, granular neurons. In order to identify the direct genetic regulation exerted by T3 on cerebellar neurons and their precursors, we used microarray RNA hybridization to perform a time course analysis of T3 induced gene expression in primary cultures of cerebellar neuronal cell. These experiments suggest that we identified a small set of genes which are directly regulated, both in vivo and in vitro, during cerebellum post-natal development. These modest changes suggest that T3 does not acts directly on granular neurons and mainly indirectly influences the cellular interactions taking place during development. PMID:22586439

Development of the cerebellum in the platypus (Ornithorhynchus anatinus) and short-beaked echidna (Tachyglossus aculeatus).

PubMed

Ashwell, Ken W S

2012-01-01

The monotremes are a unique group of mammals whose young are incubated in a leathery-shelled egg and fed with milk from teatless areolae after hatching. As soon as they hatch, monotreme young must be able to maneuver around the nest or maternal pouch to locate the areolae and stimulate milk ejection. In the present study, the embryological collections at the Museum für Naturkunde, Berlin, have been used to follow the development of the monotreme cerebellum through incubation and lactational phases, to determine whether cerebellar circuitry is able to contribute to the coordination of locomotion in the monotreme hatchling, and to correlate cerebellar development with behavioral maturation. The structure of the developing monotreme cerebellum and the arrangement of transitory neuronal populations are similar to those reported for fetal and neonatal eutherians, but the time course of the key events of later cerebellar development is spread over a much longer period. Expansion of the rostral rhombic lip and formation of the nuclear and cortical transitory zones occurs by the time of hatching, but it is not until after the end of the first post-hatching week that deep cerebellar neurons begin to settle in their definitive positions and the Purkinje cell layer can be distinguished. Granule cell formation is also prolonged over many post-hatching months and the external granular layer persists for more than 20 weeks after hatching. The findings indicate that cerebellar circuitry is unlikely to contribute to the coordination of movements in the monotreme peri-hatching period. Those activities are most likely controlled by the spinal cord and medullary reticular formation circuitry. Copyright © 2012 S. Karger AG, Basel.

A Quasi-Experimental Analysis of Second Graders with Dyslexia Using the Motor Markers in the Cerebellar Deficit Hypothesis

ERIC Educational Resources Information Center

Stark, Sandra Kathleen

2013-01-01

Developmental dyslexia is a specific impairment of reading ability in the presence of normal intelligence and adequate reading instruction. Current research has linked dyslexia to genetic underpinnings, which are identifiable. Furthermore, there are cognitive processes that are influenced by unique genetically programmed neural networks that…

Impaired Cerebellar Maturation, Growth Restriction, and Circulating Insulin-Like Growth Factor 1 in Preterm Rabbit Pups

PubMed Central

Sveinsdóttir, Kristbjörg; Länsberg, John-Kalle; Sveinsdóttir, Snjólaug; Garwicz, Martin; Ohlsson, Lennart; Hellström, Ann; Smith, Lois; Gram, Magnus; Ley, David

2018-01-01

Cerebellar growth is impeded following very preterm birth in human infants and the observed reduction in cerebellar volume is associated with neurodevelopmental impairment. Decreased levels of circulating insulin-like growth factor 1 (IGF-1) are associated with decreased cerebellar volume. The relationship between preterm birth, circulating IGF-1, and key cell populations supporting cerebellar proliferation is unknown. The aim of this study was to evaluate the effect of preterm birth on postnatal growth, circulating IGF-1, and cerebellar maturation in a preterm rabbit pup model. Preterm rabbit pups (PT) were delivered by cesarean section at day 29 of gestation, cared for in closed incubators with humidified air, and gavage fed with formula. Control term pups (T) delivered by spontaneous vaginal delivery at day 32 of gestation were housed and fed by their lactating doe. In vivo perfusion-fixation for immunohistochemical evaluation of cerebellar proliferation, cell maturation, and apoptosis was performed at repeated time points in PT and T pups. Results show that the mean weight of the pups and circulating IGF-1 protein levels were lower in the PT group at all time points (p < 0.05) than in the T group. Postnatal weight development correlated with circulating IGF-1 (r2 = 0.89) independently of gestational age at birth and postnatal age. The proliferative (Ki-67-positive) portion of the external granular layer (EGL) was decreased in the PT group at postnatal day 2 (P2) compared to in the T group (p = 0.01). Purkinje cells exhibited decreased calbindin staining at P0 (p = 0.003), P2 (p = 0.004), and P5 (p = 0.04) in the PT group compared to in the T group. Staining for sonic hedgehog was positive in neuronal EGL progenitors and Purkinje cells at early time points but was restricted to a well-defined Purkinje cell monolayer at later time points. Preterm birth in rabbit pups is associated with lower circulating levels of IGF-1, decreased postnatal growth, and decreased cerebellar EGL proliferation and Purkinje cell maturation. The preterm rabbit pup model exhibits important characteristics of human preterm birth, and may thus be suitable for the evaluation of interventions aiming to modify growth and cerebellar development in the preterm population. PMID:28972955

Neurodevelopmental Outcomes in Children with Cerebellar Malformations: A Systematic Review

ERIC Educational Resources Information Center

Bolduc, Marie-Eve; Limperopoulos, Catherine

2009-01-01

Cerebellar malformations are increasingly diagnosed in the fetal period. Consequently, their consideration requires stressful and often critical decisions from both clinicians and families. This has resulted in an emergent need to understand better the impact of these early life lesions on child development. We performed a comprehensive literature…

l-Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons

PubMed Central

Furuya, Shigeki; Tabata, Toshihide; Mitoma, Junya; Yamada, Keiko; Yamasaki, Miwako; Makino, Asami; Yamamoto, Toshifumi; Watanabe, Masahiko; Kano, Masanobu; Hirabayashi, Yoshio

2000-01-01

Glial cells support the survival and development of central neurons through the supply of trophic factors. Here we demonstrate that l-serine (l-Ser) and glycine (Gly) also are glia-derived trophic factors. These amino acids are released by astroglial cells and promote the survival, dendritogenesis, and electrophysiological development of cultured cerebellar Purkinje neurons. Although l-Ser and Gly are generally classified as nonessential amino acids, 3-phosphoglycerate dehydrogenase (3PGDH), a key enzyme for their biosynthesis, is not expressed in Purkinje neurons. By contrast, the Bergman glia, a native astroglia in the cerebellar cortex, highly expresses 3PGDH. These data suggest that l-Ser and Gly mediate the trophic actions of glial cells on Purkinje neurons. PMID:11016963

Cerebellum Development and Tumorigenesis: A p53-Centric Perspective.

PubMed

Barthelery, Nicolas J; Manfredi, James J

2016-05-01

The p53 protein has been extensively studied for its role in suppressing tumorigenesis, in part through surveillance and maintenance of genomic stability. p53 has been associated with the induction of a variety of cellular outcomes including cell cycle arrest, senescence, and apoptosis. This occurs primarily, but not exclusively, through transcriptional activation of specific target genes. By contrast, the participation of p53 in normal developmental processes has been largely understudied. This review focuses on possible functions of p53 in cerebellar development. It can be argued that a better understanding of such mechanisms will provide needed insight into the genesis of certain embryonic cancers including medulloblastomas, and thus lead to more effective therapies. Copyright © 2016 Elsevier Ltd. All rights reserved.

All in the blink of an eye: new insight into cerebellar and brainstem function in DYT1 and DYT6 dystonia.

PubMed

Sadnicka, A; Teo, J T; Kojovic, M; Pareés, I; Saifee, T A; Kassavetis, P; Schwingenschuh, P; Katschnig-Winter, P; Stamelou, M; Mencacci, N E; Rothwell, J C; Edwards, M J; Bhatia, K P

2015-05-01

Traditionally dystonia has been considered a disorder of basal ganglia dysfunction. However, recent research has advocated a more complex neuroanatomical network. In particular, there is increasing interest in the pathophysiological role of the cerebellum. Patients with cervical and focal hand dystonia have impaired cerebellar associative learning using the paradigm eyeblink conditioning. This is perhaps the most direct evidence to date that the cerebellum is implicated in patients. Eleven patients with DYT1 dystonia and five patients with DYT6 dystonia were examined and rates of eyeblink conditioning were compared with age-matched controls. A marker of brainstem excitability, the blink reflex recovery, was also studied in the same groups. Patients with DYT1 and DYT6 dystonia have a normal ability to acquire conditioned responses. Blink reflex recovery was enhanced in DYT1 but this effect was not seen in DYT6. If the cerebellum is an important driver in DYT1 and DYT6 dystonia our data suggest that there is specific cerebellar dysfunction such that the circuits essential for conditioning function normally. Our data are contrary to observations in focal dystonia and suggest that the cerebellum may have a distinct role in different subsets of dystonia. Evidence of enhanced blink reflex recovery in all patients with dystonia was not found and recent studies calling for the blink recovery reflex to be used as a diagnostic test for dystonic tremor may require further corroboration. © 2014 The Author(s) European Journal of Neurology © 2014 EAN.

Cerebellar microfolia and other abnormalities of neuronal growth, migration, and lamination in the Pit1dw-J homozygote mutant mouse

NASA Technical Reports Server (NTRS)

Sekiguchi, M.; Abe, H.; Moriya, M.; Tanaka, O.; Nowakowski, R. S.

1998-01-01

The Snell dwarf mouse (Pit1dw-J homozygote) has a mutation in the Pit1 gene that prevents the normal formation of the anterior pituitary. In neonates and adults there is almost complete absence of growth hormone (GH), prolactin (PRL), thyroxin (T4), and thyroid-stimulating hormone (TSH). Since these hormones have been suggested to play a role in normal development of the central nervous system (CNS), we have investigated the effects of the Pit1dw-J mutation on the cerebellum and hippocampal formation. In the cerebellum, there were abnormalities of both foliation and lamination. The major foliation anomalies were 1) changes in the relative size of specific folia and also the proportional sizes of the anterior vs posterior cerebellum; and 2) the presence of between one and three microfolia per half cerebellum. The microfolia were all in the medial portion of the hemisphere in the caudal part of the cerebellum. Each microfolium was just rostral to a normal fissure and interposed between the fissure and a normal gyrus. Lamination abnormalities included an increase in the number of single ectopic granule cells in the molecular layer in both cerebellar vermis (86%) and hemisphere (40%) in comparison with the wild-type mouse. In the hippocampus of the Pit1dw-J homozygote mouse, the number of pyramidal cells was decreased, although the width of the pyramidal cell layer throughout areas CA1-CA3 appeared to be normal, but less densely populated than in the wild-type mouse. Moreover, the number of granule cells that form the granule cell layer was decreased from the wild-type mouse and some ectopic granule cells (occurring both as single cells and as small clusters) were observed in the innermost portion of the molecular layer. The abnormalities observed in the Pit1dw-J homozygote mouse seem to be caused by both direct and indirect effects of the deficiency of TSH (or T4), PRL, or GH rather than by a direct effect of the deletion of Pit1.

Behavior modification after inactivation of cerebellar dentate nuclei.

PubMed

Peterson, Todd C; Villatoro, Lee; Arneson, Tom; Ahuja, Brittany; Voss, Stephanie; Swain, Rodney A

2012-08-01

Effort-based decision making occurs when subjects are given a choice between a reward available at a high response cost and a reward available at a low response cost and is altered in individuals with disorders such as autism or particular patterns of brain injury. The current study explored the relationship between effort-based decision making and reinforcement characteristics in the T maze. This was done using both normal animals and animals with bilateral inactivation of the cerebellar dentate nuclei. Rats chose between alternatives in which one arm contained high-density reinforcement (HR) and the other arm contained low-density reinforcement (LR). During training, the HR arm was obstructed and the point at which the animal no longer worked for reinforcement (breaking point) was determined. The cerebellar dentate nuclei were then transiently inactivated and once again breaking points were assessed. The results indicated that inactivation of the dentate nucleus disrupted effort-based decision making. Additionally, altering both the palatability and the magnitude of the reinforcement were assessed in an attempt to reestablish the original preinactivation breaking point. It was hypothesized that an increase in the strength or magnitude of the reinforcement would promote an increase in the breaking point of the animal even when the cerebellum was inactivated. The results indicated that with both strategies animals effectively reestablished original breaking points. The results of this study will inform the current literature regarding the modification of behavior after brain injury and further the understanding of the behavioral deficits associated with cerebellar dysfunction.

The contribution of the cerebellum to speech production and speech perception: clinical and functional imaging data.

PubMed

Ackermann, Hermann; Mathiak, Klaus; Riecker, Axel

2007-01-01

A classical tenet of clinical neurology proposes that cerebellar disorders may give rise to speech motor disorders (ataxic dysarthria), but spare perceptual and cognitive aspects of verbal communication. During the past two decades, however, a variety of higher-order deficits of speech production, e.g., more or less exclusive agrammatism, amnesic or transcortical motor aphasia, have been noted in patients with vascular cerebellar lesions, and transient mutism following resection of posterior fossa tumors in children may develop into similar constellations. Perfusion studies provided evidence for cerebello-cerebral diaschisis as a possible pathomechanism in these instances. Tight functional connectivity between the language-dominant frontal lobe and the contralateral cerebellar hemisphere represents a prerequisite of such long-distance effects. Recent functional imaging data point at a contribution of the right cerebellar hemisphere, concomitant with language-dominant dorsolateral and medial frontal areas, to the temporal organization of a prearticulatory verbal code ('inner speech'), in terms of the sequencing of syllable strings at a speaker's habitual speech rate. Besides motor control, this network also appears to be engaged in executive functions, e.g., subvocal rehearsal mechanisms of verbal working memory, and seems to be recruited during distinct speech perception tasks. Taken together, thus, a prearticulatory verbal code bound to reciprocal right cerebellar/left frontal interactions might represent a common platform for a variety of cerebellar engagements in cognitive functions. The distinct computational operation provided by cerebellar structures within this framework appears to be the concatenation of syllable strings into coarticulated sequences.

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

PubMed Central

Baldarçara, Leonardo; Currie, Stuart; Hadjivassiliou, M.; Hoggard, Nigel; Jack, Allison; Jackowski, Andrea P.; Mascalchi, Mario; Parazzini, Cecilia; Reetz, Kathrin; Righini, Andrea; Schulz, Jörg B.; Vella, Alessandra; Webb, Sara Jane; Habas, Christophe

2016-01-01

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine. PMID:25382714

A toolbox to visually explore cerebellar shape changes in cerebellar disease and dysfunction.

PubMed

Abulnaga, S Mazdak; Yang, Zhen; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M; Onyike, Chiadi U; Ying, Sarah H; Prince, Jerry L

2016-02-27

The cerebellum plays an important role in motor control and is also involved in cognitive processes. Cerebellar function is specialized by location, although the exact topographic functional relationship is not fully understood. The spinocerebellar ataxias are a group of neurodegenerative diseases that cause regional atrophy in the cerebellum, yielding distinct motor and cognitive problems. The ability to study the region-specific atrophy patterns can provide insight into the problem of relating cerebellar function to location. In an effort to study these structural change patterns, we developed a toolbox in MATLAB to provide researchers a unique way to visually explore the correlation between cerebellar lobule shape changes and function loss, with a rich set of visualization and analysis modules. In this paper, we outline the functions and highlight the utility of the toolbox. The toolbox takes as input landmark shape representations of subjects' cerebellar substructures. A principal component analysis is used for dimension reduction. Following this, a linear discriminant analysis and a regression analysis can be performed to find the discriminant direction associated with a specific disease type, or the regression line of a specific functional measure can be generated. The characteristic structural change pattern of a disease type or of a functional score is visualized by sampling points on the discriminant or regression line. The sampled points are used to reconstruct synthetic cerebellar lobule shapes. We showed a few case studies highlighting the utility of the toolbox and we compare the analysis results with the literature.

A toolbox to visually explore cerebellar shape changes in cerebellar disease and dysfunction

NASA Astrophysics Data System (ADS)

Abulnaga, S. Mazdak; Yang, Zhen; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi U.; Ying, Sarah H.; Prince, Jerry L.

2016-03-01

The cerebellum plays an important role in motor control and is also involved in cognitive processes. Cerebellar function is specialized by location, although the exact topographic functional relationship is not fully understood. The spinocerebellar ataxias are a group of neurodegenerative diseases that cause regional atrophy in the cerebellum, yielding distinct motor and cognitive problems. The ability to study the region-specific atrophy patterns can provide insight into the problem of relating cerebellar function to location. In an effort to study these structural change patterns, we developed a toolbox in MATLAB to provide researchers a unique way to visually explore the correlation between cerebellar lobule shape changes and function loss, with a rich set of visualization and analysis modules. In this paper, we outline the functions and highlight the utility of the toolbox. The toolbox takes as input landmark shape representations of subjects' cerebellar substructures. A principal component analysis is used for dimension reduction. Following this, a linear discriminant analysis and a regression analysis can be performed to find the discriminant direction associated with a specific disease type, or the regression line of a specific functional measure can be generated. The characteristic structural change pattern of a disease type or of a functional score is visualized by sampling points on the discriminant or regression line. The sampled points are used to reconstruct synthetic cerebellar lobule shapes. We showed a few case studies highlighting the utility of the toolbox and we compare the analysis results with the literature.

A low-density culture method of cerebellar granule neurons with paracrine support applicable for the study of neuronal morphogenesis.

PubMed

Kubota, Kenta; Seno, Takeshi; Konishi, Yoshiyuki

2013-11-20

Cerebellar granule neuronal cultures have been used to study the molecular mechanisms underlying neuronal functions, including neuronal morphogenesis. However, a limitation of this system is the difficulty to analyze isolated neurons because these are required to be maintained at a high density. Therefore, in the present study, we aimed to develop a simple and cost-effective method for culturing low-density cerebellar granule neurons. Cerebellar granule cells at two different densities (low- and high-density) were co-cultivated in order for the low-density culture to be supported by the paracrine signals from the high-density culture. This method enabled morphology analysis of isolated cerebellar granule neurons without astrocytic feeder cultures or supplements such as B27. Using this method, we investigated the function of a polarity factor. Studies using hippocampal neurons suggested that glycogen synthase kinase-3 (GSK-3) is an essential regulator of neuronal polarity, and inhibition of GSK-3 results in the formation of multiple axons. Pharmacological inhibitors for GSK-3 (6-bromoindirubin-3'-oxime and lithium chloride) did not cause the formation of multiple axons of cerebellar granule neurons but significantly reduced their length. Consistent results were obtained by introducing kinase-dead form of GSK-3 beta (K85A). These results indicated that GSK-3 is not directly involved in the control of neuronal polarity in cerebellar granule neurons. Overall, this study provides a simple method for culturing low-density cerebellar granule neurons and insights in to the neuronal-type dependent function of GSK-3 in neuronal morphogenesis. © 2013 Elsevier B.V. All rights reserved.

Increased protein kinase C gamma activity induces Purkinje cell pathology in a mouse model of spinocerebellar ataxia 14.

PubMed

Ji, Jingmin; Hassler, Melanie L; Shimobayashi, Etsuko; Paka, Nagendher; Streit, Raphael; Kapfhammer, Josef P

2014-10-01

Spinocerebellar ataxias (SCAs) are hereditary diseases leading to Purkinje cell degeneration and cerebellar dysfunction. Most forms of SCA are caused by expansion of CAG repeats similar to other polyglutamine disorders such as Huntington's disease. In contrast, in the autosomal dominant SCA-14 the disease is caused by mutations in the protein kinase C gamma (PKCγ) gene which is a well characterized signaling molecule in cerebellar Purkinje cells. The study of SCA-14, therefore, offers the unique opportunity to reveal the molecular and pathological mechanism eventually leading to Purkinje cell dysfunction and degeneration. We have created a mouse model of SCA-14 in which PKCγ protein with a mutation found in SCA-14 is specifically expressed in cerebellar Purkinje cells. We find that in mice expressing the mutated PKCγ protein the morphology of Purkinje cells in cerebellar slice cultures is drastically altered and mimics closely the morphology seen after pharmacological PKC activation. Similar morphological abnormalities were seen in localized areas of the cerebellum of juvenile transgenic mice in vivo. In adult transgenic mice there is evidence for some localized loss of Purkinje cells but there is no overall cerebellar atrophy. Transgenic mice show a mild cerebellar ataxia revealed by testing on the rotarod and on the walking beam. Our findings provide evidence for both an increased PKCγ activity in Purkinje cells in vivo and for pathological changes typical for cerebellar disease thus linking the increased and dysregulated activity of PKCγ tightly to the development of cerebellar disease in SCA-14 and possibly also in other forms of SCA. Copyright © 2014 Elsevier Inc. All rights reserved.

FGF-2 signal promotes proliferation of cerebellar progenitor cells and their oligodendrocytic differentiation at early postnatal stage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Naruse, Masae; Shibasaki, Koji; Ishizaki, Yasuki, E-mail: yasukiishizaki@gunma-u.ac.jp

The origins and developmental regulation of cerebellar oligodendrocytes are largely unknown, although some hypotheses of embryonic origins have been suggested. Neural stem cells exist in the white matter of postnatal cerebellum, but it is unclear whether these neural stem cells generate oligodendrocytes at postnatal stages. We previously showed that cerebellar progenitor cells, including neural stem cells, widely express CD44 at around postnatal day 3. In the present study, we showed that CD44-positive cells prepared from the postnatal day 3 cerebellum gave rise to neurospheres, while CD44-negative cells prepared from the same cerebellum did not. These neurospheres differentiated mainly into oligodendrocytesmore » and astrocytes, suggesting that CD44-positive neural stem/progenitor cells might generate oligodendrocytes in postnatal cerebellum. We cultured CD44-positive cells from the postnatal day 3 cerebellum in the presence of signaling molecules known as mitogens or inductive differentiation factors for oligodendrocyte progenitor cells. Of these, only FGF-2 promoted survival and proliferation of CD44-positive cells, and these cells differentiated into O4+ oligodendrocytes. Furthermore, we examined the effect of FGF-2 on cerebellar oligodendrocyte development ex vivo. FGF-2 enhanced proliferation of oligodendrocyte progenitor cells and increased the number of O4+ and CC1+ oligodendrocytes in slice cultures. These results suggest that CD44-positive cells might be a source of cerebellar oligodendrocytes and that FGF-2 plays important roles in their development at an early postnatal stage. - Highlights: • CD44 is expressed in cerebellar neural stem/progenitor cells at postnatal day 3 (P3). • FGF-2 promoted proliferation of CD44-positive progenitor cells from P3 cerebellum. • FGF-2 promoted oligodendrocytic differentiation of CD44-positive progenitor cells. • FGF-2 increased the number of oligodendrocytes in P3 cerebellar slice culture.« less

Periconception Maternal Folate Status and Human Embryonic Cerebellum Growth Trajectories: The Rotterdam Predict Study

PubMed Central

Koning, Irene V.; Groenenberg, Irene A. L.; Gotink, Anniek W.; Willemsen, Sten P.; Gijtenbeek, Manon; Dudink, Jeroen; Go, Attie T. J. I.; Reiss, Irwin K. M.; Steegers, Eric A. P.; Steegers-Theunissen, Régine P. M.

2015-01-01

We aimed to investigate whether periconceptional maternal folate status affects human embryonic cerebellar size and growth trajectories. In a prospective periconceptional cohort participants filled out questionnaires and received weekly transvaginal 3D-ultrasounds between 7+0 and 12+6 weeks gestational age (GA). Viable non-malformed singleton pregnancies were selected for cerebellar measurements; transcerebellar diameter, (TCD), left and right cerebellar diameters (LCD, RCD). Linear mixed models were performed to estimate associations between questionnaire data on the timing of maternal folic acid supplement initiation and longitudinal cerebellar measurements as a function of crown-rump length (CRL) and GA. Maternal red blood cell folate concentrations were analysed before 8 weeks GA to validate the associations. A total of 263 serial high quality three-dimensional ultrasound scans of 135 pregnancies were studied. Preconceptional compared to postconceptional initiation of folic acid use was associated with slightly larger cerebellar diameters per millimetre increase of CRL (TCD: β = 0.260mm, 95%CI = 0.023–0.491, p<0.05; LCD: β = 0.171mm, 95%CI = 0.038–0.305, p<0.05; RCD: β = 0.156mm, 95%CI = 0.032–0.280, p<0.05) and with proportional cerebellar growth (TCD/CRL:β = 0.015mm/mm, 95%CI = 0.005–0.024, p<0.01; LCD/CRL:β = 0.012mm/mm, 95%CI = 0.005–0.018, p<0.01; RCD/CRL:β = 0.011mm/mm, 95%CI = 0.005–0.017, p<0.01). Cerebellar growth was significantly highest in the third quartile of maternal red blood cell folate levels (1538–1813 nmol/L). These first findings show that periconceptional maternal folate status is associated with human embryonic cerebellar development. Implications of these small but significant variations for fetal cerebellar growth trajectories and the child’s neurodevelopmental outcome are yet unknown and warrant further investigation. PMID:26491876

The Origin of Mathematics and Number Sense in the Cerebellum: with Implications for Finger Counting and Dyscalculia.

PubMed

Vandervert, Larry

2017-01-01

Mathematicians and scientists have struggled to adequately describe the ultimate foundations of mathematics. Nobel laureates Albert Einstein and Eugene Wigner were perplexed by this issue, with Wigner concluding that the workability of mathematics in the real world is a mystery we cannot explain. In response to this classic enigma, the major purpose of this article is to provide a theoretical model of the ultimate origin of mathematics and "number sense" (as defined by S. Dehaene) that is proposed to involve the learning of inverse dynamics models through the collaboration of the cerebellum and the cerebral cortex (but prominently cerebellum-driven). This model is based upon (1) the modern definition of mathematics as the "science of patterns," (2) cerebellar sequence (pattern) detection, and (3) findings that the manipulation of numbers is automated in the cerebellum. This cerebro-cerebellar approach does not necessarily conflict with mathematics or number sense models that focus on brain functions associated with especially the intraparietal sulcus region of the cerebral cortex. A direct corollary purpose of this article is to offer a cerebellar inner speech explanation for difficulty in developing "number sense" in developmental dyscalculia. It is argued that during infancy the cerebellum learns (1) a first tier of internal models for a primitive physics that constitutes the foundations of visual-spatial working memory, and (2) a second (and more abstract) tier of internal models based on (1) that learns "number" and relationships among dimensions across the primitive physics of the first tier. Within this context it is further argued that difficulty in the early development of the second tier of abstraction (and "number sense") is based on the more demanding attentional requirements imposed on cerebellar inner speech executive control during the learning of cerebellar inverse dynamics models. Finally, it is argued that finger counting improves (does not originate) "number sense" by extending focus of attention in executive control of silent cerebellar inner speech. It is suggested that (1) the origin of mathematics has historically been an enigma only because it is learned below the level of conscious awareness in cerebellar internal models, (2) understandings of the development of "number sense" and developmental dyscalculia can be advanced by first understanding the ultimate foundations of number and mathematics do not simply originate in the cerebral cortex, but rather in cerebro-cerebellar collaboration (predominately driven by the cerebellum). It is concluded that difficulty with "number sense" results from the extended demands on executive control in learning inverse dynamics models associated with cerebellar inner speech related to the second tier of abstraction (numbers) of the infant's primitive physics.

Endovascular treatment of AICA flow dependent aneurysms. A report of three cases and review of the literature.

PubMed

Mahmoud, M; El Serwi, A; Alaa Habib, M; Abou Gamrah, S

2012-12-01

Peripheral anterior inferior cerebellar artery (AICA) aneurysms are rare, accounting for less than 1% of all cerebral aneurysms. To our knowledge 34 flow-related cases including the present study have been reported in the literature. Three patients harbouring four flow dependent aneurysms were referred to our institution. Two patients presented with subarachnoid hemorrhage, one presented with cerebellar manifestations. They were all treated by endovascular embolization of the aneurysm as well as the parent artery using liquid embolic material. Two cases were embolized using NBCA, Onyx was used in the third case. No bleeding or rebleeding were encountered during the follow-up period which ranged from five to nine months. One patient developed facial palsy, cerebellar symptoms and sensorineural hearing loss. The remaining two cases did not develop any post treatment neurological complications. Endovascular management of flow-dependent AICA aneurysms by parent artery occlusion is feasible and efficient in terms of rebleeding prevention. Post embolization neurological complications are unpredictable. This depends upon the adequacy of collaterals from other cerebellar arteries.

Fractal dimension values of cerebral and cerebellar activity in rats loaded with aluminium.

PubMed

Kekovic, Goran; Culic, Milka; Martac, Ljiljana; Stojadinovic, Gordana; Capo, Ivan; Lalosevic, Dusan; Sekulic, Slobodan

2010-07-01

Aluminium interferes with a variety of cellular metabolic processes in the mammalian nervous system and its intake might increase a risk of developing Alzheimer's disease (AD). While cerebral involvement even at the early stages of intoxication is well known, the role of cerebellum is underestimated. Our aim was to investigate cerebral and cerebellar electrocortical activity in adult male rats exposed to chronic aluminium treatment by nonlinear analytic tools. The adult rats in an aluminium-treated group were injected by AlCl(3), intraperitoneally (2 mg Al/kg, daily for 4 weeks). Fractal analysis of brain activity was performed off-line using Higuchi's algorithm. The average fractal dimension of electrocortical activity in aluminium-treated animals was lower than the average fractal dimension of electrocortical activity in the control rats, at cerebral but not at cerebellar level. The changes in the stationary and nonlinear properties of time series were more expressed in cerebral electrocortical activity than in cerebellar activity. This can be useful for developing effective diagnostic and therapeutic strategies in neurodegenerative diseases.

Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences

PubMed Central

Basson, M. Albert; Wingate, Richard J.

2013-01-01

Over the last 60 years, the spotlight of research has periodically returned to the cerebellum as new techniques and insights have emerged. Because of its simple homogeneous structure, limited diversity of cell types and characteristic behavioral pathologies, the cerebellum is a natural home for studies of cell specification, patterning, and neuronal migration. However, recent evidence has extended the traditional range of perceived cerebellar function to include modulation of cognitive processes and implicated cerebellar hypoplasia and Purkinje neuron hypo-cellularity with autistic spectrum disorder. In the light of this emerging frontier, we review the key stages and genetic mechanisms behind cerebellum development. In particular, we discuss the role of the midbrain hindbrain isthmic organizer in the development of the cerebellar vermis and the specification and differentiation of Purkinje cells and granule neurons. These developmental processes are then considered in relation to recent insights into selected human developmental cerebellar defects: Joubert syndrome, Dandy–Walker malformation, and pontocerebellar hypoplasia. Finally, we review current research that opens up the possibility of using the mouse as a genetic model to study the role of the cerebellum in cognitive function. PMID:24027500

Distributed Cerebellar Motor Learning: A Spike-Timing-Dependent Plasticity Model

PubMed Central

Luque, Niceto R.; Garrido, Jesús A.; Naveros, Francisco; Carrillo, Richard R.; D'Angelo, Egidio; Ros, Eduardo

2016-01-01

Deep cerebellar nuclei neurons receive both inhibitory (GABAergic) synaptic currents from Purkinje cells (within the cerebellar cortex) and excitatory (glutamatergic) synaptic currents from mossy fibers. Those two deep cerebellar nucleus inputs are thought to be also adaptive, embedding interesting properties in the framework of accurate movements. We show that distributed spike-timing-dependent plasticity mechanisms (STDP) located at different cerebellar sites (parallel fibers to Purkinje cells, mossy fibers to deep cerebellar nucleus cells, and Purkinje cells to deep cerebellar nucleus cells) in close-loop simulations provide an explanation for the complex learning properties of the cerebellum in motor learning. Concretely, we propose a new mechanistic cerebellar spiking model. In this new model, deep cerebellar nuclei embed a dual functionality: deep cerebellar nuclei acting as a gain adaptation mechanism and as a facilitator for the slow memory consolidation at mossy fibers to deep cerebellar nucleus synapses. Equipping the cerebellum with excitatory (e-STDP) and inhibitory (i-STDP) mechanisms at deep cerebellar nuclei afferents allows the accommodation of synaptic memories that were formed at parallel fibers to Purkinje cells synapses and then transferred to mossy fibers to deep cerebellar nucleus synapses. These adaptive mechanisms also contribute to modulate the deep-cerebellar-nucleus-output firing rate (output gain modulation toward optimizing its working range). PMID:26973504

Morphological and behavioral markers of environmentally induced retardation of brain development: an animal model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Altman, J.

1987-10-01

In most neurotoxicological studies morphological assessment focuses on pathological effects, like degenerative changes in neuronal perikarya, axonopathy, demyelination, and glial and endothelial cell reactions. Similarly, the assessment of physiological and behavioral effects center on evident neurological symptoms, like EEG and EMG abnormalities, resting and intention tremor, abnormal gait, and abnormal reflexes. This paper reviews briefly another central nervous system target of harmful environmental agents, which results in behavioral abnormalities without any qualitatively evident neuropathology. This is called microneuronal hypoplasia, a retardation of brain development characterized by a quantitative reduction in the normal population of late-generated, short-axoned neurons in specific brainmore » regions. Correlated descriptive and experimental neurogenetic studies in the rat have established that all the cerebellar granule cells and a very high proportion of hippocampal granule cells are produced postnatally, and that focal, low-dose X-irradiation either of the cerebellum or of the hippocampus after birth selectively interferes with the acquisition of the full complement of granule cells (microneuronal hypoplasia). Subsequent behavioral investigations showed that cerebellar microneuronal hypoplasia results in profound hyperactivity without motor abnormalities, while hippocampal microneuronal hypoplasia results in hyperactivity, as well as attentional and learning deficits. There is much indirect clinical evidence that various harmful environmental agents affecting the pregnant mother and/or the infant lead to such childhood disorders as hyperactivity and attentional and learning disorders. 109 references.« less

Neurog1 Genetic Inducible Fate Mapping (GIFM) Reveals the Existence of Complex Spatiotemporal Cyto-Architectures in the Developing Cerebellum.

PubMed

Obana, Edwin A; Lundell, Travis G; Yi, Kevin J; Radomski, Kryslaine L; Zhou, Qiong; Doughty, Martin L

2015-06-01

Neurog1 is a pro-neural basic helix-loop-helix (bHLH) transcription factor expressed in progenitor cells located in the ventricular zone and subsequently the presumptive white matter tracts of the developing mouse cerebellum. We used genetic inducible fate mapping (GIFM) with a transgenic Neurog1-CreER allele to characterize the contributions of Neurog1 lineages to cerebellar circuit formation in mice. GIFM reveals Neurog1-expressing progenitors are fate-mapped to become Purkinje cells and all GABAergic interneuron cell types of the cerebellar cortex but not glia. The spatiotemporal sequence of GIFM is unique to each neuronal cell type. GIFM on embryonic days (E) 10.5 to E12.5 labels Purkinje cells with different medial-lateral settling patterns depending on the day of tamoxifen delivery. GIFM on E11.5 to P7 labels interneurons and the timing of tamoxifen administration correlates with the final inside-to-outside resting position of GABAergic interneurons in the cerebellar cortex. Proliferative status and long-term BrdU retention of GIFM lineages reveals Purkinje cells express Neurog1 around the time they become post-mitotic. In contrast, GIFM labels mitotic and post-mitotic interneurons. Neurog1-CreER GIFM reveals a correlation between the timing of Neurog1 expression and the spatial organization of GABAergic neurons in the cerebellar cortex with possible implications for cerebellar circuit assembly.

Slowly progressive cerebellar ataxia and cervical dystonia: clinical presentation of a new form of spinocerebellar ataxia?

PubMed

Kuoppamäki, Mikko; Giunti, Paula; Quinn, Niall; Wood, Nicholas W; Bhatia, Kailash P

2003-02-01

We describe 5 cases with a rare combination of young-onset, slowly progressive cerebellar ataxia and cervical dystonia. Two were sporadic, whereas the other 3 were familial, including 2 from one family. The age of onset of these cases was between 16 and 37 years. The presenting symptom was cervical dystonia and/or dystonic head tremor in 3 patients and hand or lower limb tremor in 2. In 2 cases, cervical dystonia and/or dystonic head tremor developed approximately 6 to 10 years before cerebellar dysfunction, and in three they developed at the same time. Apart from cervical dystonia, there was mild dystonic limb involvement in 2 cases, but generalized dystonia was not seen. Cerebellar ataxia was slowly progressive. A literature search showed 10 cases of cervical dystonia associated with genetically undetermined (n = 5) or genetically proven (n = 5) spinocerebellar ataxia (SCA). When the genotype was known, these patients had either SCA3, 6, 7, or 12. However, our 5 cases (or their first-degree relatives) tested negative for SCA1, 2, 3, 6, and 7, and in the 4 cases (or their first-degree relatives) tested for SCA12, the result was negative. We propose that this rare phenotype manifesting as a combination of cerebellar ataxia and cervical dystonia may represent one or more new, as yet uncharacterized, genotypes of inherited young-onset spinocerebellar ataxia. Copyright Movement Disorder Society

Cerebro-cerebellar Resting-State Functional Connectivity in Children and Adolescents with Autism Spectrum Disorder.

PubMed

Khan, Amanda J; Nair, Aarti; Keown, Christopher L; Datko, Michael C; Lincoln, Alan J; Müller, Ralph-Axel

2015-11-01

The cerebellum plays important roles in sensori-motor and supramodal cognitive functions. Cellular, volumetric, and functional abnormalities of the cerebellum have been found in autism spectrum disorders (ASD), but no comprehensive investigation of cerebro-cerebellar connectivity in ASD is available. We used resting-state functional connectivity magnetic resonance imaging in 56 children and adolescents (28 subjects with ASD, 28 typically developing subjects) 8-17 years old. Partial and total correlation analyses were performed for unilateral regions of interest (ROIs), distinguished in two broad domains as sensori-motor (premotor/primary motor, somatosensory, superior temporal, and occipital) and supramodal (prefrontal, posterior parietal, and inferior and middle temporal). There were three main findings: 1) Total correlation analyses showed predominant cerebro-cerebellar functional overconnectivity in the ASD group; 2) partial correlation analyses that emphasized domain specificity (sensori-motor vs. supramodal) indicated a pattern of robustly increased connectivity in the ASD group (compared with the typically developing group) for sensori-motor ROIs but predominantly reduced connectivity for supramodal ROIs; and 3) this atypical pattern of connectivity was supported by significantly increased noncanonical connections (between sensori-motor cerebral and supramodal cerebellar ROIs and vice versa) in the ASD group. Our findings indicate that sensori-motor intrinsic functional connectivity is atypically increased in ASD, at the expense of connectivity supporting cerebellar participation in supramodal cognition. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Adrenal haemangioblastoma presenting as phaeochromocytoma: a rare manifestation of extraneural hemangioblastoma.

PubMed

Deb, Prabal; Pal, Seerat; Dutta, Vibha; Srivastava, Anand; Bhargava, Akshay; Yadav, Krishan Kumar

2012-09-01

Adrenal haemangioblastoma presenting clinically as pheochromocytoma is a rare manifestation of extraneural haemangioblastoma. We present an unusual case of von Hippel-Lindau (VHL) disease that had adrenal and cerebellar haemangioblastoma with multiple renal cysts, and a review of the literature. Unlike the usual manifestations of secondary polycythemia or increased intracranial pressure and hydrocephalus due to cerebellar lesion, this 36-year-old male presented with hypertension. Investigations revealed right suprarenal mass with raised urinary catecholamines and serum vanillylmandelic acid (VMA) levels, apparently confirming the clinical diagnosis of phaeochromocytoma. Histopathology of the biopsy specimen showed features of haemangioblastoma, which was confirmed by immunohistochemistry using antibodies to neuron specific enolase and aquaporin-1. Based on this, the patient was screened for possible features of VHL, which revealed cerebellar haemangioblastoma and multiple renal cysts with angiomatous lesion. Postoperative follow-up showed normal levels of catecholamines without any symptoms of phaeochromocytoma. Adrenal haemangioblastoma is a rare entity with only four cases reported in the literature. Surgical removal is the treatment of choice. However, screening for other possible features of VHL, even in the absence of clinical features, is essential to exclude other potential lesions.

Recovery of motor deficit, cerebellar serotonin and lipid peroxidation levels in the cortex of injured rats.

PubMed

Bueno-Nava, Antonio; Gonzalez-Pina, Rigoberto; Alfaro-Rodriguez, Alfonso; Nekrassov-Protasova, Vladimir; Durand-Rivera, Alfredo; Montes, Sergio; Ayala-Guerrero, Fructuoso

2010-10-01

The sensorimotor cortex and the cerebellum are interconnected by the corticopontocerebellar (CPC) pathway and by neuronal groups such as the serotonergic system. Our aims were to determine the levels of cerebellar serotonin (5-HT) and lipid peroxidation (LP) after cortical iron injection and to analyze the motor function produced by the injury. Rats were divided into the following three groups: control, injured and recovering. Motor function was evaluated using the beam-walking test as an assessment of overall locomotor function and the footprint test as an assessment of gait. We also determined the levels of 5-HT and LP two and twenty days post-lesion. We found an increase in cerebellar 5-HT and a concomitant increase in LP in the pons and cerebellum of injured rats, which correlated with their motor deficits. Recovering rats showed normal 5-HT and LP levels. The increase of 5-HT in injured rats could be a result of serotonergic axonal injury after cortical iron injection. The LP and motor deficits could be due to impairments in neuronal connectivity affecting the corticospinal and CPC tracts and dysmetric stride could be indicative of an ataxic gait that involves the cerebellum.

Motor neuronopathy with dropped hands and downbeat nystagmus: a distinctive disorder? A case report.

PubMed

Thakore, Nimish J; Pioro, Erik P; Rucker, Janet C; Leigh, R John

2006-01-12

Eye movements are clinically normal in most patients with motor neuron disorders until late in the disease course. Rare patients are reported to show slow vertical saccades, impaired smooth pursuit, and gaze-evoked nystagmus. We report clinical and oculomotor findings in three patients with motor neuronopathy and downbeat nystagmus, a classic sign of vestibulocerebellar disease. All patients had clinical and electrodiagnostic features of anterior horn cell disease. Involvement of finger and wrist extensors predominated, causing finger and wrist drop. Bulbar or respiratory dysfunction did not occur. All three had clinically evident downbeat nystagmus worse on lateral and downgaze, confirmed on eye movement recordings using the magnetic search coil technique in two patients. Additional oculomotor findings included alternating skew deviation and intermittent horizontal saccadic oscillations, in one patient each. One patient had mild cerebellar atrophy, while the other two had no cerebellar or brainstem abnormality on neuroimaging. The disorder is slowly progressive, with survival up to 30 years from the time of onset. The combination of motor neuronopathy, characterized by early and prominent wrist and finger extensor weakness, and downbeat nystagmus with or without other cerebellar eye movement abnormalities may represent a novel motor neuron syndrome.

Motor neuronopathy with dropped hands and downbeat nystagmus: A distinctive disorder? A case report

PubMed Central

Thakore, Nimish J; Pioro, Erik P; Rucker, Janet C; Leigh, R John

2006-01-01

Background Eye movements are clinically normal in most patients with motor neuron disorders until late in the disease course. Rare patients are reported to show slow vertical saccades, impaired smooth pursuit, and gaze-evoked nystagmus. We report clinical and oculomotor findings in three patients with motor neuronopathy and downbeat nystagmus, a classic sign of vestibulocerebellar disease. Case presentation All patients had clinical and electrodiagnostic features of anterior horn cell disease. Involvement of finger and wrist extensors predominated, causing finger and wrist drop. Bulbar or respiratory dysfunction did not occur. All three had clinically evident downbeat nystagmus worse on lateral and downgaze, confirmed on eye movement recordings using the magnetic search coil technique in two patients. Additional oculomotor findings included alternating skew deviation and intermittent horizontal saccadic oscillations, in one patient each. One patient had mild cerebellar atrophy, while the other two had no cerebellar or brainstem abnormality on neuroimaging. The disorder is slowly progressive, with survival up to 30 years from the time of onset. Conclusion The combination of motor neuronopathy, characterized by early and prominent wrist and finger extensor weakness, and downbeat nystagmus with or without other cerebellar eye movement abnormalities may represent a novel motor neuron syndrome. PMID:16409626

Gamma-aminobutyric acid (GABA)-B receptor 1 in cerebellar cortex of essential tremor.

PubMed

Luo, C; Rajput, A H; Robinson, C A; Rajput, A

2012-06-01

Some reports suggest cerebellar dysfunction as the basis of essential tremor (ET). Several drugs with the action of gamma-aminobutyric acid (GABA) are known to improve ET. Autopsy studies were performed on brains from nine former patients followed at the Movement Disorders Clinic Saskatchewan, Canada, and compared with five normal control brains. We aimed to measure the concentration of GABA B receptor 1 (GBR1) in the brains of patients who had had ET and to compare them to the GABA concentration in brains of controls. Western blot was used to determine the expression of GBR1 in cerebellar cortex tissue. We found that compared to the controls, the ET brains had three different patterns of GBR1 protein concentration--two with high, four comparable, and three with marginally low levels. There was no association between the age of onset, severity or duration of tremor, the response to alcohol or other drugs and GBR1 level. Thus, we conclude that our study does not support that GBR1 is involved in ET. Further studies are needed to verify these results. Copyright © 2011 Elsevier Ltd. All rights reserved.

Brainstem processing of vestibular sensory exafference: implications for motion sickness etiology

PubMed Central

Oman, Charles M.; Cullen, Kathleen E.

2014-01-01

The origin of the internal “sensory conflict” stimulus causing motion sickness has been debated for more than four decades. Recent studies show a subclass of neurons in the vestibular nuclei and deep cerebellar nuclei that respond preferentially to passive head movements. During active movement, the semicircular canal and otolith input (“reafference”) to these neurons is cancelled by a mechanism comparing the expected consequences of self-generated movement (estimated with an internal model-presumably located in the cerebellum) with the actual sensory feedback. The un-cancelled component (“exafference”) resulting from passive movement normally helps compensate for unexpected postural disturbances. Notably, the existence of such vestibular “sensory conflict” neurons had been postulated as early as 1982, but their existence and putative role in posture control, motion sickness has been long debated. Here we review the development of “sensory conflict” theories in relation to recent evidence for brainstem and cerebellar reafference cancellation, and identify some open research questions. We propose that conditions producing persistent activity of these neurons, or their targets, stimulates nearby brainstem emetic centers – via an as yet unidentified mechanism. We discuss how such a mechanism is consistent with the notable difference in motion sickness susceptibility of drivers as opposed to passengers, human immunity to normal self-generated movement, and why head restraint or lying horizontal confers relative immunity. Finally, we propose that fuller characterization of these mechanisms, and their potential role in motion sickness could lead to more effective, scientifically based prevention and treatment for motion sickness. PMID:24838552

Survival of adult neurons lacking cholesterol synthesis in vivo.

PubMed

Fünfschilling, Ursula; Saher, Gesine; Xiao, Le; Möbius, Wiebke; Nave, Klaus-Armin

2007-01-02

Cholesterol, an essential component of all mammalian plasma membranes, is highly enriched in the brain. Both during development and in the adult, brain cholesterol is derived from local cholesterol synthesis and not taken up from the circulation. However, the contribution of neurons and glial cells to total brain cholesterol metabolism is unknown. Using conditional gene inactivation in the mouse, we disrupted the squalene synthase gene (fdft1), which is critical for cholesterol synthesis, in cerebellar granule cells and some precerebellar nuclei. Mutant mice showed no histological signs of neuronal degeneration, displayed ultrastructurally normal synapses, and exhibited normal motor coordination. This revealed that these adult neurons do not require cell-autonomous cholesterol synthesis for survival or function. We conclude that at least some adult neurons no longer require endogenous cholesterol synthesis and can fully meet their cholesterol needs by uptake from their surrounding. Glia are a likely source of cholesterol in the central nervous system.

A Novel and Multivalent Role of Pax6 in Cerebellar Development

PubMed Central

Yeung, Joanna; Ha, Thomas J.; Swanson, Douglas J.

2016-01-01

Pax6 is a prominent gene in brain development. The deletion of Pax6 results in devastated development of eye, olfactory bulb, and cortex. However, it has been reported that the Pax6-null Sey cerebellum only has minor defects involving granule cells despite Pax6 being expressed throughout cerebellar development. The present work has uncovered a requirement of Pax6 in the development of all rhombic lip (RL) lineages. A significant downregulation of Tbr1 and Tbr2 expression is found in the Sey cerebellum, these are cell-specific markers of cerebellar nuclear (CN) neurons and unipolar brush cells (UBCs), respectively. The examination of Tbr1 and Lmx1a immunolabeling and Nissl staining confirmed the loss of CN neurons from the Sey cerebellum. CN neuron progenitors are produced in the mutant but there is an enhanced death of these neurons as shown by increased presence of caspase-3-positive cells. These data indicate that Pax6 regulates the survival of CN neuron progenitors. Furthermore, the analysis of experimental mouse chimeras suggests a cell-extrinsic role of Pax6 in CN neuron survival. For UBCs, using Tbr2 immunolabeling, these cells are significantly reduced in the Sey cerebellum. The loss of UBCs in the mutant is due partly to cell death in the RL and also to the reduced production of progenitors from the RL. These results demonstrate a critical role for Pax6 in regulating the generation and survival of UBCs. This and previous work from our laboratory demonstrate a seminal role of Pax6 in the development of all cerebellar glutamatergic neurons. SIGNIFICANCE STATEMENT Pax6 is a key molecule in development. Pax6 is best known as the master control gene in eye development with mutations causing aniridia in humans. Pax6 also plays important developmental roles in the cortex and olfactory bulb. During cerebellar development, Pax6 is robustly expressed in the germinal zone of all glutamatergic neurons [cerebellar nuclear (CN) neurons, granule cells, and unipolar brush cells (UBCs)]. Past work has not found abnormalities in the CN and UBC populations. Our study reveals that the Pax6-null mutation dramatically affects these cells and identifies Pax6 as a key regulator of cell survival in CN neurons and of cell production in UBCs. The present study shows how Pax6 is key to the development of glutamatergic cells in the cerebellum. PMID:27581449

Cerebellar Hypoplasia and Dysmorphia in Neurofibromatosis Type 1.

PubMed

Toelle, Sandra P; Poretti, Andrea; Weber, Peter; Seute, Tatjana; Bromberg, Jacoline E C; Scheer, Ianina; Boltshauser, Eugen

2015-12-01

Unidentified bright objects (UBO) and tumors are well-known cerebellar abnormalities in neurofibromatosis type 1 (NF1). Literature reports on malformative cerebellar anomalies in neurofibromatosis type 1 (NF1), however, are scant. We retrospectively studied the clinical and neuroimaging findings of 5 patients with NF1 (4 females, age 6 to 29 years at last follow-up) and cerebellar anomalies. Cerebellar symptoms on neurological examination were mild or even not evident whereas learning disabilities were more or less pronounced in four patients. Two patients had cerebellar hypoplasia (diffusely enlarged cerebellar interfoliar spaces) and three cerebellar dysmorphias involving mainly one cerebellar hemisphere. In NF1, malformative cerebellar anomalies are rare (estimated prevalence of about 1%), but most likely underestimated and easily overlooked, because physicians tend to focus on more prevalent, obvious, and well-known findings such as optic pathway gliomas, other tumors, and UBO. This kind of cerebellar anomaly in NF1 has most likely a malformative origin, but the exact pathogenesis is unknown. The individual clinical significance is difficult to determine. We suggest that cerebellar anomalies should be systematically evaluated in neuroimaging studies of NF1 patients.

Nicotinic receptor abnormalities in the cerebellar cortex in autism.

PubMed

Lee, M; Martin-Ruiz, C; Graham, A; Court, J; Jaros, E; Perry, R; Iversen, P; Bauman, M; Perry, E

2002-07-01

Autism is a common developmental disorder associated with structural and inferred neurochemical abnormalities of the brain. Cerebellar abnormalities frequently have been identified, based on neuroimaging or neuropathology. Recently, the cholinergic neurotransmitter system has been implicated on the basis of nicotinic receptor loss in the cerebral cortex. Cerebellar cholinergic activities were therefore investigated in autopsy tissue from a series of autistic individuals. The presynaptic cholinergic enzyme, choline acetyltransferase, together with nicotinic and muscarinic receptor subtypes were compared in the cerebellum from age-matched mentally retarded autistic (eight), normal control (10) and non-autistic mentally retarded individuals (11). The nicotinic receptor binding the agonist epibatidine (the high affinity receptor subtype, consisting primarily of alpha3 and alpha4, together with beta2 receptor subunits) was significantly reduced by 40-50% in the granule cell, Purkinje and molecular layers in the autistic compared with the normal group (P < 0.05). There was an opposite increase (3-fold) in the nicotinic receptor binding alpha-bungarotoxin (to the alpha7 subunit) which reached significance in the granule cell layer (P < 0.05). These receptor changes were paralleled by a significant reduction (P < 0.05) and non-significant increase, respectively, of alpha4 and alpha7 receptor subunit immunoreactivity measured using western blotting. Immunohistochemically loss of alpha(4 )reactivity was apparent from Purkinje and the other cell layers, with increased alpha7 reactivity in the granule cell layer. There were no significant changes in choline acetyltransferase activity, or in muscarinic M1 and M2 receptor subtypes in autism. In the non-autistic mentally retarded group, the only significant abnormality was a reduction in epibatidine binding in the granule cell and Purkinje layers. In two autistic cases examined histologically, Purkinje cell loss was observed in multiple lobules throughout the vermis and hemispheres. This was more severe in one case with epilepsy, which also showed vermis folial malformation. The case with less severe Purkinje cell loss also showed cerebellar white matter thinning and demyelination. These findings indicate a loss of the cerebellar nicotinic alpha4 receptor subunit in autism which may relate to the loss of Purkinje cells, and a compensatory increase in the alpha7 subunit. It remains to be determined how these receptor abnormalities are involved in neurodevelopment in autism and what is the relationship to mental function. Since nicotinic receptor agonists enhance attentional function and also induce an elevation in the high affinity receptor, nicotinic therapy in autism may be worth considering.

Cerebellum in Levodopa-Induced Dyskinesias: The Unusual Suspect in the Motor Network

PubMed Central

Kishore, Asha; Popa, Traian

2014-01-01

The exact mechanisms that generate levodopa-induced dyskinesias (LID) during chronic levodopa therapy for Parkinson’s disease (PD) are not yet fully established. The most widely accepted theories incriminate the non-physiological synthesis, release and reuptake of dopamine generated by exogenously administered levodopa in the striatum, and the aberrant plasticity in the cortico-striatal loops. However, normal motor performance requires the correct recruitment of motor maps. This depends on a high level of synergy within the primary motor cortex (M1) as well as between M1 and other cortical and subcortical areas, for which dopamine is necessary. The plastic mechanisms within M1, which are crucial for the maintenance of this synergy, are disrupted both during “OFF” and dyskinetic states in PD. When tested without levodopa, dyskinetic patients show loss of treatment benefits on long-term potentiation and long-term depression-like plasticity of the intracortical circuits. When tested with the regular pulsatile levodopa doses, they show further impairment of the M1 plasticity, such as inability to depotentiate an already facilitated synapse and paradoxical facilitation in response to afferent input aimed at synaptic inhibition. Dyskinetic patients have also severe impairment of the associative, sensorimotor plasticity of M1 attributed to deficient cerebellar modulation of sensory afferents to M1. Here, we review the anatomical and functional studies, including the recently described bidirectional connections between the cerebellum and the basal ganglia that support a key role of the cerebellum in the generation of LID. This model stipulates that aberrant neuronal synchrony in PD with LID may propagate from the subthalamic nucleus to the cerebellum and “lock” the cerebellar cortex in a hyperactive state. This could affect critical cerebellar functions such as the dynamic and discrete modulation of M1 plasticity and the matching of motor commands with sensory information from the environment during motor performance. We propose that in dyskinesias, M1 neurons have lost the ability to depotentiate an activated synapse when exposed to acute pulsatile, non-physiological, dopaminergic surges and become abnormally receptive to unfiltered, aberrant, and non-salient afferent inputs from the environment. The motor program selection in response to such non-salient and behaviorally irrelevant afferent inputs would be abnormal and involuntary. The motor responses are worsened by the lack of normal subcortico–cortical inputs from cerebellum and basal ganglia, because of the aberrant plasticity at their own synapses. Artificial cerebellar stimulation might help re-establish the cerebellar and basal ganglia control over the non-salient inputs to the motor areas during synaptic dopaminergic surges. PMID:25183959

FoxP2 expression in the cerebellum and inferior olive: development of the transverse stripe-shaped expression pattern in the mouse cerebellar cortex.

PubMed

Fujita, Hirofumi; Sugihara, Izumi

2012-02-15

Many molecules are expressed heterogeneously in subpopulations of cerebellar Purkinje cells (PCs) and inferior olive (IO) neurons during development or in adulthood. These expression patterns are often organized in longitudinal stripes in the cerebellar cortex, which may be related to functional compartmentalization. FoxP2, a transcription factor, is expressed in PCs and IO neurons, but the details of its expression pattern remain unclear. Here we examined FoxP2 expression patterns systematically by immunostaining serial sections of the hindbrain from embryonic day 14.5 to adulthood in mice. FoxP2 was highly expressed in virtually all PCs at and before postnatal day 6 (P6), except for those in the flocculus and small parts of the nodulus (vermal lobule X), where FoxP2 expression was moderate or absent. After P6, FoxP2 expression gradually diminished in PCs in some areas. In adults, FoxP2 was expressed, less intensely than in earlier stages, in subsets of PCs that were mostly arranged transversely along the folial apices. In contrast, FoxP2 was expressed intensely in most IO neurons during development and in adulthood. FoxP2 was also expressed in a small population of neurons in the cerebellar nuclei. FoxP2 expression in adult rats and chicks was generally comparable to that in adult mice, suggesting evolutionary conservation of the expression pattern. Thus, the FoxP2 expression pattern reflects new transverse compartmentalization in the adult cerebellar cortex, although its functional significance remains unclear. Copyright © 2011 Wiley-Liss, Inc.

The mouse cerebellar cortex in organotypic slice cultures: an in vitro model to analyze the consequences of mutations and pathologies on neuronal survival, development, and function.

PubMed

Lonchamp, Etienne; Dupont, Jean-Luc; Beekenkamp, Huguette; Poulain, Bernard; Bossu, Jean-Louis

2006-01-01

Thin acute slices and dissociated cell cultures taken from different parts of the brain have been widely used to examine the function of the nervous system, neuron-specific interactions, and neuronal development (specifically, neurobiology, neuropharmacology, and neurotoxicology studies). Here, we focus on an alternative in vitro model: brain-slice cultures in roller tubes, initially introduced by Beat Gähwiler for studies with rats, that we have recently adapted for studies of mouse cerebellum. Cultured cerebellar slices afford many of the advantages of dissociated cultures of neurons and thin acute slices. Organotypic slice cultures were established from newborn or 10-15-day-old mice. After 3-4 weeks in culture, the slices flattened to form a cell monolayer. The main types of cerebellar neurons could be identified with immunostaining techniques, while their electrophysiological properties could be easily characterized with the patch-clamp recording technique. When slices were taken from newborn mice and cultured for 3 weeks, aspects of the cerebellar development were displayed. A functional neuronal network was established despite the absence of mossy and climbing fibers, which are the two excitatory afferent projections to the cerebellum. When slices were made from 10-15-day-old mice, which are at a developmental stage when cerebellum organization is almost established, the structure and neuronal pathways were intact after 3-4 weeks in culture. These unique characteristics make organotypic slice cultures of mouse cerebellar cortex a valuable model for analyzing the consequences of gene mutations that profoundly alter neuronal function and compromise postnatal survival.

Neurotoxic response of infant monkeys to methylmercury.

PubMed

Willes, R F; Truelove, J F; Nera, E A

1978-02-01

Four infant monkeys were dosed orally with 500 microgram Hg/kg body wt./day /as methylmercury (MeHg) chloride dissolved sodium carbonate) beginning at 1 day of age. Neurological and behavioral signs of MeHg toxicity and blood Hg levels were monitored weekly. At first sign of MeHg intoxication, dosing with MeHg was terminated and the infants were monitored to assess reversal of the signs of MeHg toxicity. The first signs of MeHg toxicity, exhibited as a loss in dexterity and locomotor ability, were observed after 28--29 days of treatment; the blood Hg levels were 8.0--9.4 microgram Hg/g blood. Dosing was terminated at 28--29 days of treatment but the signs of MeHg toxicity continued to develop. The infants became ataxic, blind, comatose and were necropsied at 35--43 days after initiating treatment with MgHg. The mercury concentrations in tissues analyzed after necropsy were highest in liver (55.8 +/- 3.2 microgram Hg/g) followed by occipital cortex (35.6 +/- 4.8 microgram Hg/g) renal cortex (32.8 +/- 1.6 microgram Hg/g). The frontal and temporal cortices had 27.0 +/- 3.4 and 29.6 +/- 4.9 microgram Hg/g respectively while the cerebellar Hg concentration averaged 13.0 +/- 1.5 microgram Hg/g. The mean blood/brain ratio was 0.21 +/- 0.4. Histopathologic lesions were marked in the cerebrum with less severe lesions in the cerebellar nuclei. The Purkinje and granular cells of the cerebellar vermis appeared histologically normal. Lesions were not observed in the peripheral nervous system. The signs of MeHg intoxication, the tissue distribution of MeHg and histopathologic lesions observed in the infant monkeys were similar to those reported for adult monkeys.

The coevolution of play and the cortico-cerebellar system in primates.

PubMed

Kerney, Max; Smaers, Jeroen B; Schoenemann, P Thomas; Dunn, Jacob C

2017-10-01

Primates are some of the most playful animals in the natural world, yet the reason for this remains unclear. One hypothesis posits that primates are so playful because playful activity functions to help develop the sophisticated cognitive and behavioural abilities that they are also renowned for. If this hypothesis were true, then play might be expected to have coevolved with the neural substrates underlying these abilities in primates. Here, we tested this prediction by conducting phylogenetic comparative analyses to determine whether play has coevolved with the cortico-cerebellar system, a neural system known to be involved in complex cognition and the production of complex behaviour. We used phylogenetic generalised least squares analyses to compare the relative volume of the largest constituent parts of the primate cortico-cerebellar system (prefrontal cortex, non-prefrontal heteromodal cortical association areas, and posterior cerebellar hemispheres) to the mean percentage of time budget spent in play by a sample of primate species. Using a second categorical data set on play, we also used phylogenetic analysis of covariance to test for significant differences in the volume of the components of the cortico-cerebellar system among primate species exhibiting one of three different levels of adult-adult social play. Our results suggest that, in general, a positive association exists between the amount of play exhibited and the relative size of the main components of the cortico-cerebellar system in our sample of primate species. Although the explanatory power of this study is limited by the correlational nature of its analyses and by the quantity and quality of the data currently available, this finding nevertheless lends support to the hypothesis that play functions to aid the development of cognitive and behavioural abilities in primates.

In and out of the loop: external and internal modulation of the olivo-cerebellar loop

PubMed Central

Libster, Avraham M.; Yarom, Yosef

2013-01-01

Cerebellar anatomy is known for its crystal like structure, where neurons and connections are precisely and repeatedly organized with minor variations across the Cerebellar Cortex. The olivo-cerebellar loop, denoting the connections between the Cerebellar cortex, Inferior Olive and Cerebellar Nuclei (CN), is also modularly organized to form what is known as the cerebellar module. In contrast to the relatively organized and static anatomy, the cerebellum is innervated by a wide variety of neuromodulator carrying axons that are heterogeneously distributed along the olivo-cerebellar loop, providing heterogeneity to the static structure. In this manuscript we review modulatory processes in the olivo-cerebellar loop. We start by discussing the relationship between neuromodulators and the animal behavioral states. This is followed with an overview of the cerebellar neuromodulatory signals and a short discussion of why and when the cerebellar activity should be modulated. We then devote a section for three types of neurons where we briefly review its properties and propose possible neuromodulation scenarios. PMID:23626524

In utero diagnosis of PHACE syndrome by fetal magnetic resonance imaging (MRI).

PubMed

Fernández-Mayoralas, Daniel Martín; Recio-Rodríguez, Manuel; Fernández-Perrone, Ana Laura; Jiménez-de-la-Peña, Mar; Muñoz-Jareño, Nuria; Fernández-Jaén, Alberto

2014-01-01

The acronym PHACE describes the association of facial hemangioma with anomalies of the posterior fossa, cerebral arteries, and cardiovascular and ocular alterations. This study presents a case of diagnostic suspicion based on fetal MRI. We report the case of a pregnant woman whose 26-week MRI revealed a female fetus with hypoplasia of the right cerebellar hemisphere and right microphthalmia, leading to the suspicion of PHACE syndrome. The diagnosis was confirmed at birth, together with other criteria: facial hemangioma, absent posterior inferior cerebellar artery, and dysplasia of the right internal carotid artery. To our knowledge, this is the first live case described prenatally with both ocular and cerebellar findings on fetal MRI that suggest PHACE syndrome. The prenatal presence of 2 PHACE criteria led to the suspicion of this syndrome, and prenatal diagnostic criteria might be developed to improve information regarding the prognosis of cerebellar malformations.

The use of the trendelenburg position in the surgical treatment of extreme cerebellar slump.

PubMed

Dewaele, Frank; Kalmar, Alain F; Baert, Edward; Van Haver, Annemieke; Hallaert, Giorgio; De Mets, Frank; Williams, Leonie; Kalala Okito, Jean Pierre; Paemeleire, Koen; Caemaert, Jacques; Van Roost, Dirk

2016-01-01

State-of-the-art treatment for Chiari Malformation I (CM-I) consists of decompression by posterior fossa craniectomy. A rare but severe complication that develops over months to years after this procedure is cerebellar slump. Treatment options for this condition are limited. We present a new and promising approach to treat this rare condition. The patients were placed in the Trendelenburg position to facilitate ascent of the cerebellum. After almost complete dissolution of neurologic symptoms, surgical reconstruction was performed by tonsillar resection and the creation of a new structural support using a bone graft. Both patients experienced good clinical and morphological outcomes immediately after surgery, and for two years thereafter. Neurological symptoms related to cerebellar or brainstem slump can be adequately reversed by placing the patient in the Trendelenburg position. After uneventful gravitational reversal of the slump, safe surgical reconstruction of the cerebellar support can be performed to securely preserve the anatomical reversal.

Cerebellar cysticercosis caused by larval Taenia crassiceps tapeworm in immunocompetent woman, Germany.

PubMed

Ntoukas, Vasileios; Tappe, Dennis; Pfütze, Daniel; Simon, Michaela; Holzmann, Thomas

2013-12-01

Human cysticercosis caused by Taenia crassiceps tapeworm larvae involves the muscles and subcutis mostly in immunocompromised patients and the eye in immunocompetent persons. We report a successfully treated cerebellar infection in an immunocompetent woman. We developed serologic tests, and the parasite was identified by histologic examination and 12s rDNA PCR and sequencing.

Cerebellar infarction in the territory of the medial branch of the superior cerebellar artery.

PubMed

Sohn, Sung-Il; Lee, Hyung; Lee, Seong-Ryong; Baloh, Robert W

2006-01-10

The authors studied 14 patients with an isolated cerebellar infarct in the territory of the medial branch of the superior cerebellar artery (MSCA). The most common clinical finding was severe gait ataxia with sudden falling (n = 9) or severe veering (n = 2). Cerebellar dysarthria was found in 8 patients. Eight patients had a mild unilateral limb ataxia. These findings emphasize that MSCA territory cerebellar infarction presented with the prominent gait ataxia and cerebellar dysarthria.

Cathodal Transcranial Direct Current Stimulation (tDCS) to the Right Cerebellar Hemisphere Affects Motor Adaptation During Gait.

PubMed

Fernandez, Lara; Albein-Urios, Natalia; Kirkovski, Melissa; McGinley, Jennifer L; Murphy, Anna T; Hyde, Christian; Stokes, Mark A; Rinehart, Nicole J; Enticott, Peter G

2017-02-01

The cerebellum appears to play a key role in the development of internal rules that allow fast, predictive adjustments to novel stimuli. This is crucial for adaptive motor processes, such as those involved in walking, where cerebellar dysfunction has been found to increase variability in gait parameters. Motor adaptation is a process that results in a progressive reduction in errors as movements are adjusted to meet demands, and within the cerebellum, this seems to be localised primarily within the right hemisphere. To examine the role of the right cerebellar hemisphere in adaptive gait, cathodal transcranial direct current stimulation (tDCS) was administered to the right cerebellar hemisphere of 14 healthy adults in a randomised, double-blind, crossover study. Adaptation to a series of distinct spatial and temporal templates was assessed across tDCS condition via a pressure-sensitive gait mat (ProtoKinetics Zeno walkway), on which participants walked with an induced 'limp' at a non-preferred pace. Variability was assessed across key spatial-temporal gait parameters. It was hypothesised that cathodal tDCS to the right cerebellar hemisphere would disrupt adaptation to the templates, reflected in a failure to reduce variability following stimulation. In partial support, adaptation was disrupted following tDCS on one of the four spatial-temporal templates used. However, there was no evidence for general effects on either the spatial or temporal domain. This suggests, under specific conditions, a coupling of spatial and temporal processing in the right cerebellar hemisphere and highlights the potential importance of task complexity in cerebellar function.

Early-onset progressive ataxia associated with the first CACNA1A mutation identified within the I-II loop.

PubMed

Cricchi, F; Di Lorenzo, C; Grieco, G S; Rengo, C; Cardinale, A; Racaniello, M; Santorelli, F M; Nappi, G; Pierelli, F; Casali, C

2007-03-15

Familial hemiplegic migraine type 1, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) are allelic disorders associated with mutations in the CACNA1A gene, which encodes the alpha1 subunit of the P/Q-type calcium channel (Ca(V)2.1). SCA6 and EA2 share a number of clinical features, such as prominent cerebellar involvement and good response to acetazolamide therapy. However, while SCA6 develops as a late-onset, progressive ataxia, EA2 has an earlier, and episodic, onset. We report on two sisters with a heterogeneous clinical phenotype. The first developed progressive cerebellar ataxia after age 30, without noticeable episodes of vertigo or headache. A 1 year trial with acetazolamide did not produce significant results. The other reported episodes of vertigo, headache and gait imbalance since late childhood, with good response to acetazolamide, before developing moderate chronic cerebellar ataxia. Brain MRI showed cerebellar atrophy, especially in the vermis, in both patients. Direct sequencing of CACNA1A identified a heterozygous 1360G>A mutation in exon 11 resulting in the substitution of alanine for threonine at residue 454 (p.Ala454Thr). This is the first description of a change residing in the cytoplasmic I-II loop associated with a clinical phenotype.

Can clues from evolution unlock the molecular development of the cerebellum?

PubMed

Butts, Thomas; Chaplin, Natalie; Wingate, Richard J T

2011-02-01

The cerebellum sits at the rostral end of the vertebrate hindbrain and is responsible for sensory and motor integration. Owing to its relatively simple architecture, it is one of the most powerful model systems for studying brain evolution and development. Over the last decade, the combination of molecular fate mapping techniques in the mouse and experimental studies, both in vitro and in vivo, in mouse and chick have significantly advanced our understanding of cerebellar neurogenesis in space and time. In amniotes, the most numerous cell type in the cerebellum, and indeed the brain, is the cerebellar granule neurons, and these are born from a transient secondary proliferative zone, the external granule layer (EGL), where proliferation is driven by sonic hedgehog signalling and causes cerebellar foliation. Recent studies in zebrafish and sharks have shown that while the molecular mechanisms of neurogenesis appear conserved across vertebrates, the EGL as a site of shh-driven transit amplification is not, and is therefore implicated as a key amniote innovation that facilitated the evolution of the elaborate foliated cerebella found in birds and mammals. Ellucidating the molecular mechanisms underlying the origin of the EGL in evolution could have significant impacts on our understanding of the molecular details of cerebellar development.

Creation of a cerebellar diameter reference standard and its clinical application to the detection of cerebellar hypoplasia unique to trisomy 18.

PubMed

Hayata, Kei; Hiramatsu, Yuji; Masuyama, Hisashi; Etou, Eriko; Nobumoto, Etsuko; Mitsui, Takashi

2015-12-01

We created a new reference standard focusing on the hemispheric anteroposterior cerebellar diameter (APCD) in addition to the transverse cerebellar diameter (TCD) and discussed whether or not the cerebellar measurement was useful for the detection of trisomy 18 (T18). In 150 normal fetuses between 14 and 36 weeks of gestational age (GA), the TCD and APCD were prospectively measured. In 26 cases with T18, the value was compared with the control. At <22 weeks of gestation, the TCD reference standard was calculated as follows: TCD = (1.027 × GA) - 0.674 (R(2) = 0.97, P < 0.001). The reference standard of the APCD was calculated as follows: APCD = (0.682 × GA) - 3.925 (R(2) = 0.73, P < 0.001). In eight cases with T18, the TCD was below the 5th percentile value in 7/8 (88%) cases and the APCD was below the 5th percentile value in 8/8 (100%) cases. At >22 weeks of gestation, the reference standard of the TCD was calculated as follows: TCD = (1.603 × GA) - 13.216 (R(2) = 0.92, P < 0.001). The reference standard of the APCD was calculated as follows: APCD = (0.859 × GA) - 7.30 (R(2) = 0.84, P < 0.001). In 18 cases with T18, the TCD was below the 5th percentile value in 14/18 (78%) cases and the APCD was below the 5th percentile value in 18/18 (100%) cases. APCD reference standard, divided by the gestational age of more or less than 22 weeks, might be useful to diagnose T18. © 2015 Japan Society of Obstetrics and Gynecology.

Adaptive filter design using recurrent cerebellar model articulation controller.

PubMed

Lin, Chih-Min; Chen, Li-Yang; Yeung, Daniel S

2010-07-01

A novel adaptive filter is proposed using a recurrent cerebellar-model-articulation-controller (CMAC). The proposed locally recurrent globally feedforward recurrent CMAC (RCMAC) has favorable properties of small size, good generalization, rapid learning, and dynamic response, thus it is more suitable for high-speed signal processing. To provide fast training, an efficient parameter learning algorithm based on the normalized gradient descent method is presented, in which the learning rates are on-line adapted. Then the Lyapunov function is utilized to derive the conditions of the adaptive learning rates, so the stability of the filtering error can be guaranteed. To demonstrate the performance of the proposed adaptive RCMAC filter, it is applied to a nonlinear channel equalization system and an adaptive noise cancelation system. The advantages of the proposed filter over other adaptive filters are verified through simulations.

Stars and Stripes in the Cerebellar Cortex: A Voltage Sensitive Dye Study

PubMed Central

Rokni, Dan; Llinas, Rodolfo; Yarom, Yosef

2007-01-01

The lattice-like structure of the cerebellar cortex and its anatomical organization in two perpendicular axes provided the foundations for many theories of cerebellar function. However, the functional organization does not always match the anatomical organization. Thus direct measurement of the functional organization is central to our understanding of cerebellar processing. Here we use voltage sensitive dye imaging in the isolated cerebellar preparation to characterize the spatio-temporal organization of the climbing and mossy fiber (MF) inputs to the cerebellar cortex. Spatial and temporal parameters were used to develop reliable criteria to distinguish climbing fiber (CF) responses from MF responses. CF activation excited postsynaptic neurons along a parasagittal cortical band. These responses were composed of slow (∼25 ms), monophasic depolarizing signals. Neither the duration nor the spatial distribution of CF responses were affected by inhibition. Activation of MF generated responses that were organized in radial patches, and were composed of a fast (∼5 ms) depolarizing phase followed by a prolonged (∼100 ms) negative wave. Application of a GABAA blocker eliminated the hyperpolarizing phase and prolonged the depolarizing phase, but did not affect the spatial distribution of the response, thus suggesting that it is not the inhibitory system that is responsible for the inability of the MF input to generate beams of activity that propagate along the parallel fiber system. PMID:18958242

Reduced expression of the Ca(2+) transporter protein PMCA2 slows Ca(2+) dynamics in mouse cerebellar Purkinje neurones and alters the precision of motor coordination.

PubMed

Empson, Ruth M; Turner, Paul R; Nagaraja, Raghavendra Y; Beesley, Philip W; Knöpfel, Thomas

2010-03-15

Cerebellar Purkinje neurones (PNs) express high levels of the plasma membrane calcium ATPase, PMCA2, a transporter protein critical for the clearance of calcium from excitable cells. Genetic deletion of one PMCA2 encoding gene in heterozygous PMCA2 knock-out (PMCA2(+/-) mice enabled us to determine how PMCA2 influences PN calcium regulation without the complication of the severe morphological changes associated with complete PMCA2 knock-out (PMCA2(-/-) in these cells. The PMCA2(+/-) cerebellum expressed half the normal levels of PMCA2 and this nearly doubled the time taken for PN dendritic calcium transients to recover (mean fast and slow recovery times increased from 70 ms to 110 ms and from 600 ms to 1100 ms). The slower calcium recovery had distinct consequences for PMCA2(+/-) PN physiology. The PNs exhibited weaker climbing fibre responses, prolonged outward Ca(2+)-dependent K(+) current (mean fast and slow recovery times increased from 136 ms to 192 ms and from 595 ms to 1423 ms) and a slower mean frequency of action potential firing (7.4 Hz compared with 15.8 Hz). Our findings were consistent with prolonged calcium accumulation in the cytosol of PMCA2(+/-) Purkinje neurones. Although PMCA2(+/-) mice exhibited outwardly normal behaviour and little change in their gait pattern, when challenged to run on a narrow beam they exhibited clear deficits in hindlimb coordination. Training improved the motor performance of both PMCA2(+/-) and wild-type mice, although PMCA2(+/-) mice were always impaired. We conclude that reduced calcium clearance perturbs calcium dynamics in PN dendrites and that this is sufficient to disrupt the accuracy of cerebellar processing and motor coordination.

Magnetic resonance spectroscopy of the normal cerebellum: what degree of variability can be expected?

PubMed

Currie, Stuart; Hadjivassiliou, Marios; Wilkinson, Iain David; Griffiths, Paul David; Hoggard, Nigel

2013-04-01

The objectives of this paper are (a) to establish the reliability of relative metabolite concentrations determined with (1)H-MR spectroscopy of the cerebellum using a method appropriate to the constraints of clinical radiology and (b) to record normal values for metabolites within the cerebellum and to look for differences in metabolite concentrations between the cerebellar hemispheric white matter and the superior vermis. 3-T (1)H-MR spectra were obtained from voxels positioned in the right cerebellar hemispheric white matter and the superior vermis in 55 healthy adults (mean age 41 years, range 20 to 77) using a single voxel PRESS sequence (TR/TE = 2,000/144 ms). One volunteer (male, age 34 years) was examined in six separate sessions over a period of 3 weeks. Reliability of intra- and inter-subject metabolite fitted area ratios was determined by evaluating coefficients of variance (%). Inter- and intra-subject coefficients of variance (%) in metabolite ratios were consistently lower in the vermis (4 to 11.6) compared to those of the hemisphere (7.2 to 14.3). Cho/Cr was significantly higher in the vermis (0.83 ± 0.10) compared to the hemisphere (0.76 ± 0.11) and NAA/Cho was significantly lower in the vermis (1.19 ± 0.12) compared to the hemisphere (1.35 ± 0.16). Low inter- and intra-subject variability can be achieved when using a (1)H-MR spectroscopy technique that is appropriate to the time constraints of clinical radiology. The regional variations of Cho/Cr and NAA/Cho within the hemisphere and vermis should be considered when performing studies of diseases, which may preferentially target a particular cerebellar location.

False-Positive Head-Impulse Test in Cerebellar Ataxia

PubMed Central

Kremmyda, Olympia; Kirchner, Hanni; Glasauer, Stefan; Brandt, Thomas; Jahn, Klaus; Strupp, Michael

2012-01-01

The objective of this study was to compare the findings of the bedside head-impulse test (HIT), passive head rotation gain, and caloric irrigation in patients with cerebellar ataxia (CA). In 16 patients with CA and bilaterally pathological bedside HIT, vestibuloocular reflex (VOR) gains were measured during HIT and passive head rotation by scleral search coil technique. Eight of the patients had pathologically reduced caloric responsiveness, while the other eight had normal caloric responses. Those with normal calorics showed a slightly reduced HIT gain (mean ± SD: 0.73 ± 0.15). In those with pathological calorics, gains 80 and 100 ms after the HIT as well as the passive rotation VOR gains were significantly lower. The corrective saccade after head turn occurred earlier in patients with pathological calorics (111 ± 62 ms after onset of the HIT) than in those with normal calorics (191 ± 17 ms, p = 0.0064). We identified two groups of patients with CA: those with an isolated moderate HIT deficit only, probably due to floccular dysfunction, and those with combined HIT, passive rotation, and caloric deficit, probably due to a peripheral vestibular deficit. From a clinical point of view, these results show that the bedside HIT alone can be false-positive for establishing a diagnosis of a bilateral peripheral vestibular deficit in patients with CA. PMID:23162531

What does low-intensity rTMS do to the cerebellum?

PubMed

Morellini, N; Grehl, S; Tang, A; Rodger, J; Mariani, J; Lohof, A M; Sherrard, R M

2015-02-01

Non-invasive stimulation of the human cerebellum, such as by transcranial magnetic stimulation (TMS), is increasingly used to investigate cerebellar function and identify potential treatment for cerebellar dysfunction. However, the effects of TMS on cerebellar neurons remain poorly defined. We applied low-intensity repetitive TMS (LI-rTMS) to the mouse cerebellum in vivo and in vitro and examined the cellular and molecular sequelae. In normal C57/Bl6 mice, 4 weeks of LI-rTMS using a complex biomimetic high-frequency stimulation (BHFS) alters Purkinje cell (PC) dendritic and spine morphology; the effects persist 4 weeks after the end of stimulation. We then evaluated whether LI-rTMS could induce climbing fibre (CF) reinnervation to denervated PCs. After unilateral pedunculotomy in adult mice and 2 weeks sham or BHFS stimulation, VGLUT2 immunohistochemistry was used to quantify CF reinnervation. In contrast to sham, LI-rTMS induced CF reinnervation to the denervated hemicerebellum. To examine potential mechanisms underlying the LI-rTMS effect, we verified that BHFS could induce CF reinnervation using our in vitro olivocerebellar explants in which denervated cerebellar tissue is co-cultured adjacent to intact cerebella and treated with brain-derived neurotrophic factor (BDNF) (as a positive control), sham or LI-rTMS for 2 weeks. Compared with sham, BDNF and BHFS LI-rTMS significantly increased CF reinnervation, without additive effect. To identify potential underlying mechanisms, we examined intracellular calcium flux during the 10-min stimulation. Complex high-frequency stimulation increased intracellular calcium by release from intracellular stores. Thus, even at low intensity, rTMS modifies PC structure and induces CF reinnervation.

Rapid Onset of Motor Deficits in a Mouse Model of Spinocerebellar Ataxia Type 6 Precedes Late Cerebellar Degeneration1,2,3

PubMed Central

Ljungberg, Lovisa; Cormier, Alexander; Quilez, Sabrina

2015-01-01

Abstract Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant cerebellar ataxia that has been associated with loss of cerebellar Purkinje cells. Disease onset is typically at midlife, although it can vary widely from late teens to old age in SCA6 patients. Our study focused on an SCA6 knock-in mouse model with a hyper-expanded (84X) CAG repeat expansion that displays midlife-onset motor deficits at ∼7 months old, reminiscent of midlife-onset symptoms in SCA6 patients, although a detailed phenotypic analysis of these mice has not yet been reported. Here, we characterize the onset of motor deficits in SCA684Q mice using a battery of behavioral assays to test for impairments in motor coordination, balance, and gait. We found that these mice performed normally on these assays up to and including at 6 months, but motor impairment was detected at 7 months with all motor coordination assays used, suggesting that motor deficits emerge rapidly during a narrow age window in SCA684Q mice. In contrast to what is seen in SCA6 patients, the decrease in motor coordination was observed without alterations in gait. No loss of cerebellar Purkinje cells or striatal neurons were observed at 7 months, the age at which motor deficits were first detected, but significant Purkinje cell loss was observed in 2-year-old SCA684Q mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6. PMID:26730403

Dual Tasking and Working Memory in Alcoholism: Relation to Frontocerebellar Circuitry

PubMed Central

Chanraud, Sandra; Pitel, Anne-Lise; Rohlfing, Torsten; Pfefferbaum, Adolf; Sullivan, Edith V

2010-01-01

Controversy exists regarding the role of cerebellar systems in cognition and whether working memory compromise commonly marking alcoholism can be explained by compromise of nodes of corticocerebellar circuitry. We tested 17 alcoholics and 31 age-matched controls with dual-task, working memory paradigms. Interference tasks competed with verbal and spatial working memory tasks using low (three item) or high (six item) memory loads. Participants also underwent structural MRI to obtain volumes of nodes of the frontocerebellar system. On the verbal working memory task, both groups performed equally. On the spatial working memory with the high-load task, the alcoholic group was disproportionately more affected by the arithmetic distractor than were controls. In alcoholics, volumes of the left thalamus and left cerebellar Crus I volumes were more robust predictors of performance in the spatial working memory task with the arithmetic distractor than the left frontal superior cortex. In controls, volumes of the right middle frontal gyrus and right cerebellar Crus I were independent predictors over the left cerebellar Crus I, left thalamus, right superior parietal cortex, or left middle frontal gyrus of spatial working memory performance with tracking interference. The brain–behavior correlations suggest that alcoholics and controls relied on the integrity of certain nodes of corticocerebellar systems to perform these verbal and spatial working memory tasks, but that the specific pattern of relationships differed by group. The resulting brain structure–function patterns provide correlational support that components of this corticocerebellar system not typically related to normal performance in dual-task conditions may be available to augment otherwise dampened performance by alcoholics. PMID:20410871

Diffusion tensor imaging of the human cerebellar pathways and their interplay with cerebral macrostructure

PubMed Central

Keser, Zafer; Hasan, Khader M.; Mwangi, Benson I.; Kamali, Arash; Ucisik-Keser, Fehime Eymen; Riascos, Roy F.; Yozbatiran, Nuray; Francisco, Gerard E.; Narayana, Ponnada A.

2015-01-01

Cerebellar white matter (WM) connections to the central nervous system are classified functionally into the Spinocerebellar (SC), vestibulocerebellar (VC), and cerebrocerebellar subdivisions. The SC pathways project from spinal cord to cerebellum, whereas the VC pathways project from vestibular organs of the inner ear. Cerebrocerebellar connections are composed of feed forward and feedback connections between cerebrum and cerebellum including the cortico-ponto-cerebellar (CPC) pathways being of cortical origin and the dentate-rubro-thalamo-cortical (DRTC) pathway being of cerebellar origin. In this study we systematically quantified the whole cerebellar system connections using diffusion tensor magnetic resonance imaging (DT-MRI). Ten right-handed healthy subjects (7 males and 3 females, age range 20–51 years) were studied. DT-MRI data were acquired with a voxel size = 2 mm × 2 mm × 2 mm at a 3.0 Tesla clinical MRI scanner. The DT-MRI data were prepared and analyzed using anatomically-guided deterministic tractography methods to reconstruct the SC, DRTC, fronto-ponto-cerebellar (FPC), parieto-ponto-cerebellar (PPC), temporo-ponto-cerebellar (TPC) and occipito-ponto-cerebellar (OPC). The DTI-attributes or the cerebellar tracts along with their cortical representation (Brodmann areas) were presented in standard Montréal Neurological Institute space. All cerebellar tract volumes were quantified and correlated with volumes of cerebral cortical, subcortical gray matter (GM), cerebral WM and cerebellar GM, and cerebellar WM. On our healthy cohort, the ratio of total cerebellar GM-to-WM was ~3.29 ± 0.24, whereas the ratio of cerebral GM-to-WM was approximately 1.10 ± 0.11. The sum of all cerebellar tract volumes is ~25.8 ± 7.3 mL, or a percentage of 1.6 ± 0.45 of the total intracranial volume (ICV). PMID:25904851

Cell biology of spinocerebellar ataxia.

PubMed

Orr, Harry T

2012-04-16

Ataxia is a neurological disorder characterized by loss of control of body movements. Spinocerebellar ataxia (SCA), previously known as autosomal dominant cerebellar ataxia, is a biologically robust group of close to 30 progressive neurodegenerative diseases. Six SCAs, including the more prevalent SCA1, SCA2, SCA3, and SCA6 along with SCA7 and SCA17 are caused by expansion of a CAG repeat that encodes a polyglutamine tract in the affected protein. How the mutated proteins in these polyglutamine SCAs cause disease is highly debated. Recent work suggests that the mutated protein contributes to pathogenesis within the context of its "normal" cellular function. Thus, understanding the cellular function of these proteins could aid in the development of therapeutics.

Magnetic Resonance Imaging of Malformations of Midbrain-Hindbrain.

PubMed

Abdel Razek, Ahmed Abdel Khalek; Castillo, Mauricio

2016-01-01

We aim to review the magnetic resonance imaging appearance of malformations of midbrain and hindbrain. These can be classified as predominantly cerebellar malformations, combined cerebellar and brain stem malformations, and predominantly brain stem malformations. The diagnostic criteria for the majority of these morphological malformations are based on neuroimaging findings. The predominantly cerebellar malformations include predominantly vermian hypoplasia seen in Dandy-Walker malformation and rhombencephalosynapsis, global cerebellar hypoplasia reported in lissencephaly and microlissencephaly, and unilateral cerebellar hypoplasia seen in PHACES, vanishing cerebellum, and cerebellar cleft. Cerebellar dysplasias are seen in Chudley-McCullough syndrome, associated with LAMA1 mutations and GPR56 mutations; Lhermitte-Duclos disease; and focal cerebellar dysplasias. Cerebellar hyperplasias are seen in megalencephaly-related syndromes and hemimegalencephaly with ipsilateral cerebellomegaly. Cerebellar and brain stem malformations include tubulinopathies, Joubert syndrome, cobblestone malformations, pontocerebellar hypoplasias, and congenital disorders of glycosylation type Ia. Predominantly brain stem malformations include congenital innervation dysgenesis syndrome, pontine tegmental cap dysplasia, diencephalic-mesencephalic junction dysplasia, disconnection syndrome, and pontine clefts.

Decreased cerebellar-cerebral connectivity contributes to complex task performance

PubMed Central

Knops, André

2016-01-01

The cerebellum's role in nonmotor processes is now well accepted, but cerebellar interaction with cerebral targets is not well understood. Complex cognitive tasks activate cerebellar, parietal, and frontal regions, but the effective connectivity between these regions has never been tested. To this end, we used psycho-physiological interactions (PPI) analysis to test connectivity changes of cerebellar and parietal seed regions in complex (2-digit by 1-digit multiplication, e.g., 12 × 3) vs. simple (1-digit by 1-digit multiplication, e.g., 4 × 3) task conditions (“complex − simple”). For cerebellar seed regions (lobule VI, hemisphere and vermis), we found significantly decreased cerebellar-parietal, cerebellar-cingulate, and cerebellar-frontal connectivity in complex multiplication. For parietal seed regions (PFcm, PFop, PFm) we found significantly increased parietal-parietal and parietal-frontal connectivity in complex multiplication. These results suggest that decreased cerebellar-cerebral connectivity contributes to complex task performance. Interestingly, BOLD activity contrasts revealed partially overlapping parietal areas of increased BOLD activity but decreased cerebellar-parietal PPI connectivity. PMID:27334957

Triple stimulation technique in patients with spinocerebellar ataxia type 6.

PubMed

Sakuma, Kenji; Adachi, Yoshiki; Fukuda, Hiroki; Kai, Tohru; Nakashima, Kenji

2005-11-01

To establish further evidence that SCA6 may not be a pure cerebellar syndrome. Seven patients with genetically confirmed SCA6 and 9 age-matched normal controls were studied. Recordings of the CMAP were obtained from the right first dorsal interosseus muscle. Transcranial magnetic stimulation of the left motor cortex was applied to the contralateral scalp with a plane figure-of-8 coil. Conventional transcranial magnetic stimulation (TMS), central motor conduction time (CMCT) by F-wave method and the triple stimulation technique (TST) amplitude ratio (TST test/TST control) were investigated. The mean resting motor threshold and mean CMCT did not show significant differences between normal controls and patients, but the mean TST amplitude ratio was significantly smaller in patients than in controls. An abnormal TST represents upper motor neuron loss, central axon lesions or conduction blocks, or inexcitability in response to TMS. The lack of pathological changes in the corticospinal tract of patients with SCA6 indicates that this abnormality may be caused by crossed cerebellar diaschisis, or a functional disorder in the brain resulting from CACNA1A mutations. TST is a useful method for quantifying corticospinal tract dysfunction.

Cerebellar Cysticercosis Caused by Larval Taenia crassiceps Tapeworm in Immunocompetent Woman, Germany

PubMed Central

Ntoukas, Vasileios; Tappe, Dennis; Pfütze, Daniel; Simon, Michaela

2013-01-01

Human cysticercosis caused by Taenia crassiceps tapeworm larvae involves the muscles and subcutis mostly in immunocompromised patients and the eye in immunocompetent persons. We report a successfully treated cerebellar infection in an immunocompetent woman. We developed serologic tests, and the parasite was identified by histologic examination and 12s rDNA PCR and sequencing. PMID:24274258

Magnetic resonance imaging findings in patients presenting with (sub)acute cerebellar ataxia.

PubMed

Schneider, Tanja; Thomalla, Götz; Goebell, Einar; Piotrowski, Anna; Yousem, David Mark

2015-06-01

Acute or subacute cerebellar inflammation is mainly caused by postinfectious, toxic, neoplastic, vascular, or idiopathic processes and can result in cerebellar ataxia. Previous magnetic resonance (MR) studies in single patients who developed acute or subacute ataxia showed varying imaging features. Eighteen patients presenting with acute and subacute onset of ataxia were included in this study. Cases of chronic-progressive/hereditary and noncerebellar causes (ischemia, multiple sclerosis lesions, metastasis, bleedings) were excluded. MR imaging findings were then matched with the clinical history of the patient. An underlying etiology for ataxic symptoms were found in 14/18 patients (postinfectious/infectious, paraneoplastic, autoimmune, drug-induced). In two of five patients without MR imaging findings and three of eight patients with minimal imaging features (cerebellar atrophy, slight signal alterations, and small areas of restricted diffusion), adverse clinical outcomes were documented. Of the five patients with prominent MR findings (cerebellar swelling, contrast enhancement, or broad signal abnormalities), two were lost to follow-up and two showed long-term sequelae. No correlation was found between the presence of initial MRI findings in subacute or acute ataxia patients and their long-term clinical outcome. MR imaging was more flagrantly positive in cases due to encephalitis.

Laminin α1 is essential for mouse cerebellar development

PubMed Central

Ichikawa-Tomikawa, Naoki; Ogawa, Junko; Douet, Vanessa; Xu, Zhuo; Kamikubo, Yuji; Sakurai, Takashi; Kohsaka, Shinichi; Chiba, Hideki; Hattori, Nobutaka; Yamada, Yoshihiko; Arikawa-Hirasawa, Eri

2011-01-01

Laminin α1 (Lama1), which is a subunit of laminin-1 (laminin-111), a heterotrimeric ECM protein, is essential for embryonic development and promotes neurite outgrowth in culture. Because the deletion of Lama1 causes lethality at early embryonic stages in mice, the in vivo role of Lama1 in neural development and functions has not yet been possible to determine. In this study, we generated conditional Lama1 knockout (Lama1CKO) mice in the epiblast lineage using Sox2-Cre mice. These Lama1CKO mice survived, but displayed behavioral disorders and impaired formation of the cerebellum. Deficiency of Lama1 in the pial basement membrane of the meninges resulted in defects in the conformation of the meninges. During cerebellar development, Lama1 deficiency also caused a decrease in the proliferation and migration of granule cell precursors, disorganization of Bergmann glial fibers and endfeet, and a transient reduction in the activity of Akt. A marked reduction in numbers of dendritic processes in Purkinje cells was observed in Lama1CKO mice. Together, these results indicate that Lama1 is required for cerebellar development and functions. PMID:21983115

Cerebellar contributions to biological motion perception in autism and typical development.

PubMed

Jack, Allison; Keifer, Cara M; Pelphrey, Kevin A

2017-04-01

Growing evidence suggests that posterior cerebellar lobe contributes to social perception in healthy adults. However, they know little about how this process varies across age and with development. Using cross-sectional fMRI data, they examined cerebellar response to biological (BIO) versus scrambled (SCRAM) motion within typically developing (TD) and autism spectrum disorder (ASD) samples (age 4-30 years old), characterizing cerebellar response and BIO > SCRAM-selective effective connectivity, as well as associations with age and social ability. TD individuals recruited regions throughout cerebellar posterior lobe during BIO > SCRAM, especially bilateral lobule VI, and demonstrated connectivity with right posterior superior temporal sulcus (RpSTS) in left VI, Crus I/II, and VIIIb. ASD individuals showed BIO > SCRAM activity in left VI and left Crus I/II, and bilateral connectivity with RpSTS in Crus I/II and VIIIb/IX. No between-group differences emerged in well-matched subsamples. Among TD individuals, older age predicted greater BIO > SCRAM response in left VIIb and left VIIIa/b, but reduced connectivity between RpSTS and widespread regions of the right cerebellum. In ASD, older age predicted greater response in left Crus I and bilateral Crus II, but decreased effective connectivity with RpSTS in bilateral Crus I/II. In ASD, increased BIO > SCRAM signal in left VI/Crus I and right Crus II, VIIb, and dentate predicted lower social symptomaticity; increased effective connectivity with RpSTS in right Crus I/II and bilateral VI and I-V predicted greater symptomaticity. These data suggest that posterior cerebellum contributes to the neurodevelopment of social perception in both basic and clinical populations. Hum Brain Mapp 38:1914-1932, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Shp2-Dependent ERK Signaling Is Essential for Induction of Bergmann Glia and Foliation of the Cerebellum

PubMed Central

Li, Kairong; Leung, Alan W.; Guo, Qiuxia; Yang, Wentian

2014-01-01

Folding of the cortex and the persistence of radial glia (RG)-like cells called Bergmann glia (BG) are hallmarks of the mammalian cerebellum. Similar to basal RG in the embryonic neocortex, BG maintain only basal processes and continuously express neural stem cell markers. Past studies had focused on the function of BG in granule cell migration and how granule cell progenitors (GCP) regulate cerebellar foliation. The molecular control of BG generation and its role in cerebellar foliation are less understood. Here, we have analyzed the function of the protein tyrosine phosphatase Shp2 in mice by deleting its gene Ptpn11 in the entire cerebellum or selectively in the GCP lineage. Deleting Ptpn11 in the entire cerebellum by En1-cre blocks transformation of RG into BG but preserves other major cerebellar cell types. In the absence of BG, inward invagination of GCP persists but is uncoupled from the folding of the Purkinje cell layer and the basement membrane, leading to disorganized lamination and an absence of cerebellar folia. In contrast, removing Ptpn11 in the GCP lineage by Atoh1-cre has no effect on cerebellar development, indicating that Shp2 is not cell autonomously required in GCP. Furthermore, we demonstrate that Ptpn11 interacts with Fgf8 and is essential for ERK activation in RG and nascent BG. Finally, expressing constitutively active MEK1 rescues BG formation and cerebellar foliation in Shp2-deficient cerebella. Our results demonstrate an essential role of Shp2 in BG specification via fibroblast growth factor/extracellular signal-regulated protein kinase signaling, and reveal a crucial function of BG in organizing cerebellar foliation. PMID:24431450

Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability

PubMed Central

Dell'Orco, James M.; Wasserman, Aaron H.; Chopra, Ravi; Ingram, Melissa A. C.; Hu, Yuan-Shih; Singh, Vikrant; Wulff, Heike; Opal, Puneet; Orr, Harry T.

2015-01-01

Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. SIGNIFICANCE STATEMENT In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated compensatory role for neuronal shrinkage. Purkinje neuron firing in these mice is initially normal, but is followed by abnormal membrane depolarization resulting from a reduction in potassium channels. Subsequently, these electrophysiological effects are counteracted by cell atrophy, which by restoring normal potassium channel membrane density, re-establishes pacemaker firing. Reversing the initial membrane depolarization improved motor function and Purkinje neuron morphology in the SCA1 mice. These results suggest that Purkinje neuron remodeling in ataxia is an active compensatory response that serves to normalize intrinsic membrane excitability. PMID:26269637

Tissue Plasminogen Activator Induction in Purkinje Neurons After Cerebellar Motor Learning

NASA Astrophysics Data System (ADS)

Seeds, Nicholas W.; Williams, Brian L.; Bickford, Paula C.

1995-12-01

The cerebellar cortex is implicated in the learning of complex motor skills. This learning may require synaptic remodeling of Purkinje cell inputs. An extracellular serine protease, tissue plasminogen activator (tPA), is involved in remodeling various nonneural tissues and is associated with developing and regenerating neurons. In situ hybridization showed that expression of tPA messenger RNA was increased in the Purkinje neurons of rats within an hour of their being trained for a complex motor task. Antibody to tPA also showed the induction of tPA protein associated with cerebellar Purkinje cells. Thus, the induction of tPA during motor learning may play a role in activity-dependent synaptic plasticity.

Isolated rhomboencephalosynapsis - a rare cerebellar anomaly.

PubMed

Paprocka, Justyna; Jamroz, Ewa; Scieszka, Ewa; Kluczewska, Ewa

2012-01-01

Rhomboencephalosynapsis (RES, RS) is a unique entity usually recognized in infancy based on neuroimaging. Cerebellar fusion and absence of cerebellar vermis is often associated with supratentorial findings. Since now there are about 50 cases described worldwide, with approximately 36 patients diagnosed by MRI. The authors present the first in Poland case of this uncommon malformation and review the literature. The authors describe a 28-month-old-girl with microcephaly and proper psychomotor development. The family history was unrelevant. Based on MRI the congenital malformation of posterior fossa-rhombencephalosynapsis was confirmed Presented patient is a typical example of MRI usefulness especially in patients with RES. RES symptoms are mild and that is why the diagnosis is usually made only in adulthood.

Functional imaging and the cerebellum: recent developments and challenges. Editorial.

PubMed

Habas, Christophe

2012-06-01

Recent neuroimaging developments allow a better in vivo characterization of the structural and functional connectivity of the human cerebellum. Ultrahigh fields, which considerably increase spatial resolution, enable to visualize deep cerebellar nuclei and cerebello-cortical sublayers. Tractography reconstructs afferent and efferent pathway of the cerebellum. Resting-state functional connectivity individualizes the prewired, parallel close-looped sensorimotor, cognitive, and affective networks passing through the cerebellum. These results are un agreement with activation maps obtained during stimulation functional neuroimaging or inferred from neurological deficits due to cerebellar lesions. Therefore, neuroimaging supports the hypothesis that cerebellum constitutes a general modulator involved in optimizing mental performance and computing internal models. However, the great challenges will remain to unravel: (1) the functional role of red and bulbar olivary nuclei, (2) the information processing in the cerebellar microcircuitry, and (3) the abstract computation performed by the cerebellum and shared by sensorimotor, cognitive, and affective domains.

Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE.

PubMed

Yuan, Junhui; Higuchi, Yujiro; Nagado, Tatsui; Nozuma, Satoshi; Nakamura, Tomonori; Matsuura, Eiji; Hashiguchi, Akihiro; Sakiyama, Yusuke; Yoshimura, Akiko; Takashima, Hiroshi

2013-03-01

DNMT1, encoding DNA methyltransferase 1 (Dnmt1), is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. To date, two phenotypes produced by DNMT1 mutations have been reported, including hereditary sensory and autonomic neuropathy (HSAN) type IE with mutations in exon 20, and autosomal dominant cerebellar ataxia, deafness, and narcolepsy caused by mutations in exon 21. We report a sporadic case in a Japanese patient with loss of pain and vibration sense, chronic osteomyelitis, autonomic system dysfunctions, hearing loss, and mild dementia, but without definite cerebellar ataxia. Electrophysiological studies revealed absent sensory nerve action potential with nearly normal motor nerve conduction studies. Brain magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy. Using a next-generation sequencing system, 16 candidate genes were analyzed and a novel missense mutation, c.1706A>G (p.His569Arg), was identified in exon 21 of DNMT1. Our findings suggest that mutation in exon 21 of DNMT1 may also produce a HSAN phenotype. Because all reported mutations of DNMT1 are concentrated in exons 20 and 21, which encode the replication focus targeting sequence (RFTS) domain of Dnmt1, the RFTS domain could be a mutation hot spot. © 2013 Peripheral Nerve Society.

Spinocerebellum Ataxia Type 6: Molecular Mechanisms and Calcium Channel Genetics.

PubMed

Du, Xiaofei; Gomez, Christopher Manuel

2018-01-01

Spinocerebellar ataxia (SCA) type 6 is an autosomal dominant disease affecting cerebellar degeneration. Clinically, it is characterized by pure cerebellar dysfunction, slowly progressive unsteadiness of gait and stance, slurred speech, and abnormal eye movements with late onset. Pathological findings of SCA6 include a diffuse loss of Purkinje cells, predominantly in the cerebellar vermis. Genetically, SCA6 is caused by expansion of a trinucleotide CAG repeat in the last exon of longest isoform CACNA1A gene on chromosome 19p13.1-p13.2. Normal alleles have 4-18 repeats, while alleles causing disease contain 19-33 repeats. Due to presence of a novel internal ribosomal entry site (IRES) with the mRNA, CACNA1A encodes two structurally unrelated proteins with distinct functions within an overlapping open reading frame (ORF) of the same mRNA: (1) α1A subunit of P/Q-type voltage gated calcium channel; (2) α1ACT, a newly recognized transcription factor, with polyglutamine repeat at C-terminal end. Understanding the function of α1ACT in physiological and pathological conditions may elucidate the pathogenesis of SCA6. More importantly, the IRES, as the translational control element of α1ACT, provides a potential therapeutic target for the treatment of SCA6.

Blood harmane is correlated with cerebellar metabolism in essential tremor: a pilot study.

PubMed

Louis, Elan D; Zheng, Wei; Mao, Xiangling; Shungu, Dikoma C

2007-08-07

On proton magnetic resonance spectroscopic imaging ((1)H MRSI), there is a decrease in cerebellar N-acetylaspartate/total creatine (NAA/tCr) in essential tremor (ET), signifying cerebellar neuronal dysfunction or degeneration. Harmane, which is present in the human diet, is a potent tremor-producing neurotoxin. Blood harmane concentrations seem to be elevated in ET. To assess in patients with ET whether blood harmane concentration is correlated with cerebellar NAA/tCR, a neuroimaging measure of neuronal dysfunction or degeneration. Twelve patients with ET underwent (1)H MRSI. The major neuroanatomic structure of interest was the cerebellar cortex. Secondary regions were the central cerebellar white matter, cerebellar vermis, thalamus, and basal ganglia. Blood concentrations of harmane and another neurotoxin, lead, were also assessed. Mean +/- SD cerebellar NAA/tCR was 1.52 +/- 0.41. In a linear regression model that adjusted for age and gender, log blood harmane concentration was a predictor of cerebellar NAA/tCR (beta = -0.41, p = 0.009); every 1 g(-10)/mL unit increase in log blood harmane concentration was associated with a 0.41 unit decrease in cerebellar NAA/tCR. The association between blood harmane concentration and brain NAA/tCR only occurred in the cerebellar cortex; it was not observed in secondary brain regions of interest. Furthermore, the association was specific to harmane and not another neurotoxin, lead. This study provides additional support for the emerging link between harmane, a neurotoxin, and ET. Further studies are warranted to address whether cerebellar harmane concentrations are associated with cerebellar pathology in postmortem studies of the ET brain.

Recent Advances in Cerebellar Ischemic Stroke Syndromes Causing Vertigo and Hearing Loss.

PubMed

Kim, Hyun-Ah; Yi, Hyon-Ah; Lee, Hyung

2016-12-01

Cerebellar ischemic stroke is one of the common causes of vascular vertigo. It usually accompanies other neurological symptoms or signs, but a small infarct in the cerebellum can present with vertigo without other localizing symptoms. Approximately 11 % of the patients with isolated cerebellar infarction simulated acute peripheral vestibulopathy, and most patients had an infarct in the territory of the medial branch of the posterior inferior cerebellar artery (PICA). A head impulse test can differentiate acute isolated vertigo associated with PICA territory cerebellar infarction from more benign disorders involving the inner ear. Acute hearing loss (AHL) of a vascular cause is mostly associated with cerebellar infarction in the territory of the anterior inferior cerebellar artery (AICA), but PICA territory cerebellar infarction rarely causes AHL. To date, at least eight subgroups of AICA territory infarction have been identified according to the pattern of neurotological presentations, among which the most common pattern of audiovestibular dysfunction is the combined loss of auditory and vestibular functions. Sometimes acute isolated audiovestibular loss can be the initial symptom of impending posterior circulation ischemic stroke (particularly within the territory of the AICA). Audiovestibular loss from cerebellar infarction has a good long-term outcome than previously thought. Approximately half of patients with superior cerebellar artery territory (SCA) cerebellar infarction experienced true vertigo, suggesting that the vertigo and nystagmus in the SCA territory cerebellar infarctions are more common than previously thought. In this article, recent findings on clinical features of vertigo and hearing loss from cerebellar ischemic stroke syndrome are summarized.

Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients.

PubMed

Cassandrini, Denise; Cilio, Maria Roberta; Bianchi, Marzia; Doimo, Mara; Balestri, Martina; Tessa, Alessandra; Rizza, Teresa; Sartori, Geppo; Meschini, Maria Chiara; Nesti, Claudia; Tozzi, Giulia; Petruzzella, Vittoria; Piemonte, Fiorella; Bisceglia, Luigi; Bruno, Claudio; Dionisi-Vici, Carlo; D'Amico, Adele; Fattori, Fabiana; Carrozzo, Rosalba; Salviati, Leonardo; Santorelli, Filippo M; Bertini, Enrico

2013-01-01

Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in RARS2. All patients rapidly developed a neonatal or early-infantile epileptic encephalopathy with intractable seizures. The long-term follow-up revealed a virtual absence of psychomotor development, progressive microcephaly, and feeding difficulties. Mitochondrial respiratory chain enzymes in muscle and fibroblasts were normal in two. Blood and CSF lactate was abnormally elevated in all five patients at early stages while appearing only occasionally abnormal with the progression of the disease. Cerebellar vermis hypoplasia with normal aspect of the cerebral and cerebellar hemispheres appeared within the first months of life at brain MRI. In three patients follow-up neuroimaging revealed a progressive pontocerebellar and cerebral cortical atrophy. Molecular investigations of RARS2 disclosed the c.25A>G/p.I9V and the c.1586+3A>T in family A, the c.734G>A/p.R245Q and the c.1406G>A/p.R469H in family B, and the c.721T>A/p.W241R and c.35A>G/p.Q12R in family C. Functional complementation studies in Saccharomyces cerevisiae showed that mutation MSR1-R531H (equivalent to human p.R469H) abolished respiration whereas the MSR1-R306Q strain (corresponding to p.R245Q) displayed a reduced growth on non-fermentable YPG medium. Although mutations functionally disrupted yeast we found a relatively well preserved arginine aminoacylation of mitochondrial tRNA. Clinical and neuroimaging findings are important clues to raise suspicion and to reach diagnostic accuracy for RARS2 mutations considering that biochemical abnormalities may be absent in muscle biopsy.

Understanding the Role of TSC1/2 in Cerebellar Purkinje Neurons

DTIC Science & Technology

2016-09-01

development of new pharmacotherapy for TSC-patients with autism . 15. SUBJECT TERMS autism , tuberous sclerosis, cerebellum 16. SECURITY CLASSIFICATION...patients with TSC display symptoms of autism spectrum disorder (ASD). Although much research has been conducted, the neural circuitry and molecular...mechanism underlying autism remain unclear. Specific cerebellar defects have been seen in TSC patients, suggesting a crucial role for the cerebellum

Cerebellar degeneration following neuroleptic malignant syndrome.

PubMed Central

Lal, V.; Sardana, V.; Thussu, A.; Sawhney, I. M.; Prabhakar, S.

1997-01-01

A 55-year-old woman with a history of bipolar affective disorder developed hyperpyrexia, rigidity and depressed consciousness (neuroleptic malignant syndrome) after commencing neuroleptic therapy. On regaining consciousness, she was mute and had signs suggesting pancerebellar involvement. Hyperpyrexia, which is a cardinal feature of neuroleptic malignant syndrome, may have caused cerebellar damage. Neuroleptic malignant syndrome needs both early recognition and prompt treatment to obviate devastating complications. PMID:9519191

Right side neglect in right cerebellar lesion

PubMed Central

Silveri, M; Misciagna, S; Terrezza, G

2001-01-01

A patient is described who developed right side hemineglect after a right cerebellar lesion. This spatial disorder was interpreted as a secondary effect of a deficit of the motor organisation in the right hemispace due to left frontal diaschisis. The pathological base may be the interruption of a highly integrated system which includes the lateral cerebellum and the contralateral frontal lobe.

 PMID:11413276

[Cerebellar Infarction After Carbon Monoxide Poisoning and Hyperbaric Oxygen Therapy].

PubMed

Wick, Matthias; Schneiker, André; Bele, Sylvia; Pawlik, Michael; Meyringer, Helmut; Graf, Bernhard; Wendl, Christina; Kieninger, Martin

2017-06-01

We report on a patient who developed a space-occupying cerebellar infarction with occlusive hydrocephalus after a poisoning with carbon monoxide with the intention to commit suicide. A neurosurgical and intensive care therapy were needed. The patient's survival without severe neurological deficits could be secured due to the early detection of the intracerebral lesions. Georg Thieme Verlag KG Stuttgart · New York.

Development of involuntary movements after ventriculoperitoneal shunting for normal pressure hydrocephalus in a patient with chronic-phase thalamic haemorrhage.

PubMed

Shindo, Keiichiro; Kondo, Takeo; Sugiyama, Ken; Nishijima, Kazunori; Furusawa, Yoshihito; Mori, Takayuki; Izumi, Shin-Ichi

2007-10-01

Delayed-onset involuntary movements have been described after thalamic stroke. We treated a patient with involuntary movements that increased after ventriculoperitoneal shunting (VPS) for normal pressure hydrocephalus (NPH) following thalamic haemorrage. One and one-half years after right thalamic and intraventricular haemorrhage, NPH suggested clinical evaluation and neuroimaging studies in a 56-year-old man. Hemidystonia and pseudochoreoathetosis were evident in the left arm, leg and trunk. Proprioceptive impairment and mild cerebellar dysfunction affected the left upper and lower extremity. Yet the patient could walk unassisted and carry out activities of daily living (ADL) rated as 90 points according to the Barthel Index (BI). Lumbar puncture lessened both gait disturbance and cognitive impairment. After VPS, cognition and urinary continence improved, but involuntary movements worsened, precluding unaided ambulation and decreasing the BI score to 65 points. Computed tomography after VPS showed resolution of NPH, while single-photon emission computed tomography showed increased cerebral blood flow after VPS. Increased cerebral blood flow after VPS is suspected to have promoted development of abnormal neuronal circuitry.

The volume of the cerebellum in the second semester of gestation.

PubMed

Vulturar, Damiana; Fărcăşanu, Alexandru; Turcu, Flaviu; Boitor, Dan; Crivii, Carmen

2018-01-01

The cerebellum ("little brain"), the largest part of hind brain, lies in the posterior cranial fossa, beneath the occipital lobe and dorsal to the brainstem. It develops over a long period: it is one of the first structures in the brain to begin to differentiate, but one of the last to mature. The use of ultrasonography has significantly improved the evaluation of fetal growth and development and has permitted prenatal diagnosis of a variety of congenital malformations.The aim of our study was to evaluate the cerebellar growth and development using 2 different measuring techniques: microMRI and ultrasound technique. The cerebellum measurements were related to gestational age. We used 14 human fetuses corresponding to 15-28 gestational weeks, immersed in a 9% formalin solution. Magnetic Resonance Imaging (MRI) was performed by employing a Bruker BioSpec 70/16USR scanner (Bruker BioSpin MRI GmbH, Ettlingen, Germany), operated at 7.04 Tesla for cerebellar volume measurement. Ultrasonographic measurements of the cerebellum diameter were performed on 14 pregnant women, 15 - 28 gestational weeks. Ultrasound scan used 5-10 MHZ for transvaginal approach. Taking into consideration the values of the cerebellum dimensions and considering the general shape of the cerebellum as a transverse ellipsoid, the volume of the cerebellum was calculated by a mathematical formula for ellipsoid volume. The study correlates the measurements from the microMRI study with the ultrasounds data and the results are superposable. Both established the exponential volume growth after the 22-23 GW. We used the ellipsoid volume formula for the cerebellar volume using the half of the three diameters of the cerebellum determined by ultrasound measurements:Cerebellar Volume = Ellipsoid volume = 3/4 π r1 r2 r3. There is a linear correlation between the microMRI measurements and ultrasound determinations. Based on all collected data we could apply an easy formula to calculate the volume of cerebellum, a useful criterion in the evaluation of the cerebellar development and the appreciation of the gestational age.

Homozygous Mutations in NEUROD1 Are Responsible for a Novel Syndrome of Permanent Neonatal Diabetes and Neurological Abnormalities

PubMed Central

Rubio-Cabezas, Oscar; Minton, Jayne A.L.; Kantor, Iren; Williams, Denise; Ellard, Sian; Hattersley, Andrew T.

2010-01-01

OBJECTIVE NEUROD1 is expressed in both developing and mature β-cells. Studies in mice suggest that this basic helix-loop-helix transcription factor is critical in the development of endocrine cell lineage. Heterozygous mutations have previously been identified as a rare cause of maturity-onset diabetes of the young (MODY). We aimed to explore the potential contribution of NEUROD1 mutations in patients with permanent neonatal diabetes. RESEARCH DESIGN AND METHODS We sequenced the NEUROD1 gene in 44 unrelated patients with permanent neonatal diabetes of unknown genetic etiology. RESULTS Two homozygous mutations in NEUROD1 (c.427_ 428del and c.364dupG) were identified in two patients. Both mutations introduced a frameshift that would be predicted to generate a truncated protein completely lacking the activating domain. Both patients had permanent diabetes diagnosed in the first 2 months of life with no evidence of exocrine pancreatic dysfunction and a morphologically normal pancreas on abdominal imaging. In addition to diabetes, they had learning difficulties, severe cerebellar hypoplasia, profound sensorineural deafness, and visual impairment due to severe myopia and retinal dystrophy. CONCLUSIONS We describe a novel clinical syndrome that results from homozygous loss of function mutations in NEUROD1. It is characterized by permanent neonatal diabetes and a consistent pattern of neurological abnormalities including cerebellar hypoplasia, learning difficulties, sensorineural deafness, and visual impairment. This syndrome highlights the critical role of NEUROD1 in both the development of the endocrine pancreas and the central nervous system in humans. PMID:20573748

Insights into cerebellar development and medulloblastoma.

PubMed

Bihannic, Laure; Ayrault, Olivier

2016-01-01

Cerebellar development is an extensive process that begins during early embryonic stages and persists more than one year after birth in human. Therefore, the cerebellum is susceptible to acquire various developmental abnormalities leading to numerous diseases such as medulloblastoma, the most common pediatric malignant brain tumor. One third of the patients with medulloblastoma are incurable and survivors have a poor quality of life due to the aggressiveness of the broad-spectrum treatments. Within the past few years, it has been highlighted that medulloblastoma is a heterogeneous disease that is divided in four molecular subgroups. This recent advance in the field, combined with the development of associated preclinical models for each subgroup, should enable, in the future, the discovery and use of targeted therapy in clinical treatments for each subtype of medulloblastoma. In this review, we first aim to show how deregulation of cerebellar development can lead to medulloblastoma formation and then to present the advances in the molecular subgrouping of medulloblastoma and the associated preclinical models. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Cerebellar abiotrophy in a miniature schnauzer.

PubMed

Berry, Michelle L; Blas-Machado, Uriel

2003-08-01

A 3.5-month-old miniature schnauzer was presented for signs of progressive cerebellar ataxia. Necropsy revealed cerebellar abiotrophy. This is the first reported case of cerebellar abiotrophy in a purebred miniature schnauzer.

Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms.

PubMed

Haldipur, Parthiv; Dang, Derek; Aldinger, Kimberly A; Janson, Olivia K; Guimiot, Fabien; Adle-Biasette, Homa; Dobyns, William B; Siebert, Joseph R; Russo, Rosa; Millen, Kathleen J

2017-01-16

FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic Foxc1 mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human.

Allometric Analysis Detects Brain Size-Independent Effects of Sex and Sex Chromosome Complement on Human Cerebellar Organization

PubMed Central

Mankiw, Catherine; Park, Min Tae M.; Reardon, P.K.; Fish, Ari M.; Clasen, Liv S.; Greenstein, Deanna; Blumenthal, Jonathan D.; Lerch, Jason P.; Chakravarty, M. Mallar

2017-01-01

The cerebellum is a large hindbrain structure that is increasingly recognized for its contribution to diverse domains of cognitive and affective processing in human health and disease. Although several of these domains are sex biased, our fundamental understanding of cerebellar sex differences—including their spatial distribution, potential biological determinants, and independence from brain volume variation—lags far behind that for the cerebrum. Here, we harness automated neuroimaging methods for cerebellar morphometrics in 417 individuals to (1) localize normative male–female differences in raw cerebellar volume, (2) compare these to sex chromosome effects estimated across five rare sex (X/Y) chromosome aneuploidy (SCA) syndromes, and (3) clarify brain size-independent effects of sex and SCA on cerebellar anatomy using a generalizable allometric approach that considers scaling relationships between regional cerebellar volume and brain volume in health. The integration of these approaches shows that (1) sex and SCA effects on raw cerebellar volume are large and distributed, but regionally heterogeneous, (2) human cerebellar volume scales with brain volume in a highly nonlinear and regionally heterogeneous fashion that departs from documented patterns of cerebellar scaling in phylogeny, and (3) cerebellar organization is modified in a brain size-independent manner by sex (relative expansion of total cerebellum, flocculus, and Crus II-lobule VIIIB volumes in males) and SCA (contraction of total cerebellar, lobule IV, and Crus I volumes with additional X- or Y-chromosomes; X-specific contraction of Crus II-lobule VIIIB). Our methods and results clarify the shifts in human cerebellar organization that accompany interwoven variations in sex, sex chromosome complement, and brain size. SIGNIFICANCE STATEMENT Cerebellar systems are implicated in diverse domains of sex-biased behavior and pathology, but we lack a basic understanding of how sex differences in the human cerebellum are distributed and determined. We leverage a rare neuroimaging dataset to deconvolve the interwoven effects of sex, sex chromosome complement, and brain size on human cerebellar organization. We reveal topographically variegated scaling relationships between regional cerebellar volume and brain size in humans, which (1) are distinct from those observed in phylogeny, (2) invalidate a traditional neuroimaging method for brain volume correction, and (3) allow more valid and accurate resolution of which cerebellar subcomponents are sensitive to sex and sex chromosome complement. These findings advance understanding of cerebellar organization in health and sex chromosome aneuploidy. PMID:28314818

Cerebellar abiotrophy in a miniature schnauzer

PubMed Central

Berry, Michelle L.; Blas-Machado, Uriel

2003-01-01

A 3.5-month-old miniature schnauzer was presented for signs of progressive cerebellar ataxia. Necropsy revealed cerebellar abiotrophy. This is the first reported case of cerebellar abiotrophy in a purebred miniature schnauzer. PMID:13677598

Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia.

PubMed

Benussi, Alberto; Dell'Era, Valentina; Cotelli, Maria Sofia; Turla, Marinella; Casali, Carlo; Padovani, Alessandro; Borroni, Barbara

Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias. The present study investigated whether a two-weeks' treatment with cerebellar anodal tDCS could improve symptoms in patients with neurodegenerative cerebellar ataxia and could modulate cerebello-motor connectivity, at short and long term. We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia. Each patient underwent a clinical evaluation pre- and post-anodal tDCS or sham stimulation. A follow-up evaluation was performed at one and three months. Cerebello-motor connectivity was evaluated using transcranial magnetic stimulation (TMS) at baseline and at follow-up. Patients who underwent anodal tDCS showed a significant improvement in all performance scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale, 9-hole peg test, 8-m walking time) and in cerebellar brain inhibition compared to patients who underwent sham stimulation. A two-weeks' treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia. Copyright © 2016 Elsevier Inc. All rights reserved.

Developmental subchronic exposure to diphenylarsinic acid induced increased exploratory behavior, impaired learning behavior, and decreased cerebellar glutathione concentration in rats.

PubMed

Negishi, Takayuki; Matsunaga, Yuki; Kobayashi, Yayoi; Hirano, Seishiro; Tashiro, Tomoko

2013-12-01

In Japan, people using water from the well contaminated with high-level arsenic developed neurological, mostly cerebellar, symptoms, where diphenylarsinic acid (DPAA) was a major compound. Here, we investigated the adverse effects of developmental exposure to 20mg/l DPAA in drinking water (early period [0-6 weeks of age] and/or late period [7-12]) on behavior and cerebellar development in male rats. In the open field test at 6 weeks of age, early exposure to DPAA significantly increased exploratory behaviors. At 12 weeks of age, late exposure to DPAA similarly increased exploratory behavior independent of the early exposure although a 6-week recovery from DPAA could reverse that change. In the passive avoidance test at 6 weeks of age, early exposure to DPAA significantly decreased the avoidance performance. Even at 12 weeks of age, early exposure to DPAA significantly decreased the test performance, which was independent of the late exposure to DPAA. These results suggest that the DPAA-induced increase in exploratory behavior is transient, whereas the DPAA-induced impairment of passive avoidance is long lasting. At 6 weeks of age, early exposure to DPAA significantly reduced the concentration of cerebellar total glutathione. At 12 weeks of age, late, but not early, exposure to DPAA also significantly reduced the concentration of cerebellar glutathione, which might be a primary cause of oxidative stress. Early exposure to DPAA induced late-onset suppressed expression of NMDAR1 and PSD95 protein at 12 weeks of age, indicating impaired glutamatergic system in the cerebellum of rats developmentally exposed to DPAA.

Brain injury and development in preterm infants exposed to fentanyl

PubMed Central

McPherson, Christopher; Haslam, Matthew; Pineda, Roberta; Rogers, Cynthia; Neil, Jeffrey J.; Inder, Terrie E.

2015-01-01

Background Fentanyl is commonly utilized in preterm infants. Relatively little is known regarding the neurodevelopmental outcomes of preterm infants exposed to fentanyl. Objective To investigate the association between cumulative fentanyl dose and brain injury and diameters in a cohort of preterm infants Methods Data on demographics, perinatal course, and neonatal course, including total fentanyl exposure prior to term equivalent age, were retrospectively evaluated for 103 infants born at ≤ 30 weeks gestational age who underwent magnetic resonance imaging at term equivalent age (mean gestational age 26.9 ± 1.8 weeks). Magnetic resonance images were evaluated for brain injury and regional brain diameters. Developmental testing was conducted at term equivalent and 2 years of age. Results Seventy-eight infants (76%) received fentanyl (median cumulative dose 3 μg/kg, interquartile range 1 – 441 μg/kg). Cumulative fentanyl dose in the first week of life correlated with the incidence of cerebellar hemorrhage after correction for covariates (OR 2.1, 95% confidence interval 1.1 – 4.1). Cumulative fentanyl dose before term equivalent age correlated with reductions in transverse cerebellar diameter after correction for covariates including the presence of cerebellar hemorrhage (r = 0.461, p = 0.002). No correlation was detected between cumulative fentanyl dose and development at 2 years of age. Conclusions Higher cumulative fentanyl dose in preterm infants correlated with a higher incidence of cerebellar injury and lower cerebellar diameter at term equivalent age. Our findings must be taken with caution, but emphasize the need for future prospective trials examining the risks and benefits of commonly utilized analgesic agents in preterm infants. PMID:26369570

Gestational lead exposure induces developmental abnormalities and up-regulates apoptosis of fetal cerebellar cells in rats.

PubMed

Mousa, Alyaa M; Al-Fadhli, Ameera S; Rao, Muddanna S; Kilarkaje, Narayana

2015-01-01

Lead (Pb), a known environmental toxicant, adversely affects almost all organ systems. In this study, we investigated the effects of maternal lead exposure on fetal rat cerebellum. Female Sprague-Dawley rats were given lead nitrate in drinking water (0, 0.5, and 1%) for two weeks before conception, and during pregnancy. Fetuses were collected by caesarian section on gestational day 21 and observed for developmental abnormalities. The fetal cerebellar sections from control and 1% lead group were stained with cresyl violet. Immunohistochemical expressions of p53, Bax, Bcl-2, and caspase 3 were quantified by AnalySIS image analyzer (Life Science, Germany). Lead exposure induced developmental abnormalities of eyes, ear, limbs, neck and ventral abdominal wall; however, these abnormalities were commonly seen in the 1% lead-treated group. In addition, lead also caused fetal mortality and reduced body growth in both dose groups and reduced brain weight in the 1% lead-treated group. The fetal cerebella from the 1% lead-treated group showed unorganized cerebellar cortical layers, and degenerative changes in granule and Purkinje cells such as the formation of clumps of Nissl granules. An increase in Bax and caspase 3, and a decrease in Bcl-2 (p < 0.05), but not in p53, showed apoptosis of the neurons. In conclusion, gestational lead exposure in rats induces fetal toxicity and developmental abnormalities. The lead exposure also impairs development of cerebellar layers, induces structural changes, and apoptosis in the fetal cerebellar cortex. These results suggest that lead exposure during gestation is extremely toxic to developing cerebellum in rats.

Cerebellar liponeurocytoma with extracranial extension: case report.

PubMed

Ben Nsir, A; Ben Said, I; Hammami, N; Sebai, R; Jemel, H

2014-01-01

Cerebellar liponeurocytoma is a newly recognized, rare clinicopathological entity commonly described in the cerebellar hemispheres or the vermis. We present a rare case of cerebellar liponeurocytoma arising from the left cerebellar amygdala with extracranial extension. Such a condition has never been previously reported. Copyright © 2014 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Cerebellar Hematoma Location: Implications for the Underlying Microangiopathy.

PubMed

Pasi, Marco; Marini, Sandro; Morotti, Andrea; Boulouis, Gregoire; Xiong, Li; Charidimou, Andreas; Ayres, Alison M; Lee, Myung Joo; Biffi, Alessandro; Goldstein, Joshua N; Rosand, Jonathan; Gurol, M Edip; Greenberg, Steven M; Viswanathan, Anand

2018-01-01

Spontaneous cerebellar intracerebral hemorrhage (ICH) has been reported to be mainly associated with vascular changes secondary to hypertension. However, a subgroup of cerebellar ICH seems related to vascular amyloid deposition (cerebral amyloid angiopathy). We sought to determine whether location of hematoma in the cerebellum (deep and superficial regions) was suggestive of a particular hemorrhage-prone small-vessel disease pathology (cerebral amyloid angiopathy or hypertensive vasculopathy). Consecutive patients with cerebellar ICH from a single tertiary care medical center were recruited. Based on data from pathological reports, patients were divided according to the location of the primary cerebellar hematoma (deep versus superficial). Location of cerebral microbleeds (CMBs; strictly lobar, strictly deep, and mixed CMB) was evaluated on magnetic resonance imaging. One-hundred and eight patients (84%) had a deep cerebellar hematoma, and 20 (16%) a superficial cerebellar hematoma. Hypertension was more prevalent in deep than in patients with superficial cerebellar ICH (89% versus 65%, respectively; P <0.05). Among patients who underwent magnetic resonance imaging, those with superficial cerebellar ICH had higher prevalence of strictly lobar CMB (43%) and lower prevalence of strictly deep or mixed CMB (0%) compared with those with deep superficial cerebellar ICH (6%, 17%, and 38%, respectively). In a multivariable model, presence of strictly lobar CMB was associated with superficial cerebellar ICH (odds ratio, 3.8; 95% confidence interval, 1.5-8.5; P =0.004). Our study showed that superficial cerebellar ICH is related to the presence of strictly lobar CMB-a pathologically proven marker of cerebral amyloid angiopathy. Cerebellar hematoma location may thus help to identify those patients likely to have cerebral amyloid angiopathy pathology. © 2017 American Heart Association, Inc.

Cerebellar mutism syndrome and its relation to cerebellar cognitive and affective function: Review of the literature

PubMed Central

Yildiz, Ozlem; Kabatas, Serdar; Yilmaz, Cem; Altinors, Nur; Agaoglu, Belma

2010-01-01

Tumors of the cerebellum and brainstem account for half of all brain tumors in children. The realization that cerebellar lesions produce clinically relevant intellectual disability makes it important to determine whether neuropsychological abnormalities occur in long-term survivors of pediatric cerebellar tumors. Little is known about the neurobehavioral sequale resulting specifically from the resection of these tumors in this population. We therefore reviewed neuropsychological findings associated with postoperative cerebellar mutism syndrome and discuss the further implications for cerebellar cognitive function. PMID:20436742

Mechanisms of potentiation of mossy fiber EPSCs in the cerebellar nuclei by coincident synaptic excitation and inhibition

PubMed Central

Pugh, Jason R.; Raman, Indira M.

2008-01-01

Neurons of the cerebellar nuclei receive synaptic excitation from cerebellar mossy fibers. Unlike in many principal neurons, coincident presynaptic activity and postsynaptic depolarization do not generate long-term potentiation at these synapses. Instead, EPSCs are potentiated by high-frequency trains of presynaptic activity applied with postsynaptic hyperpolarization, in patterns resembling the mossy fiber-mediated excitation and Purkinje cell-mediated inhibition predicted to occur during delay eyelid conditioning. Here, we have used electrophysiology and Ca imaging to test how synaptic excitation and inhibition interact to generate long-lasting synaptic plasticity in nuclear cells in cerebellar slices. We find that the extent of plasticity varies with the relative timing of synaptic excitation and hyperpolarization. Potentiation is most effective when synaptic stimuli precede the post-inhibitory rebound by ~400 ms, whereas with longer intervals, or with a reverse sequence, EPSCs tend to depress. When basal intracellular Ca is raised by spontaneous firing or reduced by voltage-clamping at subthreshold potentials, potentiation is induced as long as the synaptic-rebound temporal sequence is maintained, suggesting that plasticity does not require Ca levels to exceed a threshold or attain a specific concentration. Although rebound and spike-dependent Ca influx are global, potentiation is synapse-specific, and is disrupted by inhibitors of calcineurin or CaMKII, but not PKC. When IPSPs replace the hyperpolarizing step in the induction protocol, potentiation proceeds normally. These results lead us to propose that synaptic and inhibitory/rebound stimuli initiate separate processes, with local NMDA-receptor-mediated Ca influx “priming” synapses, and Ca changes from the inhibition and rebound “triggering” potentiation at recently activated synapses. PMID:18923031

Cognitive processes involved in smooth pursuit eye movements: behavioral evidence, neural substrate and clinical correlation

PubMed Central

Fukushima, Kikuro; Fukushima, Junko; Warabi, Tateo; Barnes, Graham R.

2013-01-01

Smooth-pursuit eye movements allow primates to track moving objects. Efficient pursuit requires appropriate target selection and predictive compensation for inherent processing delays. Prediction depends on expectation of future object motion, storage of motion information and use of extra-retinal mechanisms in addition to visual feedback. We present behavioral evidence of how cognitive processes are involved in predictive pursuit in normal humans and then describe neuronal responses in monkeys and behavioral responses in patients using a new technique to test these cognitive controls. The new technique examines the neural substrate of working memory and movement preparation for predictive pursuit by using a memory-based task in macaque monkeys trained to pursue (go) or not pursue (no-go) according to a go/no-go cue, in a direction based on memory of a previously presented visual motion display. Single-unit task-related neuronal activity was examined in medial superior temporal cortex (MST), supplementary eye fields (SEF), caudal frontal eye fields (FEF), cerebellar dorsal vermis lobules VI–VII, caudal fastigial nuclei (cFN), and floccular region. Neuronal activity reflecting working memory of visual motion direction and go/no-go selection was found predominantly in SEF, cerebellar dorsal vermis and cFN, whereas movement preparation related signals were found predominantly in caudal FEF and the same cerebellar areas. Chemical inactivation produced effects consistent with differences in signals represented in each area. When applied to patients with Parkinson's disease (PD), the task revealed deficits in movement preparation but not working memory. In contrast, patients with frontal cortical or cerebellar dysfunction had high error rates, suggesting impaired working memory. We show how neuronal activity may be explained by models of retinal and extra-retinal interaction in target selection and predictive control and thus aid understanding of underlying pathophysiology. PMID:23515488

Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out

PubMed Central

Yokoi, Fumiaki; Dang, Mai Tu; Li, Yuqing

2012-01-01

Early-onset generalized torsion dystonia (dystonia 1) is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most patients have a 3-base pair deletion (ΔGAG) in one allele of DYT1, corresponding to a loss of a glutamic acid residue (ΔE) in the C-terminal region of the protein. Functional alterations in basal ganglia circuits and the cerebellum have been reported in dystonia. Pharmacological manipulations or mutations in genes that result in functional alterations of the cerebellum have been reported to have dystonic symptoms and have been used as phenotypic rodent models. Additionally, structural lesions in the abnormal cerebellar circuits, such as cerebellectomy, have therapeutic effects in these models. A previous study has shown that the Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits in the beam-walking test. Both Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 Purkinje cell-specific knockout (Dyt1 pKO) mice exhibit dendritic alterations of cerebellar Purkinje cells. Here, Dyt1 pKO mice exhibited significantly less slip numbers in the beam-walking test, suggesting better motor performance than control littermates, and normal gait. Furthermore, Dyt1 ΔGAG KI/Dyt1 pKO double mutant mice exhibited significantly lower numbers of slips than Dyt1 ΔGAG heterozygous KI mice, suggesting Purkinje-cell specific knockout of Dyt1 wild-type (WT) allele in Dyt1 ΔGAG heterozygous KI mice rescued the motor deficits. The results suggest that molecular lesions of torsinA in Purkinje cells by gene therapy or intervening in the signaling pathway downstream of the cerebellar Purkinje cells may rescue motor symptoms in dystonia 1. PMID:22391119

Effects of accuracy constraints on reach-to-grasp movements in cerebellar patients.

PubMed

Rand, M K; Shimansky, Y; Stelmach, G E; Bracha, V; Bloedel, J R

2000-11-01

Reach-to-grasp movements of patients with pathology restricted to the cerebellum were compared with those of normal controls. Two types of paradigms with different accuracy constraints were used to examine whether cerebellar impairment disrupts the stereotypic relationship between arm transport and grip aperture and whether the variability of this relationship is altered when greater accuracy is required. The movements were made to either a vertical dowel or to a cross bar of a small cross. All subjects were asked to reach for either target at a fast but comfortable speed, grasp the object between the index finger and thumb, and lift it a short distance off the table. In terms of the relationship between arm transport and grip aperture, the control subjects showed a high consistency in grip aperture and wrist velocity profiles from trial to trial for movements to both the dowel and the cross. The relationship between the maximum velocity of the wrist and the time at which grip aperture was maximal during the reach was highly consistent throughout the experiment. In contrast, the time of maximum grip aperture and maximum wrist velocity of the cerebellar patients was quite variable from trial to trial, and the relationship of these measurements also varied considerably. These abnormalities were present regardless of the accuracy requirement. In addition, the cerebellar patients required a significantly longer time to grasp and lift the objects than the control subjects. Furthermore, the patients exhibited a greater grip aperture during reach than the controls. These data indicate that the cerebellum contributes substantially to the coordination of movements required to perform reach-to-grasp movements. Specifically, the cerebellum is critical for executing this behavior with a consistent, well-timed relationship between the transport and grasp components. This contribution is apparent even when accuracy demands are minimal.

Perinatal intermittent hypoxia alters γ-aminobutyric acid: a receptor levels in rat cerebellum.

PubMed

Pae, Eung-Kwon; Yoon, Audrey J; Ahuja, Bhoomika; Lau, Gary W; Nguyen, Daniel D; Kim, Yong; Harper, Ronald M

2011-12-01

Perinatal hypoxia commonly causes brain injury in infants, but the time course and mechanisms underlying the preferential male injury are unclear. Intermittent hypoxia disturbs cerebellar γ-aminobutyric (GABA)-A receptor profiles during the perinatal period, possibly responding to transient excitatory processes associated with GABA(A) receptors. We examined whether hypoxic insults were particularly damaging to the male rodent cerebellum during a specific developmental time window. We evaluated cerebellar injury and GABA(A) receptor profiles following 5-h intermittent hypoxia (IH: 20.8% and 10.3% ambient oxygen, switched every 240s) or room-air control in groups of male and female rat pups on postnatal d 1-2, wk 1, or wk 3. The cerebella were harvested and compared between groups. The mRNA levels of GABA(A) receptors α6, normalized to a house-keeping gene GAPDH, and assessed using real-time reverse-transcriptase PCR assays were up-regulated by IH at wk 1, more extensively in male rats, with sex influencing the regulatory time-course. In contrast, GABA(A) α6 receptor protein expression levels, assessed using Western blot assays, reached a nadir at wk 1 in both male and female rats, possibly indicating involvement of a post-transcriptional mechanism. The extent of cerebellar damage and level of apoptosis, assessed by DNA fragmentation, were greatest in the wk 3 IH-exposed group. The findings suggest partial protection for female rats against early hypoxic insult in the cerebellum, and that down-regulation of GABA(A) receptors, rather than direct neural injury assessed by DNA fragmentation may modify cerebellar function, with potential later motor and other deficits. Copyright © 2011 ISDN. Published by Elsevier Ltd. All rights reserved.

Cerebellar contribution to motor and cognitive performance in multiple sclerosis: An MRI sub-regional volumetric analysis.

PubMed

D'Ambrosio, Alessandro; Pagani, Elisabetta; Riccitelli, Gianna C; Colombo, Bruno; Rodegher, Mariaemma; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo; Rocca, Maria A

2017-08-01

To investigate the role of cerebellar sub-regions on motor and cognitive performance in multiple sclerosis (MS) patients. Whole and sub-regional cerebellar volumes, brain volumes, T2 hyperintense lesion volumes (LV), and motor performance scores were obtained from 95 relapse-onset MS patients and 32 healthy controls (HC). MS patients also underwent an evaluation of working memory and processing speed functions. Cerebellar anterior and posterior lobes were segmented using the Spatially Unbiased Infratentorial Toolbox (SUIT) from Statistical Parametric Mapping (SPM12). Multivariate linear regression models assessed the relationship between magnetic resonance imaging (MRI) measures and motor/cognitive scores. Compared to HC, only secondary progressive multiple sclerosis (SPMS) patients had lower cerebellar volumes (total and posterior cerebellum). In MS patients, lower anterior cerebellar volume and brain T2 LV predicted worse motor performance, whereas lower posterior cerebellar volume and brain T2 LV predicted poor cognitive performance. Global measures of brain volume and infratentorial T2 LV were not selected by the final multivariate models. Cerebellar volumetric abnormalities are likely to play an important contribution to explain motor and cognitive performance in MS patients. Consistently with functional mapping studies, cerebellar posterior-inferior volume accounted for variance in cognitive measures, whereas anterior cerebellar volume accounted for variance in motor performance, supporting the assessment of cerebellar damage at sub-regional level.

Crossed cerebellar diaschisis in patients with acute middle cerebral artery infarction: Occurrence and perfusion characteristics

PubMed Central

Sommer, Wieland H; Bollwein, Christine; Thierfelder, Kolja M; Baumann, Alena; Janssen, Hendrik; Ertl-Wagner, Birgit; Reiser, Maximilian F; Plate, Annika; Straube, Andreas

2015-01-01

We aimed to investigate the overall prevalence and possible factors influencing the occurrence of crossed cerebellar diaschisis after acute middle cerebral artery infarction using whole-brain CT perfusion. A total of 156 patients with unilateral hypoperfusion of the middle cerebral artery territory formed the study cohort; 352 patients without hypoperfusion served as controls. We performed blinded reading of different perfusion maps for the presence of crossed cerebellar diaschisis and determined the relative supratentorial and cerebellar perfusion reduction. Moreover, imaging patterns (location and volume of hypoperfusion) and clinical factors (age, sex, time from symptom onset) resulting in crossed cerebellar diaschisis were analysed. Crossed cerebellar diaschisis was detected in 35.3% of the patients with middle cerebral artery infarction. Crossed cerebellar diaschisis was significantly associated with hypoperfusion involving the left hemisphere, the frontal lobe and the thalamus. The degree of the relative supratentorial perfusion reduction was significantly more pronounced in crossed cerebellar diaschisis-positive patients but did not correlate with the relative cerebellar perfusion reduction. Our data suggest that (i) crossed cerebellar diaschisis is a common feature after middle cerebral artery infarction which can robustly be detected using whole-brain CT perfusion, (ii) its occurrence is influenced by location and degree of the supratentorial perfusion reduction rather than infarct volume (iii) other clinical factors (age, sex and time from symptom onset) did not affect the occurrence of crossed cerebellar diaschisis. PMID:26661242

Cerebellar contributions to motor control and language comprehension: searching for common computational principles.

PubMed

Moberget, Torgeir; Ivry, Richard B

2016-04-01

The past 25 years have seen the functional domain of the cerebellum extend beyond the realm of motor control, with considerable discussion of how this subcortical structure contributes to cognitive domains including attention, memory, and language. Drawing on evidence from neuroanatomy, physiology, neuropsychology, and computational work, sophisticated models have been developed to describe cerebellar function in sensorimotor control and learning. In contrast, mechanistic accounts of how the cerebellum contributes to cognition have remained elusive. Inspired by the homogeneous cerebellar microanatomy and a desire for parsimony, many researchers have sought to extend mechanistic ideas from motor control to cognition. One influential hypothesis centers on the idea that the cerebellum implements internal models, representations of the context-specific dynamics of an agent's interactions with the environment, enabling predictive control. We briefly review cerebellar anatomy and physiology, to review the internal model hypothesis as applied in the motor domain, before turning to extensions of these ideas in the linguistic domain, focusing on speech perception and semantic processing. While recent findings are consistent with this computational generalization, they also raise challenging questions regarding the nature of cerebellar learning, and may thus inspire revisions of our views on the role of the cerebellum in sensorimotor control. © 2016 New York Academy of Sciences.

The Contribution of Brainstem and Cerebellar Pathways to Auditory Recognition

PubMed Central

McLachlan, Neil M.; Wilson, Sarah J.

2017-01-01

The cerebellum has been known to play an important role in motor functions for many years. More recently its role has been expanded to include a range of cognitive and sensory-motor processes, and substantial neuroimaging and clinical evidence now points to cerebellar involvement in most auditory processing tasks. In particular, an increase in the size of the cerebellum over recent human evolution has been attributed in part to the development of speech. Despite this, the auditory cognition literature has largely overlooked afferent auditory connections to the cerebellum that have been implicated in acoustically conditioned reflexes in animals, and could subserve speech and other auditory processing in humans. This review expands our understanding of auditory processing by incorporating cerebellar pathways into the anatomy and functions of the human auditory system. We reason that plasticity in the cerebellar pathways underpins implicit learning of spectrotemporal information necessary for sound and speech recognition. Once learnt, this information automatically recognizes incoming auditory signals and predicts likely subsequent information based on previous experience. Since sound recognition processes involving the brainstem and cerebellum initiate early in auditory processing, learnt information stored in cerebellar memory templates could then support a range of auditory processing functions such as streaming, habituation, the integration of auditory feature information such as pitch, and the recognition of vocal communications. PMID:28373850

Cerebellar nicotinic cholinergic receptors are intrinsic to the cerebellum: implications for diverse functional roles.

PubMed

Turner, Jill R; Ortinski, Pavel I; Sherrard, Rachel M; Kellar, Kenneth J

2011-12-01

Although recent studies have delineated the specific nicotinic subtypes present in the mammalian cerebellum, very little is known about their location or function within the cerebellum. This is of increased interest since nicotinic receptors (nAChRs) in the cerebellum have recently been implicated in the pathology of autism spectrum disorders. To begin to better understand the roles of these heteromeric nAChRs in the cerebellar circuitry and their therapeutic potential as targets for drug development, we used various chemical and stereotaxic lesion models in conjunction with slice electrophysiology to examine how specific heteromeric nAChR subtypes may influence the surrounding cerebellar circuitry. Using subunit-specific immunoprecipitation of radiolabeled nAChRs in the cerebella following N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, p-chloroamphetamine, and pendunculotomy lesions, we show that most, if not all, cerebellar nicotinic receptors are present in cells within the cerebellum itself and not in extracerebellar afferents. Furthermore, we demonstrate that the β4-containing, but not the β2-containing, nAChRs intrinsic to the cerebellum can regulate inhibitory synaptic efficacy at two major classes of cerebellar neurons. These tandem findings suggest that nAChRs may present a potential drug target for disorders involving the cerebellum.

Cerebellar Nicotinic Cholinergic Receptors are Intrinsic to the Cerebellum: Implications for Diverse Functional Roles

PubMed Central

Turner, Jill R.; Ortinski, Pavel I.; Sherrard, Rachel M.

2016-01-01

Although recent studies have delineated the specific nicotinic subtypes present in the mammalian cerebellum, very little is known about their location or function within the cerebellum. This is of increased interest since nicotinic receptors (nAChRs) in the cerebellum have recently been implicated in the pathology of autism spectrum disorders. To begin to better understand the roles of these heteromeric nAChRs in the cerebellar circuitry and their therapeutic potential as targets for drug development, we used various chemical and stereotaxic lesion models in conjunction with slice electrophysiology to examine how specific heteromeric nAChR subtypes may influence the surrounding cerebellar circuitry. Using subunit-specific immunoprecipitation of radiolabeled nAChRs in the cerebella following N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, p-chloroamphetamine, and pendunculotomy lesions, we show that most, if not all, cerebellar nicotinic receptors are present in cells within the cerebellum itself and not in extracerebellar afferents. Furthermore, we demonstrate that the β4-containing, but not the β2-containing, nAChRs intrinsic to the cerebellum can regulate inhibitory synaptic efficacy at two major classes of cerebellar neurons. These tandem findings suggest that nAChRs may present a potential drug target for disorders involving the cerebellum. PMID:21562921

Early Cerebellar Network Shifting in Spinocerebellar Ataxia Type 6

PubMed Central

Falcon, M.I.; Gomez, C.M.; Chen, E.E.; Shereen, A.; Solodkin, A.

2016-01-01

Spinocerebellar ataxia 6 (SCA6), an autosomal dominant degenerative disease, is characterized by diplopia, gait ataxia, and incoordination due to severe progressive degeneration of Purkinje cells in the vestibulo- and spinocerebellum. Ocular motor deficits are common, including difficulty fixating on moving objects, nystagmus and disruption of smooth pursuit movements. In presymptomatic SCA6, there are alterations in saccades and smooth-pursuit movements. We sought to assess functional and structural changes in cerebellar connectivity associated with a visual task, hypothesizing that gradual changes would parallel disease progression. We acquired functional magnetic resonance imaging and diffusion tensor imaging data during a passive smooth-pursuit task in 14 SCA6 patients, representing a range of disease duration and severity, and performed a cross-sectional comparison of cerebellar networks compared with healthy controls. We identified a shift in activation from vermis in presymptomatic individuals to lateral cerebellum in moderate-to-severe cases. Concomitantly, effective connectivity between regions of cerebral cortex and cerebellum was at its highest in moderate cases, and disappeared in severe cases. Finally, we noted structural differences in the cerebral and cerebellar peduncles. These unique results, spanning both functional and structural domains, highlight widespread changes in SCA6 and compensatory mechanisms associated with cerebellar physiology that could be utilized in developing new therapies. PMID:26209844

Long-term supratentorial brain structure and cognitive function following cerebellar tumour resections in childhood.

PubMed

Moberget, T; Andersson, S; Lundar, T; Due-Tønnessen, B J; Heldal, A; Endestad, T; Westlye, L T

2015-03-01

The cerebellum is connected to extensive regions of the cerebrum, and cognitive deficits following cerebellar lesions may thus be related to disrupted cerebello-cerebral connectivity. Moreover, early cerebellar lesions could affect distal brain development, effectively inducing long-term changes in brain structure and cognitive function. Here, we characterize supratentorial brain structure and cognitive function in 20 adult patients treated for cerebellar tumours in childhood (mean age at surgery: 7.1 years) and 26 matched controls. Relative to controls, patients showed reduced cognitive function and increased grey matter density in bilateral cingulum, left orbitofrontal cortex and the left hippocampus. Within the patient group, increased grey matter density in these regions was associated with decreased performance on tests of processing speed and executive function. Further, diffusion tensor imaging revealed widespread alterations in white matter microstructure in patients. While current ventricle volume (an index of previous hydrocephalus severity it patients) was associated with grey matter density and white matter microstructure in patients, this could only partially account for the observed group differences in brain structure and cognitive function. In conclusion, our results show distal effects of cerebellar lesions on cerebral integrity and wiring, likely caused by a combination of neurodegenerative processes and perturbed neurodevelopment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cerebellar Alterations and Gait Defects as Therapeutic Outcome Measures for Enzyme Replacement Therapy in α-Mannosidosis

PubMed Central

Damme, Markus; Stroobants, Stijn; Walkley, Steven U.; Lüllmann-Rauch, Renate; D`Hooge, Rudi; Fogh, Jens; Saftig, Paul; Lübke, Torben; Blanz, Judith

2011-01-01

α-Mannosidosis is a rare lysosomal storage disease with accumulation of undegraded mannosyl-linked oligosaccharides in cells throughout the body, most notably in the CNS. This leads to a broad spectrum of neurological manifestations, including progressive intellectual impairment, disturbed motor functions and cerebellar atrophy. To develop therapeutic outcome measures for enzyme replacement therapy (ERT) that could be used for human patients, a gene knockout model of α-mannosidosis in mice was analyzed for CNS pathology and motor deficits. In the cerebellar molecular layer, α-mannosidosis mice display clusters of activated Bergman glia, infiltration of phagocytic macrophages and accumulation of free cholesterol and gangliosides (GM1), notably in regions lacking Purkinje cells. α-mannosidosis brain lysates also displayed increased expression of Lamp1 and hyperglycosylation of the cholesterol binding protein NPC2. Detailed assessment of motor function revealed age-dependent gait defects in the mice that resemble the disturbed motor function in human patients. Short-term ERT partially reversed the observed cerebellar pathology with fewer activated macrophages and astrocytes but unchanged levels of hyperglycosylated NPC2, gangliosides and cholesterol. The present study demonstrates cerebellar alterations in α-mannosidosis mice that relate to the motor deficits and pathological changes seen in human patients and can be used as therapeutic outcome measures. PMID:21157375

A case report of HTLV-I associated myelopathy presenting with cerebellar ataxia and nystagmus.

PubMed

Taki, Masakatsu; Nin, Fumiaki; Hasegawa, Tatsuhisa; Sakaguchi, Hirofumi; Suzuki, Toshihiro; Hisa, Yasuo; Azuma, Yumiko; Nakagawa, Masanori

2011-06-01

HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) is characterized by spastic paraparesis in the lower extremities, and urinary disturbance. HAM/TSP has also been less frequently associated with cerebellar syndromes and nystagmus. We report a case of HAM/TSP presenting with cerebellar ataxia and nystagmus. The patient was a 73-year-old woman who was born in southern Japan. At age 41, she developed pain and spasticity in the bilateral lower limbs and gradually progressive gait disturbance. At age 57, she was diagnosed with HAM/TSP based on spastic paraparesis in the lower limbs, urinary disturbance and positive anti HTLV-I antibody in serum and cerebrospinal fluid. In June 2008, she was referred to our university and hospitalized for rehabilitation. Twenty days later, she experienced rotatory vertigo sensation. Magnetic resonance imaging revealed pontocerebellar atrophy. The patient presented with cerebellar signs in the upper limbs, gaze-evoked nystagmus in the sitting position and right-beating horizontal nystagmus in the supine and head-hanging positions. Electronystagmography (ENG) showed horizontal saccadic overshoot dysmetria and horizontal saccadic pursuit. Nystagmus is rare among the literature on HAM/TSP. ENG is helpful to evaluate and confirm the cerebellar syndromes of HAM/TSP. Copyright © 2010. Published by Elsevier Ireland Ltd.

Cerebro-cerebellar resting state functional connectivity in children and adolescents with autism spectrum disorder

PubMed Central

Khan, Amanda J.; Nair, Aarti; Keown, Christopher L.; Datko, Michael C.; Lincoln, Alan J.; Müller, Ralph-Axel

2017-01-01

Background The cerebellum plays important roles in both sensorimotor and supramodal cognitive functions. Cellular, volumetric, and functional abnormalities of the cerebellum have been found in autism spectrum disorders (ASD), but no comprehensive investigation of cerebro-cerebellar connectivity in ASD is available. Methods We used resting-state functional connectivity MRI in 56 children and adolescents (28 ASD, 28 typically developing [TD]) aged 8–17 years. Partial and total correlation analyses were performed for unilateral regions of interest (ROIs), distinguished in two broad domains as sensorimotor (premotor/primary motor, somatosensory, superior temporal, occipital) and supramodal (prefrontal, posterior parietal, and inferior and middle temporal). Results There were three main findings: (i) Total correlation analyses showed predominant cerebro-cerebellar functional overconnectivity in the ASD group; (ii) partial correlation analyses that emphasized domain-specificity (sensorimotor vs. supramodal) indicated a pattern of robustly increased connectivity in the ASD group (compared to the TD group) for sensorimotor ROIs, but predominantly reduced connectivity for supramodal ROIs; (iii) this atypical pattern of connectivity was supported by significantly increased non-canonical connections (between sensorimotor cerebral and supramodal cerebellar ROIs, and vice versa) in the ASD group. Conclusions Our findings indicate that sensorimotor intrinsic functional connectivity is atypically increased in ASD, at the expense of connectivity supporting cerebellar participation in supramodal cognition. PMID:25959247

Injury to the Premature Cerebellum: Outcome is Related to Remote Cortical Development

PubMed Central

Limperopoulos, Catherine; Chilingaryan, Gevorg; Sullivan, Nancy; Guizard, Nicolas; Robertson, Richard L.; du Plessis, Adré J.

2014-01-01

Cerebellar injury is an important complication of preterm birth with far-reaching neuropsychiatric sequelae. We have previously shown a significant association between isolated injury to the premature cerebellum and subsequent impairment of regional volumetric growth in the contralateral cerebrum. In the current study, we examine the relationship between these remote regional impairments of cerebral volumetric growth and domain-specific functional deficits in these children. In 40 ex-preterm infants with isolated cerebellar injury, we performed neurodevelopmental evaluations and quantitative magnetic resonance imaging (MRI) studies at a mean age of 34 months. We measured cortical gray matter volumes in 8 parcellated regions of each cerebral hemisphere, as well as right and left cerebellar volumes. We show highly significant associations between early signs of autism and dorsolateral prefrontal cortex volume (P < 0.001); gross motor scores and sensorimotor cortical volumes (P < 0.001); and cognitive and expressive language scores and premotor and mid-temporal cortical volumes (P < 0.001). By multivariate analyses, each unit increase in the corresponding regional cerebral volume was associated with lower odds of abnormal outcome score, adjusted for age at MRI and contralateral cerebellar volume. This is the first report linking secondary impairment of remote cerebral cortical growth and functional disabilities in survivors of prematurity-related cerebellar brain injury. PMID:23146968

Cerebellar contribution to mental rotation: a cTBS study.

PubMed

Picazio, Silvia; Oliveri, Massimiliano; Koch, Giacomo; Caltagirone, Carlo; Petrosini, Laura

2013-12-01

A cerebellar role in spatial information processing has been advanced even in the absence of physical manipulation, as occurring in mental rotation. The present study was aimed at investigating the specific involvement of left and right cerebellar hemispheres in two tasks of mental rotation. We used continuous theta burst stimulation to downregulate cerebellar hemisphere excitability in healthy adult subjects performing two mental rotation tasks: an Embodied Mental Rotation (EMR) task, entailing an egocentric strategy, and an Abstract Mental Rotation (AMR) task entailing an allocentric strategy. Following downregulation of left cerebellar hemisphere, reaction times were slower in comparison to sham stimulation in both EMR and AMR tasks. Conversely, identical reaction times were obtained in both tasks following right cerebellar hemisphere and sham stimulations. No effect of cerebellar stimulation side was found on response accuracy. The present findings document a specialization of the left cerebellar hemisphere in mental rotation regardless of the kind of stimulus to be rotated.

Cerebro-Cerebellar Functional Connectivity is Associated with Cerebellar Excitation-Inhibition Balance in Autism Spectrum Disorder.

PubMed

Hegarty, John P; Weber, Dylan J; Cirstea, Carmen M; Beversdorf, David Q

2018-05-23

Atypical functional connectivity (FC) and an imbalance of excitation-to-inhibition (E/I) have been previously reported in cerebro-cerebellar circuits in autism spectrum disorder (ASD). The current investigation used resting state fMRI and proton magnetic resonance spectroscopy ( 1 H-MRS) to examine the relationships between E/I (glutamate + glutamine/GABA) and FC of the dorsolateral prefrontal cortex and posterolateral cerebellar hemisphere from 14 adolescents/adults with ASD and 12 age/sex/IQ-matched controls. In this pilot sample, cerebro-cerebellar FC was positively associated with cerebellar E/I and listening comprehension abilities in individuals with ASD but not controls. Additionally, a subgroup of individuals with ASD and low FC (n = 5) exhibited reduced E/I and impaired listening comprehension. Thus, altered functional coherence of cerebro-cerebellar circuits in ASD may be related with a cerebellar E/I imbalance.

Optimization of cerebellar purkinje neuron cultures and development of a plasmid-based method for purkinje neuron-specific, miRNA-mediated protein knockdown.

PubMed

Alexander, C J; Hammer, J A

2016-01-01

We present a simple and efficient method to knock down proteins specifically in Purkinje neurons (PN) present in mixed mouse primary cerebellar cultures. This method utilizes the introduction via nucleofection of a plasmid encoding a specific miRNA downstream of the L7/Pcp2 promoter, which drives PN-specific expression. As proof-of-principle, we used this plasmid to knock down the motor protein myosin Va, which is required for the targeting of smooth endoplasmic reticulum (ER) into PN spines. Consistent with effective knockdown, transfected PNs robustly phenocopied PNs from dilute-lethal (myosin Va-null) mice with regard to the ER targeting defect. Importantly, our plasmid-based approach is less challenging technically and more specific to PNs than several alternative methods (e.g., biolistic- and lentiviral-based introduction of siRNAs). We also present a number of improvements for generating mixed cerebellar cultures that shorten the procedure and improve the total yield of PNs, and of transfected PNs, considerably. Finally, we present a method to rescue cerebellar cultures that develop large cell aggregates, a common problem that otherwise precludes the further use of the culture. Copyright © 2016 Elsevier Inc. All rights reserved.

Hindbrain regional growth in preterm newborns and its impairment in relation to brain injury

PubMed Central

Kim, Hosung; Gano, Dawn; Ho, Mai-Lan; Guo, Xiaoyue M.; Unzueta, Alisa; Hess, Christopher; Ferriero, Donna M.; Xu, Duan; Barkovich, A. James

2016-01-01

Premature birth globally affects about 11.1% of all newborns and is a risk factor for neurodevelopmental disability in surviving infants. Histology has suggested that hindbrain subdivisions grow differentially, especially in the third trimester. Prematurity-related brain injuries occurring in this period may selectively affect more rapidly developing areas of hindbrain, thus accompanying region-specific impairments in growth and ultimately neurodevelopmental deficits. The current study aimed to quantify regional growth of the cerebellum and the brainstem in preterm neonates (n=65 with individually multiple scans). We probed associations of the regional volumes with severity of brain injury. In neonates with no imaging evidence of injury, our analysis using a mixed-effect linear model showed faster growth in the pons and the lateral convexity of anterior/posterior cerebellar lobes. Different patterns of growth impairment were found in relation to early cerebral intraventricular hemorrhage and cerebellar hemorrhage (p<0.05), likely explaining different mechanisms through which neurogenesis is disrupted. The pattern of cerebellar growth identified in our study agreed excellently with details of cerebellar morphogenesis in perinatal development, which has only been observed in histological data. Our proposed analytic framework may provide predictive imaging biomarkers for neurodevelopmental outcome, enabling early identification and treatment of high-risk patients. PMID:26589992

Tubulin-related cerebellar dysplasia: definition of a distinct pattern of cerebellar malformation.

PubMed

Romaniello, Romina; Arrigoni, Filippo; Panzeri, Elena; Poretti, Andrea; Micalizzi, Alessia; Citterio, Andrea; Bedeschi, Maria Francesca; Berardinelli, Angela; Cusmai, Raffaella; D'Arrigo, Stefano; Ferraris, Alessandro; Hackenberg, Annette; Kuechler, Alma; Mancardi, Margherita; Nuovo, Sara; Oehl-Jaschkowitz, Barbara; Rossi, Andrea; Signorini, Sabrina; Tüttelmann, Frank; Wahl, Dagmar; Hehr, Ute; Boltshauser, Eugen; Bassi, Maria Teresa; Valente, Enza Maria; Borgatti, Renato

2017-12-01

To determine the neuroimaging pattern of cerebellar dysplasia (CD) and other posterior fossa morphological anomalies associated with mutations in tubulin genes and to perform clinical and genetic correlations. Twenty-eight patients harbouring 23 heterozygous pathogenic variants (ten novel) in tubulin genes TUBA1A (n = 10), TUBB2B (n = 8) or TUBB3 (n = 5) were studied by a brain MRI scan performed either on a 1.5 T (n = 10) or 3 T (n = 18) MR scanner with focus on the posterior fossa. Cerebellar anomalies were detected in 24/28 patients (86%). CD was recognised in 19/28 (68%) including cortical cerebellar dysplasia (CCD) in 18/28, either involving only the cerebellar hemispheres (12/28) or associated with vermis dysplasia (6/28). CCD was located only in the right hemisphere in 13/18 (72%), including four TUBB2B-, four TUBB3- and five TUBA1A-mutated patients, while in the other five TUBA1A cases it was located only in the left hemisphere or in both hemispheres. The postero-superior region of the cerebellar hemispheres was most frequently affected. The cerebellar involvement in tubulinopathies shows specific features that may be labelled as 'tubulin-related CD'. This pattern is unique and differs from other genetic causes of cerebellar dysplasia. • Cortical cerebellar dysplasia without cysts is suggestive of tubulin-related disorder. • Cerebellar dysplasia in tubulinopathies shows specific features labelled as 'tubulin-related CD'. • Focal and unilateral involvement of cerebellar hemispheres has important implications for counselling.

Consensus Paper: Pathological Role of the Cerebellum in Autism

PubMed Central

Fatemi, S. Hossein; Aldinger, Kimberly A.; Ashwood, Paul; Bauman, Margaret L.; Blaha, Charles D.; Blatt, Gene J.; Chauhan, Abha; Chauhan, Ved; Dager, Stephen R.; Dickson, Price E.; Estes, Annette M.; Goldowitz, Dan; Heck, Detlef H.; Kemper, Thomas L.; King, Bryan H.; Martin, Loren A.; Millen, Kathleen J.; Mittleman, Guy; Mosconi, Matthew W.; Persico, Antonio M.; Sweeney, John A.; Webb, Sara J.; Welsh, John P.

2013-01-01

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation. PMID:22370873

Dystonia and Cerebellar Degeneration in the Leaner Mouse Mutant

PubMed Central

Raike, Robert S.; Hess, Ellen J.; Jinnah, H.A.

2015-01-01

Cerebellar degeneration is traditionally associated with ataxia. Yet, there are examples of both ataxia and dystonia occurring in individuals with cerebellar degeneration. There is also substantial evidence suggesting that cerebellar dysfunction alone may cause dystonia. The types of cerebellar defects that may cause ataxia, dystonia, or both have not been delineated. In the current study, we explored the relationship between cerebellar degeneration and dystonia using the leaner mouse mutant. Leaner mice have severe dystonia that is associated with dysfunctional and degenerating cerebellar Purkinje cells. Whereas the density of Purkinje cells was not significantly reduced in 4 week-old leaner mice, approximately 50% of the neurons were lost by 34 weeks of age. On the other hand, the dystonia and associated functional disability became significantly less severe during this same interval. In other words, dystonia improved as Purkinje cells were lost, suggesting that dysfunctional Purkinje cells, rather than Purkinje cell loss, contribute to the dystonia. These results provide evidence that distorted cerebellar function may cause dystonia and support the concept that different types of cerebellar defects can have different functional consequences. PMID:25791619

Consensus paper: pathological role of the cerebellum in autism.

PubMed

Fatemi, S Hossein; Aldinger, Kimberly A; Ashwood, Paul; Bauman, Margaret L; Blaha, Charles D; Blatt, Gene J; Chauhan, Abha; Chauhan, Ved; Dager, Stephen R; Dickson, Price E; Estes, Annette M; Goldowitz, Dan; Heck, Detlef H; Kemper, Thomas L; King, Bryan H; Martin, Loren A; Millen, Kathleen J; Mittleman, Guy; Mosconi, Matthew W; Persico, Antonio M; Sweeney, John A; Webb, Sara J; Welsh, John P

2012-09-01

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

CNS listeriosis: rhomboencephalitis in a healthy, immunocompetent person.

PubMed

Katz, R I; McGlamery, M E; Levy, R

1979-08-01

A previously healthy woman had a febrile illness resembling aseptic meningoencephalitis. With the exception of mild increase in both CSF pressure and protein concentration, initial findings were normal, including negative bacterial cultures. Bilateral pyramidal and cerebellar signs with multiple lower cranial nerve pareses developed over a 48-hour period beginning on the tenth hospital day. Repeated blood and CSF studies had previously been nondiagnostic, but at that time, cultures became positive for Listeria monocytogenes. No underlying systemic disease or immunodeficiency was discovered. With appropriate antibiotic and supportive therapy, she made slow but significant improvement and, by the time of discharge from the hospital, had only minimal residual neurologic deficit. Clinical aspects of CNS listeriosis including the rare pontomedullary involvement are discussed.

Allometric Analysis Detects Brain Size-Independent Effects of Sex and Sex Chromosome Complement on Human Cerebellar Organization.

PubMed

Mankiw, Catherine; Park, Min Tae M; Reardon, P K; Fish, Ari M; Clasen, Liv S; Greenstein, Deanna; Giedd, Jay N; Blumenthal, Jonathan D; Lerch, Jason P; Chakravarty, M Mallar; Raznahan, Armin

2017-05-24

The cerebellum is a large hindbrain structure that is increasingly recognized for its contribution to diverse domains of cognitive and affective processing in human health and disease. Although several of these domains are sex biased, our fundamental understanding of cerebellar sex differences-including their spatial distribution, potential biological determinants, and independence from brain volume variation-lags far behind that for the cerebrum. Here, we harness automated neuroimaging methods for cerebellar morphometrics in 417 individuals to (1) localize normative male-female differences in raw cerebellar volume, (2) compare these to sex chromosome effects estimated across five rare sex (X/Y) chromosome aneuploidy (SCA) syndromes, and (3) clarify brain size-independent effects of sex and SCA on cerebellar anatomy using a generalizable allometric approach that considers scaling relationships between regional cerebellar volume and brain volume in health. The integration of these approaches shows that (1) sex and SCA effects on raw cerebellar volume are large and distributed, but regionally heterogeneous, (2) human cerebellar volume scales with brain volume in a highly nonlinear and regionally heterogeneous fashion that departs from documented patterns of cerebellar scaling in phylogeny, and (3) cerebellar organization is modified in a brain size-independent manner by sex (relative expansion of total cerebellum, flocculus, and Crus II-lobule VIIIB volumes in males) and SCA (contraction of total cerebellar, lobule IV, and Crus I volumes with additional X- or Y-chromosomes; X-specific contraction of Crus II-lobule VIIIB). Our methods and results clarify the shifts in human cerebellar organization that accompany interwoven variations in sex, sex chromosome complement, and brain size. SIGNIFICANCE STATEMENT Cerebellar systems are implicated in diverse domains of sex-biased behavior and pathology, but we lack a basic understanding of how sex differences in the human cerebellum are distributed and determined. We leverage a rare neuroimaging dataset to deconvolve the interwoven effects of sex, sex chromosome complement, and brain size on human cerebellar organization. We reveal topographically variegated scaling relationships between regional cerebellar volume and brain size in humans, which (1) are distinct from those observed in phylogeny, (2) invalidate a traditional neuroimaging method for brain volume correction, and (3) allow more valid and accurate resolution of which cerebellar subcomponents are sensitive to sex and sex chromosome complement. These findings advance understanding of cerebellar organization in health and sex chromosome aneuploidy. Copyright © 2017 the authors 0270-6474/17/375222-11$15.00/0.

Training-induced improvements in postural control are accompanied by alterations in cerebellar white matter in brain injured patients.

PubMed

Drijkoningen, David; Caeyenberghs, Karen; Leunissen, Inge; Vander Linden, Catharine; Leemans, Alexander; Sunaert, Stefan; Duysens, Jacques; Swinnen, Stephan P

2015-01-01

We investigated whether balance control in young TBI patients can be promoted by an 8-week balance training program and whether this is associated with neuroplastic alterations in brain structure. The cerebellum and cerebellar peduncles were selected as regions of interest because of their importance in postural control as well as their vulnerability to brain injury. Young patients with moderate to severe TBI and typically developing (TD) subjects participated in balance training using PC-based portable balancers with storage of training data and real-time visual feedback. An additional control group of TD subjects did not attend balance training. Mean diffusivity and fractional anisotropy were determined with diffusion MRI scans and were acquired before, during (4 weeks) and at completion of training (8 weeks) together with balance assessments on the EquiTest® System (NeuroCom) which included the Sensory Organization Test, Rhythmic Weight Shift and Limits of Stability protocols. Following training, TBI patients showed significant improvements on all EquiTest protocols, as well as a significant increase in mean diffusivity in the inferior cerebellar peduncle. Moreover, in both training groups, diffusion metrics in the cerebellum and/or cerebellar peduncles at baseline were predictive of the amount of performance increase after training. Finally, amount of training-induced improvement on the Rhythmic Weight Shift test in TBI patients was positively correlated with amount of change in fractional anisotropy in the inferior cerebellar peduncle. This suggests that training-induced plastic changes in balance control are associated with alterations in the cerebellar white matter microstructure in TBI patients.

Training-induced improvements in postural control are accompanied by alterations in cerebellar white matter in brain injured patients

PubMed Central

Drijkoningen, David; Caeyenberghs, Karen; Leunissen, Inge; Vander Linden, Catharine; Leemans, Alexander; Sunaert, Stefan; Duysens, Jacques; Swinnen, Stephan P.

2014-01-01

We investigated whether balance control in young TBI patients can be promoted by an 8-week balance training program and whether this is associated with neuroplastic alterations in brain structure. The cerebellum and cerebellar peduncles were selected as regions of interest because of their importance in postural control as well as their vulnerability to brain injury. Young patients with moderate to severe TBI and typically developing (TD) subjects participated in balance training using PC-based portable balancers with storage of training data and real-time visual feedback. An additional control group of TD subjects did not attend balance training. Mean diffusivity and fractional anisotropy were determined with diffusion MRI scans and were acquired before, during (4 weeks) and at completion of training (8 weeks) together with balance assessments on the EquiTest® System (NeuroCom) which included the Sensory Organization Test, Rhythmic Weight Shift and Limits of Stability protocols. Following training, TBI patients showed significant improvements on all EquiTest protocols, as well as a significant increase in mean diffusivity in the inferior cerebellar peduncle. Moreover, in both training groups, diffusion metrics in the cerebellum and/or cerebellar peduncles at baseline were predictive of the amount of performance increase after training. Finally, amount of training-induced improvement on the Rhythmic Weight Shift test in TBI patients was positively correlated with amount of change in fractional anisotropy in the inferior cerebellar peduncle. This suggests that training-induced plastic changes in balance control are associated with alterations in the cerebellar white matter microstructure in TBI patients. PMID:25610786

Abnormal nuclear envelope in the cerebellar Purkinje cells and impaired motor learning in DYT11 myoclonus-dystonia mouse models

PubMed Central

Yokoi, Fumiaki; Dang, Mai T.; Yang, Guang; Li, JinDong; Doroodchi, Atbin; Zhou, Tong; Li, Yuqing

2011-01-01

Myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonia. DYT11 M-D is caused by mutations in SGCE which codes for ε-sarcoglycan. SGCE is maternally imprinted and paternally expressed. Abnormal nuclear envelope has been reported in mouse models of DYT1 generalized torsion dystonia. However, it is not known whether similar alterations occur in DYT11 M-D. We developed a mouse model of DYT11 M-D using paternally-inherited Sgce heterozygous knockout (Sgce KO) mice and reported that they had myoclonus and motor coordination and learning deficits in the beam-walking test. However, the specific brain regions that contribute to these phenotypes have not been identified. Since ε-sarcoglycan is highly expressed in the cerebellar Purkinje cells, here we examined the nuclear envelope in these cells using a transmission electron microscope and found that they are abnormal in Sgce KO mice. Our results put DYT11 M-D in a growing family of nuclear envelopathies. To analyze the effect of loss of ε-sarcoglycan function in the cerebellar Purkinje cells, we produced paternally-inherited cerebellar Purkinje cell-specific Sgce conditional knockout (Sgce pKO) mice. Sgce pKO mice showed motor learning deficits, while they did not show abnormal nuclear envelope in the cerebellar Purkinje cells, robust motor deficits, or myoclonus. The results suggest that ε-sarcoglycan in the cerebellar Purkinje cells contributes to the motor learning, while loss of ε-sarcoglycan in other brain regions may contribute to nuclear envelope abnormality, myoclonus and motor coordination deficits. PMID:22040906

The contributions of the cerebellum in sensorimotor control: what are the prevailing opinions which will guide forthcoming studies?

PubMed

Manto, Mario; Oulad Ben Taib, Nordeyn

2013-06-01

Although considerable progress has been made in developing models of cerebellar function in sensorimotor control, the exact nature of the basic operations performed by the cerebellum remain elusive. Several major theories have emerged these last decades. According to the hypothesis of Marr and Albus, the climbing fiber input carries an error signal weakening the strength of a subset of parallel fibers/Purkinje neurons synapses in the cerebellar cortex. Cerebellar circuits would gain the control of movement through trial and error. The hypothesis of internal models emulating movements is currently highly cited. There is a general agreement that (1) the central nervous system has to cope with an intrinsic time delay of sensory feedback related to motor activities and (2) estimations of future motor states are essential to perform fast and accurate movements. According to this second theory, cerebellar dysmetria, one of the cardinal cerebellar deficits, would result from a distorted predictive control. A third popular theory relates to the inverse models that would be stored in the cerebellum. Acquisition of a motor act would require forward models, and the acquisition process itself would generate an inverse model to allow an unconscious coordinated movement. Recently, an international panel of experts from various disciplines discussed the prevailing opinions in a consensus statement and tried to extract their clinical relevance in terms of pathogenesis of the clinical symptoms. Although a consensus is still not reached, the prevailing opinions provide a sound framework to conduct novel studies and try to discover the secrets of cerebellar circuits.

The effectiveness of allied health care in patients with ataxia: a systematic review.

PubMed

Fonteyn, Ella M R; Keus, Samyra H J; Verstappen, Carla C P; Schöls, Ludger; de Groot, Imelda J M; van de Warrenburg, Bart P C

2014-02-01

Many patients with cerebellar ataxia have serious disabilities in daily life, while pharmacological treatment options are absent. Therefore, allied health care is considered to be important in the management of these patients. The goal of this review is to evaluate scientific evidence for allied health care in cerebellar ataxia, to identify effective treatment strategies, and to give recommendations for clinical practice and further research. A systematic search for clinical trials concerning allied health care in cerebellar ataxias was conducted using the electronic databases of PubMed, Medline, Embase, Cinahl and Pedro, and references lists of articles, in the time period from 1980 up to and including December 2011 in English and Dutch. We identified 14 trials, of which the four best studies were formally of moderate methodological quality. There was a wide variation in disease entities and interventions. The combined data indicate that physical therapy may lead to an improvement of ataxia symptoms and daily life functions in patients with degenerative cerebellar ataxia (level 2), and in other diseases causing cerebellar ataxia (level 3). When added to physical therapy, occupational therapy might improve global functional status, and occupational therapy alone may diminish symptoms of depression (level 3). There are insufficient data for speech and language therapy. Despite the widespread use of allied health care interventions in cerebellar ataxia, there is a lack of good quality studies that have evaluated such interventions. We found some support for the implementation of physical therapy and occupational therapy, but more research is needed to develop recommendations for clinical practice.

The effect of cerebellar transplantation and enforced physical activity on motor skills and spatial learning in adult Lurcher mutant mice.

PubMed

Cendelín, Jan; Korelusová, Ivana; Vozeh, Frantisek

2009-03-01

Lurcher mutant mice represent a model of olivocerebellar degeneration. They are used to investigate cerebellar functions, consequences of cerebellar degeneration and methods of therapy influencing them. The aim of the work was to assess the effect of foetal cerebellar graft transplantation, repeated enforced physical activity and the combination of both these types of treatment on motor skills, spontaneous motor activity and spatial learning ability in adult B6CBA Lurcher mice. Foetal cerebellar grafts were applied into the cerebellum of Lurchers in the form of solid tissue pieces. Enforced motor activity was realised through rotarod training. Motor functions were examined using bar, ladder and rotarod tests. Spatial learning was tested in the Morris water maze. Spontaneous motor activity in the open field was observed. The presence of the graft was examined histologically. Enforced physical activity led to moderate improvement of some motor skills and to a significant amelioration of spatial learning ability in Lurchers. The transplantation of cerebellar tissue did not influence motor functions significantly but led to an improvement of spatial learning ability. Mutual advancement of the effects of both types of treatment was not observed. Spontaneous motor activity was influenced neither by physical activity nor by the transplantation. Physical activity did not influence the graft survival and development. Because nerve sprouting and cell migration from the graft to the host cerebellum was poor, the functional effects of the graft should be explained with regard to its trophic influence rather than with any involvement of the grafted cells into neural circuitries.

Structural Basis of Cerebellar Microcircuits in the Rat

PubMed Central

Cerminara, Nadia L.; Aoki, Hanako; Loft, Michaela; Apps, Richard

2013-01-01

The topography of the cerebellar cortex is described by at least three different maps, with the basic units of each map termed “microzones,” “patches,” and “bands.” These are defined, respectively, by different patterns of climbing fiber input, mossy fiber input, and Purkinje cell (PC) phenotype. Based on embryological development, the “one-map” hypothesis proposes that the basic units of each map align in the adult animal and the aim of the present study was to test this possibility. In barbiturate anesthetized adult rats, nanoinjections of bidirectional tracer (Retrobeads and biotinylated dextran amine) were made into somatotopically identified regions within the hindlimb C1 zone in copula pyramidis. Injection sites were mapped relative to PC bands defined by the molecular marker zebrin II and were correlated with the pattern of retrograde cell labeling within the inferior olive and in the basilar pontine nuclei to determine connectivity of microzones and patches, respectively, and also with the distributions of biotinylated dextran amine-labeled PC terminals in the cerebellar nuclei. Zebrin bands were found to be related to both climbing fiber and mossy fiber inputs and also to cortical representation of different parts of the ipsilateral hindpaw, indicating a precise spatial organization within cerebellar microcircuitry. This precise connectivity extends to PC terminal fields in the cerebellar nuclei and olivonuclear projections. These findings strongly support the one-map hypothesis and suggest that, at the microcircuit level of resolution, the cerebellar cortex has a common plan of spatial organization for major inputs, outputs, and PC phenotype. PMID:24133249

Attention and Working Memory in Adolescents with Autism Spectrum Disorder: A Functional MRI Study.

PubMed

Rahko, Jukka S; Vuontela, Virve A; Carlson, Synnöve; Nikkinen, Juha; Hurtig, Tuula M; Kuusikko-Gauffin, Sanna; Mattila, Marja-Leena; Jussila, Katja K; Remes, Jukka J; Jansson-Verkasalo, Eira M; Aronen, Eeva T; Pauls, David L; Ebeling, Hanna E; Tervonen, Osmo; Moilanen, Irma K; Kiviniemi, Vesa J

2016-06-01

The present study examined attention and memory load-dependent differences in the brain activation and deactivation patterns between adolescents with autism spectrum disorders (ASDs) and typically developing (TD) controls using functional magnetic resonance imaging. Attentional (0-back) and working memory (WM; 2-back) processing and load differences (0 vs. 2-back) were analysed. WM-related areas activated and default mode network deactivated normally in ASDs as a function of task load. ASDs performed the attentional 0-back task similarly to TD controls but showed increased deactivation in cerebellum and right temporal cortical areas and weaker activation in other cerebellar areas. Increasing task load resulted in multiple responses in ASDs compared to TD and in inadequate modulation of brain activity in right insula, primary somatosensory, motor and auditory cortices. The changes during attentional task may reflect compensatory mechanisms enabling normal behavioral performance. The inadequate memory load-dependent modulation of activity suggests diminished compensatory potential in ASD.

Survival of adult neurons lacking cholesterol synthesis in vivo

PubMed Central

Fünfschilling, Ursula; Saher, Gesine; Xiao, Le; Möbius, Wiebke; Nave, Klaus-Armin

2007-01-01

Background Cholesterol, an essential component of all mammalian plasma membranes, is highly enriched in the brain. Both during development and in the adult, brain cholesterol is derived from local cholesterol synthesis and not taken up from the circulation. However, the contribution of neurons and glial cells to total brain cholesterol metabolism is unknown. Results Using conditional gene inactivation in the mouse, we disrupted the squalene synthase gene (fdft1), which is critical for cholesterol synthesis, in cerebellar granule cells and some precerebellar nuclei. Mutant mice showed no histological signs of neuronal degeneration, displayed ultrastructurally normal synapses, and exhibited normal motor coordination. This revealed that these adult neurons do not require cell-autonomous cholesterol synthesis for survival or function. Conclusion We conclude that at least some adult neurons no longer require endogenous cholesterol synthesis and can fully meet their cholesterol needs by uptake from their surrounding. Glia are a likely source of cholesterol in the central nervous system. PMID:17199885

A probabilistic atlas of the cerebellar white matter.

PubMed

van Baarsen, K M; Kleinnijenhuis, M; Jbabdi, S; Sotiropoulos, S N; Grotenhuis, J A; van Cappellen van Walsum, A M

2016-01-01

Imaging of the cerebellar cortex, deep cerebellar nuclei and their connectivity are gaining attraction, due to the important role the cerebellum plays in cognition and motor control. Atlases of the cerebellar cortex and nuclei are used to locate regions of interest in clinical and neuroscience studies. However, the white matter that connects these relay stations is of at least similar functional importance. Damage to these cerebellar white matter tracts may lead to serious language, cognitive and emotional disturbances, although the pathophysiological mechanism behind it is still debated. Differences in white matter integrity between patients and controls might shed light on structure-function correlations. A probabilistic parcellation atlas of the cerebellar white matter would help these studies by facilitating automatic segmentation of the cerebellar peduncles, the localization of lesions and the comparison of white matter integrity between patients and controls. In this work a digital three-dimensional probabilistic atlas of the cerebellar white matter is presented, based on high quality 3T, 1.25mm resolution diffusion MRI data from 90 subjects participating in the Human Connectome Project. The white matter tracts were estimated using probabilistic tractography. Results over 90 subjects were symmetrical and trajectories of superior, middle and inferior cerebellar peduncles resembled the anatomy as known from anatomical studies. This atlas will contribute to a better understanding of cerebellar white matter architecture. It may eventually aid in defining structure-function correlations in patients with cerebellar disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Crossed cerebellar diaschisis in patients with acute middle cerebral artery infarction: Occurrence and perfusion characteristics.

PubMed

Sommer, Wieland H; Bollwein, Christine; Thierfelder, Kolja M; Baumann, Alena; Janssen, Hendrik; Ertl-Wagner, Birgit; Reiser, Maximilian F; Plate, Annika; Straube, Andreas; von Baumgarten, Louisa

2016-04-01

We aimed to investigate the overall prevalence and possible factors influencing the occurrence of crossed cerebellar diaschisis after acute middle cerebral artery infarction using whole-brain CT perfusion. A total of 156 patients with unilateral hypoperfusion of the middle cerebral artery territory formed the study cohort; 352 patients without hypoperfusion served as controls. We performed blinded reading of different perfusion maps for the presence of crossed cerebellar diaschisis and determined the relative supratentorial and cerebellar perfusion reduction. Moreover, imaging patterns (location and volume of hypoperfusion) and clinical factors (age, sex, time from symptom onset) resulting in crossed cerebellar diaschisis were analysed. Crossed cerebellar diaschisis was detected in 35.3% of the patients with middle cerebral artery infarction. Crossed cerebellar diaschisis was significantly associated with hypoperfusion involving the left hemisphere, the frontal lobe and the thalamus. The degree of the relative supratentorial perfusion reduction was significantly more pronounced in crossed cerebellar diaschisis-positive patients but did not correlate with the relative cerebellar perfusion reduction. Our data suggest that (i) crossed cerebellar diaschisis is a common feature after middle cerebral artery infarction which can robustly be detected using whole-brain CT perfusion, (ii) its occurrence is influenced by location and degree of the supratentorial perfusion reduction rather than infarct volume (iii) other clinical factors (age, sex and time from symptom onset) did not affect the occurrence of crossed cerebellar diaschisis. © The Author(s) 2015.

XKR4 Gene Effects on Cerebellar Development Are Not Specific to ADHD

PubMed Central

Shook, Devon; Brouwer, Rachel; de Zeeuw, Patrick; Oranje, Bob; Durston, Sarah

2017-01-01

A single-nucleotide polymorphism (SNP) of the XKR4 gene has been linked to Attention-Deficit/Hyperactivity Disorder (ADHD). This gene is preferentially expressed in cerebellum, a brain structure implicated in this disorder. This study investigated the effects of this SNP on cerebellar development in children with and without ADHD. We collected 279 longitudinal T1-weighted structural images and DNA from 58 children with ADHD and 64 typically developing (TD) children matched for age, IQ, and gender. Groups were divided by the XKR4 rs2939678 SNP into A-allele carriers versus subjects homozygous for the G-allele. Cerebellar lobular volumes were segmented into 35 regions of interest using MAGeTBrain, an automated multi-atlas segmentation pipeline for anatomical MRI, and statistically analyzed using linear mixed models. We found decreased gray matter (GM) volumes in ADHD compared to TD children in bilateral lobules VIIIA, left VIIIB, right VIIB, and vermis VI. Furthermore, we found a linear age by gene interaction in left lobule VIIB where subjects homozygous for the G-allele showed a decrease in volume over time compared to A-allele carriers. We further found quadratic age × gene and age × diagnosis interactions in left lobule IV. Subjects homozygous for the G-allele (the genotype overtransmitted in ADHD) showed more suppressed, almost flat quadratic growth curves compared to A-allele carriers, similar to individuals with ADHD compared to controls. However, there was no interaction between genotype and diagnosis, suggesting that any effects of this SNP on cerebellar development are not specific to the disorder. PMID:29311829

XKR4 Gene Effects on Cerebellar Development Are Not Specific to ADHD.

PubMed

Shook, Devon; Brouwer, Rachel; de Zeeuw, Patrick; Oranje, Bob; Durston, Sarah

2017-01-01

A single-nucleotide polymorphism (SNP) of the XKR4 gene has been linked to Attention-Deficit/Hyperactivity Disorder (ADHD). This gene is preferentially expressed in cerebellum, a brain structure implicated in this disorder. This study investigated the effects of this SNP on cerebellar development in children with and without ADHD. We collected 279 longitudinal T1-weighted structural images and DNA from 58 children with ADHD and 64 typically developing (TD) children matched for age, IQ, and gender. Groups were divided by the XKR4 rs2939678 SNP into A-allele carriers versus subjects homozygous for the G-allele. Cerebellar lobular volumes were segmented into 35 regions of interest using MAGeTBrain, an automated multi-atlas segmentation pipeline for anatomical MRI, and statistically analyzed using linear mixed models. We found decreased gray matter (GM) volumes in ADHD compared to TD children in bilateral lobules VIIIA, left VIIIB, right VIIB, and vermis VI. Furthermore, we found a linear age by gene interaction in left lobule VIIB where subjects homozygous for the G-allele showed a decrease in volume over time compared to A-allele carriers. We further found quadratic age × gene and age × diagnosis interactions in left lobule IV. Subjects homozygous for the G-allele (the genotype overtransmitted in ADHD) showed more suppressed, almost flat quadratic growth curves compared to A-allele carriers, similar to individuals with ADHD compared to controls. However, there was no interaction between genotype and diagnosis, suggesting that any effects of this SNP on cerebellar development are not specific to the disorder.

Data-driven identification of intensity normalization region based on longitudinal coherency of 18F-FDG metabolism in the healthy brain.

PubMed

Zhang, Huiwei; Wu, Ping; Ziegler, Sibylle I; Guan, Yihui; Wang, Yuetao; Ge, Jingjie; Schwaiger, Markus; Huang, Sung-Cheng; Zuo, Chuantao; Förster, Stefan; Shi, Kuangyu

2017-02-01

In brain 18 F-FDG PET data intensity normalization is usually applied to control for unwanted factors confounding brain metabolism. However, it can be difficult to determine a proper intensity normalization region as a reference for the identification of abnormal metabolism in diseased brains. In neurodegenerative disorders, differentiating disease-related changes in brain metabolism from age-associated natural changes remains challenging. This study proposes a new data-driven method to identify proper intensity normalization regions in order to improve separation of age-associated natural changes from disease related changes in brain metabolism. 127 female and 128 male healthy subjects (age: 20 to 79) with brain 18 F-FDG PET/CT in the course of a whole body cancer screening were included. Brain PET images were processed using SPM8 and were parcellated into 116 anatomical regions according to the AAL template. It is assumed that normal brain 18 F-FDG metabolism has longitudinal coherency and this coherency leads to better model fitting. The coefficient of determination R 2 was proposed as the coherence coefficient, and the total coherence coefficient (overall fitting quality) was employed as an index to assess proper intensity normalization strategies on single subjects and age-cohort averaged data. Age-associated longitudinal changes of normal subjects were derived using the identified intensity normalization method correspondingly. In addition, 15 subjects with clinically diagnosed Parkinson's disease were assessed to evaluate the clinical potential of the proposed new method. Intensity normalizations by paracentral lobule and cerebellar tonsil, both regions derived from the new data-driven coherency method, showed significantly better coherence coefficients than other intensity normalization regions, and especially better than the most widely used global mean normalization. Intensity normalization by paracentral lobule was the most consistent method within both analysis strategies (subject-based and age-cohort averaging). In addition, the proposed new intensity normalization method using the paracentral lobule generates significantly higher differentiation from the age-associated changes than other intensity normalization methods. Proper intensity normalization can enhance the longitudinal coherency of normal brain glucose metabolism. The paracentral lobule followed by the cerebellar tonsil are shown to be the two most stable intensity normalization regions concerning age-dependent brain metabolism. This may provide the potential to better differentiate disease-related changes from age-related changes in brain metabolism, which is of relevance in the diagnosis of neurodegenerative disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardiovascular studies in the rhesus monkey. [brain circulation during stress

NASA Technical Reports Server (NTRS)

Stone, H. L.; Sandler, H.

1977-01-01

Criteria are given for selecting the macaca mulatta as the analogue of the human in the study of cerebral circulation, particularly the control of the cerebral vascular bed during normal and stressful conditions. Topics discussed include surgical preparation of subject; responses to changes in arterial pressure, oxygen, and carbon dioxide; innervation of cerebral vessels; cerebral flow response to acceleration; and cerebral blood flow and cerebellar stimulation.

Longitudinal volumetric and 2D assessment of cerebellar atrophy in a large cohort of children with phosphomannomutase deficiency (PMM2-CDG).

PubMed

de Diego, Víctor; Martínez-Monseny, Antonio F; Muchart, Jordi; Cuadras, Daniel; Montero, Raquel; Artuch, Rafael; Pérez-Cerdá, Celia; Pérez, Belén; Pérez-Dueñas, Belén; Poretti, Andrea; Serrano, Mercedes

2017-09-01

We aim to delineate the progression of cerebellar atrophy (the primary neuroimaging finding) in children with phosphomannomutase-deficiency (PMM2-CDG) by analyzing longitudinal MRI studies and performing cerebellar volumetric analysis and a 2D cerebellar measurement. Statistical analysis was used to compare MRI measurements [midsagittal vermis relative diameter (MVRD) and volume] of children with PMM2-CDG and sex- and age-matched controls, and to determine the rate of progression of cerebellar atrophy at different ages. Fifty MRI studies of 33 PMM2-CDG patients were used for 2D evaluation, and 19 MRI studies were available for volumetric analysis. Results from a linear regression model showed that patients have a significantly lower MVRD and cerebellar volume compared to controls (p < 0.001 and p < 0.001 respectively). There was a significant negative correlation between age and MVRD for patients (p = 0.014). The rate of cerebellar atrophy measured by the loss of MVRD and cerebellar volume per year was higher at early ages (r = -0.578, p = 0.012 and r = -0.323, p = 0.48 respectively), particularly in patients under 11 years (p = 0.004). There was a significant positive correlation between MVRD and cerebellar volume in PMM2-CDG patients (r = 0.669, p = 0.001). Our study quantifies a progression of cerebellar atrophy in PMM2-CDG patients, particularly during the first decade of life, and suggests a simple and reliable measure, the MVRD, to monitor cerebellar atrophy. Quantitative measurement of MVRD and cerebellar volume are essential for correlation with phenotype and outcome, natural follow-up, and monitoring in view of potential therapies in children with PMM2-CDG.

An Efficient Interval Type-2 Fuzzy CMAC for Chaos Time-Series Prediction and Synchronization.

PubMed

Lee, Ching-Hung; Chang, Feng-Yu; Lin, Chih-Min

2014-03-01

This paper aims to propose a more efficient control algorithm for chaos time-series prediction and synchronization. A novel type-2 fuzzy cerebellar model articulation controller (T2FCMAC) is proposed. In some special cases, this T2FCMAC can be reduced to an interval type-2 fuzzy neural network, a fuzzy neural network, and a fuzzy cerebellar model articulation controller (CMAC). So, this T2FCMAC is a more generalized network with better learning ability, thus, it is used for the chaos time-series prediction and synchronization. Moreover, this T2FCMAC realizes the un-normalized interval type-2 fuzzy logic system based on the structure of the CMAC. It can provide better capabilities for handling uncertainty and more design degree of freedom than traditional type-1 fuzzy CMAC. Unlike most of the interval type-2 fuzzy system, the type-reduction of T2FCMAC is bypassed due to the property of un-normalized interval type-2 fuzzy logic system. This causes T2FCMAC to have lower computational complexity and is more practical. For chaos time-series prediction and synchronization applications, the training architectures with corresponding convergence analyses and optimal learning rates based on Lyapunov stability approach are introduced. Finally, two illustrated examples are presented to demonstrate the performance of the proposed T2FCMAC.

Progression of regional neuropathology in Alzheimer disease and normal elderly: findings from the Nun study.

PubMed

Wolf, D S; Gearing, M; Snowdon, D A; Mori, H; Markesbery, W R; Mirra, S S

1999-01-01

Although diffuse plaques in the neocortex may represent an early stage in the evolution of neuritic plaques, plaques in the striatum and cerebellum retain their predominantly diffuse nature in Alzheimer disease (AD), regardless of disease duration. We had the opportunity to explore the progression of these regional features by using autopsy brain specimens from 15 cognitively normal and five AD subjects, all Catholic sisters enrolled in the Nun Study, a longitudinal study on aging and AD. Neuropathologic changes were assessed in the temporal cortex, striatum, and cerebellum without knowledge of clinical status. We found diffuse plaques in the striatum in six (40%) and cerebellar plaques in none of the brains from the non-demented subjects. Striatal plaques were present in all five and cerebellar plaques in four of the five AD cases. In the 20 cases overall, the presence of striatal plaques generally paralleled the occurrence of neuritic plaques in neocortex and correlated with lower scores on several neuropsychologic tests assessing memory. Our findings suggest that striatal diffuse plaques occur relatively early in the progression of AD pathology and coincide with neocortical pathology and cognitive changes. Thus, it is unlikely that temporal factors alone account for regional differences in progression of AD neuropathology.

Repeated inhalation of sevoflurane inhibits the information transmission of Purkinje cells and delays motor development via the GABAA receptor ε subunit in neonatal mice.

PubMed

Fang, Hong; Wang, Ze-Hua; Bu, Ying-Jiang; Yuan, Zhi-Jun; Wang, Guo-Qiang; Guo, Yan; Cheng, Xiao-Yun; Qiu, Wen-Jie

2018-01-01

General anesthesia is widely used in pediatric surgery, although the influence of general anesthesia on cerebellar information transmission and motor function is unclear. In the present study, neonatal mice received repeated inhalation of sevoflurane, and electrophysiological alterations in Purkinje cells (PCs) and the development of motor functions were detected. In addition, γ‑aminobutyric acidA receptor ε (GABAA‑R ε) subunit knockout mice were used to investigate the mechanism of action of sevoflurane on cerebellar function. In the neonatal mice, the field potential response of PCs induced by sensory stimulation and the motor function indices were markedly inhibited by sevoflurane, and the inhibitory effect was positively associated with the number of repetitions of anesthesia. In additional the GABAA‑R ε subunit level of PCs was promoted by sevoflurane in a dose‑dependent manner, and the inhibitory effects of sevoflurane on PC field potential response and motor function were alleviated in GABAA‑R ε subunit knockout mice. The GABAA‑R ε subunit was activated by sevoflurane, leading to inhibition of sensory information transmission in the cerebellar cortex, field potential responses of PCs and the development of cerebellar motor function. The present study provided experimental evidence for the safe usage of sevoflurane in clinical anesthesia, and suggested that GABAA‑R ε subunit antagonists may be considered for combined application with general anesthesia with repeated inhalation of sevoflurane, for adverse effect prevention in the clinic.

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

ClinicalTrials.gov

2017-09-28

Rare Disorders; Undiagnosed Disorders; Disorders of Unknown Prevalence; Cornelia De Lange Syndrome; Prenatal Benign Hypophosphatasia; Perinatal Lethal Hypophosphatasia; Odontohypophosphatasia; Adult Hypophosphatasia; Childhood-onset Hypophosphatasia; Infantile Hypophosphatasia; Hypophosphatasia; Kabuki Syndrome; Bohring-Opitz Syndrome; Narcolepsy Without Cataplexy; Narcolepsy-cataplexy; Hypersomnolence Disorder; Idiopathic Hypersomnia Without Long Sleep Time; Idiopathic Hypersomnia With Long Sleep Time; Idiopathic Hypersomnia; Kleine-Levin Syndrome; Kawasaki Disease; Leiomyosarcoma; Leiomyosarcoma of the Corpus Uteri; Leiomyosarcoma of the Cervix Uteri; Leiomyosarcoma of Small Intestine; Acquired Myasthenia Gravis; Addison Disease; Hyperacusis (Hyperacousis); Juvenile Myasthenia Gravis; Transient Neonatal Myasthenia Gravis; Williams Syndrome; Lyme Disease; Myasthenia Gravis; Marinesco Sjogren Syndrome(Marinesco-Sjogren Syndrome); Isolated Klippel-Feil Syndrome; Frasier Syndrome; Denys-Drash Syndrome; Beckwith-Wiedemann Syndrome; Emanuel Syndrome; Isolated Aniridia; Beckwith-Wiedemann Syndrome Due to Paternal Uniparental Disomy of Chromosome 11; Beckwith-Wiedemann Syndrome Due to Imprinting Defect of 11p15; Beckwith-Wiedemann Syndrome Due to 11p15 Translocation/Inversion; Beckwith-Wiedemann Syndrome Due to 11p15 Microduplication; Beckwith-Wiedemann Syndrome Due to 11p15 Microdeletion; Axenfeld-Rieger Syndrome; Aniridia-intellectual Disability Syndrome; Aniridia - Renal Agenesis - Psychomotor Retardation; Aniridia - Ptosis - Intellectual Disability - Familial Obesity; Aniridia - Cerebellar Ataxia - Intellectual Disability; Aniridia - Absent Patella; Aniridia; Peters Anomaly - Cataract; Peters Anomaly; Potocki-Shaffer Syndrome; Silver-Russell Syndrome Due to Maternal Uniparental Disomy of Chromosome 11; Silver-Russell Syndrome Due to Imprinting Defect of 11p15; Silver-Russell Syndrome Due to 11p15 Microduplication; Syndromic Aniridia; WAGR Syndrome; Wolf-Hirschhorn Syndrome; 4p16.3 Microduplication Syndrome; 4p Deletion Syndrome, Non-Wolf-Hirschhorn Syndrome; Autosomal Recessive Stickler Syndrome; Stickler Syndrome Type 2; Stickler Syndrome Type 1; Stickler Syndrome; Mucolipidosis Type 4; X-linked Spinocerebellar Ataxia Type 4; X-linked Spinocerebellar Ataxia Type 3; X-linked Intellectual Disability - Ataxia - Apraxia; X-linked Progressive Cerebellar Ataxia; X-linked Non Progressive Cerebellar Ataxia; X-linked Cerebellar Ataxia; Vitamin B12 Deficiency Ataxia; Toxic Exposure Ataxia; Unclassified Autosomal Dominant Spinocerebellar Ataxia; Thyroid Antibody Ataxia; Sporadic Adult-onset Ataxia of Unknown Etiology; Spinocerebellar Ataxia With Oculomotor Anomaly; Spinocerebellar Ataxia With Epilepsy; Spinocerebellar Ataxia With Axonal Neuropathy Type 2; Spinocerebellar Ataxia Type 8; Spinocerebellar Ataxia Type 7; Spinocerebellar Ataxia Type 6; Spinocerebellar Ataxia Type 5; Spinocerebellar Ataxia Type 4; Spinocerebellar Ataxia Type 37; Spinocerebellar Ataxia Type 36; Spinocerebellar Ataxia Type 35; Spinocerebellar Ataxia Type 34; Spinocerebellar Ataxia Type 32; Spinocerebellar Ataxia Type 31; Spinocerebellar Ataxia Type 30; Spinocerebellar Ataxia Type 3; Spinocerebellar Ataxia Type 29; Spinocerebellar Ataxia Type 28; Spinocerebellar Ataxia Type 27; Spinocerebellar Ataxia Type 26; Spinocerebellar Ataxia Type 25; Spinocerebellar Ataxia Type 23; Spinocerebellar Ataxia Type 22; Spinocerebellar Ataxia Type 21; Spinocerebellar Ataxia Type 20; Spinocerebellar Ataxia Type 2; Spinocerebellar Ataxia Type 19/22; Spinocerebellar Ataxia Type 18; Spinocerebellar Ataxia Type 17; Spinocerebellar Ataxia Type 16; Spinocerebellar Ataxia Type 15/16; Spinocerebellar Ataxia Type 14; Spinocerebellar Ataxia Type 13; Spinocerebellar Ataxia Type 12; Spinocerebellar Ataxia Type 11; Spinocerebellar Ataxia Type 10; Spinocerebellar Ataxia Type 1 With Axonal Neuropathy; Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia - Unknown; Spinocerebellar Ataxia - Dysmorphism; Non Progressive Epilepsy and/or Ataxia With Myoclonus as a Major Feature; Spectrin-associated Autosomal Recessive Cerebellar Ataxia; Spasticity-ataxia-gait Anomalies Syndrome; Spastic Ataxia With Congenital Miosis; Spastic Ataxia - Corneal Dystrophy; Spastic Ataxia; Rare Hereditary Ataxia; Rare Ataxia; Recessive Mitochondrial Ataxia Syndrome; Progressive Epilepsy and/or Ataxia With Myoclonus as a Major Feature; Posterior Column Ataxia - Retinitis Pigmentosa; Post-Stroke Ataxia; Post-Head Injury Ataxia; Post Vaccination Ataxia; Polyneuropathy - Hearing Loss - Ataxia - Retinitis Pigmentosa - Cataract; Muscular Atrophy - Ataxia - Retinitis Pigmentosa - Diabetes Mellitus; Non-progressive Cerebellar Ataxia With Intellectual Disability; Non-hereditary Degenerative Ataxia; Paroxysmal Dystonic Choreathetosis With Episodic Ataxia and Spasticity; Olivopontocerebellar Atrophy - Deafness; NARP Syndrome; Myoclonus - Cerebellar Ataxia - Deafness; Multiple System Atrophy, Parkinsonian Type; Multiple System Atrophy, Cerebellar Type; Multiple System Atrophy; Maternally-inherited Leigh Syndrome; Machado-Joseph Disease Type 3; Machado-Joseph Disease Type 2; Machado-Joseph Disease Type 1; Lethal Ataxia With Deafness and Optic Atrophy; Leigh Syndrome; Leukoencephalopathy With Mild Cerebellar Ataxia and White Matter Edema; Leukoencephalopathy - Ataxia - Hypodontia - Hypomyelination; Leigh Syndrome With Nephrotic Syndrome; Leigh Syndrome With Leukodystrophy; Leigh Syndrome With Cardiomyopathy; Late-onset Ataxia With Dementia; Intellectual Disability-hyperkinetic Movement-truncal Ataxia Syndrome; Infection or Post Infection Ataxia; Infantile-onset Autosomal Recessive Nonprogressive Cerebellar Ataxia; Infantile Onset Spinocerebellar Ataxia; GAD Ataxia; Hereditary Episodic Ataxia; Gliadin/Gluten Ataxia; Friedreich Ataxia; Fragile X-associated Tremor/Ataxia Syndrome; Familial Paroxysmal Ataxia; Exposure to Medications Ataxia; Episodic Ataxia With Slurred Speech; Episodic Ataxia Unknown Type; Episodic Ataxia Type 7; Episodic Ataxia Type 6; Episodic Ataxia Type 5; Episodic Ataxia Type 4; Episodic Ataxia Type 3; Episodic Ataxia Type 1; Epilepsy and/or Ataxia With Myoclonus as Major Feature; Early-onset Spastic Ataxia-neuropathy Syndrome; Early-onset Progressive Neurodegeneration - Blindness - Ataxia - Spasticity; Early-onset Cerebellar Ataxia With Retained Tendon Reflexes; Early-onset Ataxia With Dementia; Childhood-onset Autosomal Recessive Slowly Progressive Spinocerebellar Ataxia; Dilated Cardiomyopathy With Ataxia; Cataract - Ataxia - Deafness; Cerebellar Ataxia, Cayman Type; Cerebellar Ataxia With Peripheral Neuropathy; Cerebellar Ataxia - Hypogonadism; Cerebellar Ataxia - Ectodermal Dysplasia; Cerebellar Ataxia - Areflexia - Pes Cavus - Optic Atrophy - Sensorineural Hearing Loss; Brain Tumor Ataxia; Brachydactyly - Nystagmus - Cerebellar Ataxia; Benign Paroxysmal Tonic Upgaze of Childhood With Ataxia; Autosomal Recessive Syndromic Cerebellar Ataxia; Autosomal Recessive Spastic Ataxia With Leukoencephalopathy; Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay; Autosomal Recessive Spastic Ataxia - Optic Atrophy - Dysarthria; Autosomal Recessive Spastic Ataxia; Autosomal Recessive Metabolic Cerebellar Ataxia; Autosomal Dominant Spinocerebellar Ataxia Due to Repeat Expansions That do Not Encode Polyglutamine; Autosomal Recessive Ataxia, Beauce Type; Autosomal Recessive Ataxia Due to Ubiquinone Deficiency; Autosomal Recessive Ataxia Due to PEX10 Deficiency; Autosomal Recessive Degenerative and Progressive Cerebellar Ataxia; Autosomal Recessive Congenital Cerebellar Ataxia Due to MGLUR1 Deficiency; Autosomal Recessive Congenital Cerebellar Ataxia Due to GRID2 Deficiency; Autosomal Recessive Congenital Cerebellar Ataxia; Autosomal Recessive Cerebellar Ataxia-pyramidal Signs-nystagmus-oculomotor Apraxia Syndrome; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to WWOX Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to TUD Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to KIAA0226 Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome; Autosomal Recessive Cerebellar Ataxia With Late-onset Spasticity; Autosomal Recessive Cerebellar Ataxia Due to STUB1 Deficiency; Autosomal Recessive Cerebellar Ataxia Due to a DNA Repair Defect; Autosomal Recessive Cerebellar Ataxia - Saccadic Intrusion; Autosomal Recessive Cerebellar Ataxia - Psychomotor Retardation; Autosomal Recessive Cerebellar Ataxia - Blindness - Deafness; Autosomal Recessive Cerebellar Ataxia; Autosomal Dominant Spinocerebellar Ataxia Due to a Polyglutamine Anomaly; Autosomal Dominant Spinocerebellar Ataxia Due to a Point Mutation; Autosomal Dominant Spinocerebellar Ataxia Due to a Channelopathy; Autosomal Dominant Spastic Ataxia Type 1; Autosomal Dominant Spastic Ataxia; Autosomal Dominant Optic Atrophy; Ataxia-telangiectasia Variant; Ataxia-telangiectasia; Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy; Autosomal Dominant Cerebellar Ataxia Type 4; Autosomal Dominant Cerebellar Ataxia Type 3; Autosomal Dominant Cerebellar Ataxia Type 2; Autosomal Dominant Cerebellar Ataxia Type 1; Autosomal Dominant Cerebellar Ataxia; Ataxia-telangiectasia-like Disorder; Ataxia-intellectual Disability-oculomotor Apraxia-cerebellar Cysts Syndrome; Ataxia-deafness-intellectual Disability Syndrome; Ataxia With Vitamin E Deficiency; Ataxia With Dementia; Ataxia Neuropathy Spectrum; Ataxia - Tapetoretinal Degeneration; Ataxia - Photosensitivity - Short Stature; Ataxia - Pancytopenia; Ataxia - Oculomotor Apraxia Type 1; Ataxia - Hypogonadism - Choroidal Dystrophy; Ataxia - Other; Ataxia - Genetic Diagnosis - Unknown; Acquired Ataxia; Adult-onset Autosomal Recessive Cerebellar Ataxia; Alcohol Related Ataxia; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type II; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2; Multiple Endocrine Neoplasia, Type IV; Multiple Endocrine Neoplasia, Type 3; Multiple Endocrine Neoplasia (MEN) Syndrome; Multiple Endocrine Neoplasia Type 2B; Multiple Endocrine Neoplasia Type 2A; Atypical Hemolytic Uremic Syndrome; Atypical HUS; Wiedemann-Steiner Syndrome; Breast Implant-Associated Anaplastic Large Cell Lymphoma; Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA); Hemophagocytic Lymphohistiocytosis; Behcet's Disease

Cerebellar development in childhood onset schizophrenia and non-psychotic siblings

PubMed Central

Greenstein, Deanna; Lenroot, Rhoshel; Clausen, Liv; Gogtay, Nitin; Rapoport, Judith

2011-01-01

We explored regional and total volumetric cerebellar differences in probands and their unaffected full siblings relative to typically developing participants. Participants included 94 (51 males) patients diagnosed with childhood onset schizophrenia (COS), 80 related non-psychotic siblings (37 males) and 110 (64 males) typically developing participants scanned longitudinally. The sample mean age was 16.87(SD=4.7; range 6.5 to 29). We performed mixed model regressions to examine group differences in trajectory and volume. The COS group had smaller bilateral anterior lobes and anterior and total vermis volumes than controls. The COS group diverged from controls over time in total, left, right, and bilateral posterior inferior cerebellum. Siblings did not have any fixed volumetric differences relative to controls but differed from controls in developmental trajectories of total and right cerebellum, left inferior posterior, left superior posterior, and superior vermis. Results are consistent with previous COS findings and several reports of decreased cerebellar volume in adult onset schizophrenia. Sibling trajectories may represent a trait marker, although the effect size for volumetric differences in early adulthood may be small. PMID:21803550

Altered cerebellar feedback projections in Asperger syndrome.

PubMed

Catani, Marco; Jones, Derek K; Daly, Eileen; Embiricos, Nitzia; Deeley, Quinton; Pugliese, Luca; Curran, Sarah; Robertson, Dene; Murphy, Declan G M

2008-07-15

It has been proposed that the biological basis of autism spectrum disorder includes cerebellar 'disconnection'. However, direct in vivo evidence in support of this is lacking. Here, the microstructural integrity of cerebellar white matter in adults with Asperger syndrome was studied using diffusion tensor magnetic resonance tractography. Fifteen adults with Asperger syndrome and 16 age-IQ-gender-matched healthy controls underwent diffusion tensor magnetic resonance imaging. For each subject, tract-specific measurements of mean diffusivity and fractional anisotropy were made within the inferior, middle, superior cerebellar peduncles and short intracerebellar fibres. No group differences were observed in mean diffusivity. However, people with Asperger syndrome had significantly lower fractional anisotropy in the short intracerebellar fibres (p<0.001) and right superior cerebellar (output) peduncle (p<0.001) compared to controls; but no difference in the input tracts. Severity of social impairment, as measured by the Autistic Diagnostic Interview, was negatively correlated with diffusion anisotropy in the fibres of the left superior cerebellar peduncle. These findings suggest a vulnerability of specific cerebellar neural pathways in people with Asperger syndrome. The localised abnormalities in the main cerebellar outflow pathway may prevent the cerebral cortex from receiving those cerebellar feedback inputs necessary for a successful adaptive social behaviour.

Gravity-dependent nystagmus and inner-ear dysfunction suggest anterior and posterior inferior cerebellar artery infarct.

PubMed

Shaikh, Aasef G; Miller, Benjamin R; Sundararajan, Sophia; Katirji, Bashar

2014-04-01

Cerebellar lesions may present with gravity-dependent nystagmus, where the direction and velocity of the drifts change with alterations in head position. Two patients had acute onset of hearing loss, vertigo, oscillopsia, nausea, and vomiting. Examination revealed gravity-dependent nystagmus, unilateral hypoactive vestibulo-ocular reflex (VOR), and hearing loss ipsilateral to the VOR hypofunction. Traditionally, the hypoactive VOR and hearing loss suggest inner-ear dysfunction. Vertigo, nausea, vomiting, and nystagmus may suggest peripheral or central vestibulopathy. The gravity-dependent modulation of nystagmus, however, localizes to the posterior cerebellar vermis. Magnetic resonance imaging in our patients revealed acute cerebellar infarct affecting posterior cerebellar vermis, in the vascular distribution of the posterior inferior cerebellar artery (PICA). This lesion explains the gravity-dependent nystagmus, nausea, and vomiting. Acute onset of unilateral hearing loss and VOR hypofunction could be the manifestation of inner-ear ischemic injury secondary to the anterior inferior cerebellar artery (AICA) compromise. In cases of combined AICA and PICA infarction, the symptoms of peripheral vestibulopathy might masquerade the central vestibular syndrome and harbor a cerebellar stroke. However, the gravity-dependent nystagmus allows prompt identification of acute cerebellar infarct. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Rhythmic finger tapping reveals cerebellar dysfunction in essential tremor.

PubMed

Buijink, A W G; Broersma, M; van der Stouwe, A M M; van Wingen, G A; Groot, P F C; Speelman, J D; Maurits, N M; van Rootselaar, A F

2015-04-01

Cerebellar circuits are hypothesized to play a central role in the pathogenesis of essential tremor. Rhythmic finger tapping is known to strongly engage the cerebellar motor circuitry. We characterize cerebellar and, more specifically, dentate nucleus function, and neural correlates of cerebellar output in essential tremor during rhythmic finger tapping employing functional MRI. Thirty-one propranolol-sensitive essential tremor patients with upper limb tremor and 29 healthy controls were measured. T2*-weighted EPI sequences were acquired. The task consisted of alternating rest and finger tapping blocks. A whole-brain and region-of-interest analysis was performed, the latter focusing on the cerebellar cortex, dentate nucleus and inferior olive nucleus. Activations were also related to tremor severity. In patients, dentate activation correlated positively with tremor severity as measured by the tremor rating scale part A. Patients had reduced activation in widespread cerebellar cortical regions, and additionally in the inferior olive nucleus, and parietal and frontal cortex, compared to controls. The increase in dentate activation with tremor severity supports involvement of the dentate nucleus in essential tremor. Cortical and cerebellar changes during a motor timing task in essential tremor might point to widespread changes in cerebellar output in essential tremor. Copyright © 2015 Elsevier Ltd. All rights reserved.

Developmental Subchronic Exposure to Diphenylarsinic Acid Induced Increased Exploratory Behavior, Impaired Learning Behavior, and Decreased Cerebellar Glutathione Concentration in Rats

PubMed Central

Negishi, Takayuki; Matsunaga, Yuki

2013-01-01

In Japan, people using water from the well contaminated with high-level arsenic developed neurological, mostly cerebellar, symptoms, where diphenylarsinic acid (DPAA) was a major compound. Here, we investigated the adverse effects of developmental exposure to 20mg/l DPAA in drinking water (early period [0–6 weeks of age] and/or late period [7–12]) on behavior and cerebellar development in male rats. In the open field test at 6 weeks of age, early exposure to DPAA significantly increased exploratory behaviors. At 12 weeks of age, late exposure to DPAA similarly increased exploratory behavior independent of the early exposure although a 6-week recovery from DPAA could reverse that change. In the passive avoidance test at 6 weeks of age, early exposure to DPAA significantly decreased the avoidance performance. Even at 12 weeks of age, early exposure to DPAA significantly decreased the test performance, which was independent of the late exposure to DPAA. These results suggest that the DPAA-induced increase in exploratory behavior is transient, whereas the DPAA-induced impairment of passive avoidance is long lasting. At 6 weeks of age, early exposure to DPAA significantly reduced the concentration of cerebellar total glutathione. At 12 weeks of age, late, but not early, exposure to DPAA also significantly reduced the concentration of cerebellar glutathione, which might be a primary cause of oxidative stress. Early exposure to DPAA induced late-onset suppressed expression of NMDAR1 and PSD95 protein at 12 weeks of age, indicating impaired glutamatergic system in the cerebellum of rats developmentally exposed to DPAA. PMID:24008832

Recovery of biological motion perception and network plasticity after cerebellar tumor removal.

PubMed

Sokolov, Arseny A; Erb, Michael; Grodd, Wolfgang; Tatagiba, Marcos S; Frackowiak, Richard S J; Pavlova, Marina A

2014-10-01

Visual perception of body motion is vital for everyday activities such as social interaction, motor learning or car driving. Tumors to the left lateral cerebellum impair visual perception of body motion. However, compensatory potential after cerebellar damage and underlying neural mechanisms remain unknown. In the present study, visual sensitivity to point-light body motion was psychophysically assessed in patient SL with dysplastic gangliocytoma (Lhermitte-Duclos disease) to the left cerebellum before and after neurosurgery, and in a group of healthy matched controls. Brain activity during processing of body motion was assessed by functional magnetic resonance imaging (MRI). Alterations in underlying cerebro-cerebellar circuitry were studied by psychophysiological interaction (PPI) analysis. Visual sensitivity to body motion in patient SL before neurosurgery was substantially lower than in controls, with significant improvement after neurosurgery. Functional MRI in patient SL revealed a similar pattern of cerebellar activation during biological motion processing as in healthy participants, but located more medially, in the left cerebellar lobules III and IX. As in normalcy, PPI analysis showed cerebellar communication with a region in the superior temporal sulcus, but located more anteriorly. The findings demonstrate a potential for recovery of visual body motion processing after cerebellar damage, likely mediated by topographic shifts within the corresponding cerebro-cerebellar circuitry induced by cerebellar reorganization. The outcome is of importance for further understanding of cerebellar plasticity and neural circuits underpinning visual social cognition.

Evolution of the cerebellar cortex: the selective expansion of prefrontal-projecting cerebellar lobules.

PubMed

Balsters, J H; Cussans, E; Diedrichsen, J; Phillips, K A; Preuss, T M; Rilling, J K; Ramnani, N

2010-02-01

It has been suggested that interconnected brain areas evolve in tandem because evolutionary pressures act on complete functional systems rather than on individual brain areas. The cerebellar cortex has reciprocal connections with both the prefrontal cortex and motor cortex, forming independent loops with each. Specifically, in capuchin monkeys cerebellar cortical lobules Crus I and Crus II connect with prefrontal cortex, whereas the primary motor cortex connects with cerebellar lobules V, VI, VIIb, and VIIIa. Comparisons of extant primate species suggest that the prefrontal cortex has expanded more than cortical motor areas in human evolution. Given the enlargement of the prefrontal cortex relative to motor cortex in humans, our hypothesis would predict corresponding volumetric increases in the parts of the cerebellum connected to the prefrontal cortex, relative to cerebellar lobules connected to the motor cortex. We tested the hypothesis by comparing the volumes of cerebellar lobules in structural MRI scans in capuchins, chimpanzees and humans. The fractions of cerebellar volume occupied by Crus I and Crus II were significantly larger in humans compared to chimpanzees and capuchins. Our results therefore support the hypothesis that in the cortico-cerebellar system, functionally related structures evolve in concert with each other. The evolutionary expansion of these prefrontal-projecting cerebellar territories might contribute to the evolution of the higher cognitive functions of humans. Copyright (c) 2009 Elsevier Inc. All rights reserved.

Local and long-range circuit elements for cerebellar function.

PubMed

Xiao, Le; Scheiffele, Peter

2018-02-01

The view of cerebellar functions has been extended from controlling sensorimotor processes to processing 'contextual' information and generating predictions for a diverse range of behaviors. These functions rely on the computation of the local cerebellar microcircuits and long-range connectivity that relays cerebellar output to various brain areas. In this review, we discuss recent work on two of the circuit elements, which are thought to be fundamental for a wide range of non-sensorimotor behaviors: The role for cerebellar granule cells in multimodal integration in the cerebellar cortex and the long-range connectivity between the deep cerebellar nuclei and the basal ganglia. Lastly, we discuss how studies on synapses and circuits of the cerebellum in rodent models of autism-spectrum disorders might contribute to our understanding of the pathophysiology of this class of neurodevelopmental disorders. Copyright © 2017. Published by Elsevier Ltd.

Changes in the cerebellar and cerebro-cerebellar circuit in type 2 diabetes.

PubMed

Fang, Peng; An, Jie; Tan, Xin; Zeng, Ling-Li; Shen, Hui; Qiu, Shijun; Hu, Dewen

2017-04-01

Currently, 422 million adults suffer from diabetes worldwide, leading to tremendous disabilities and a great burden to families and society. Functional and structural MRIs have demonstrated that patients with type 2 diabetes mellitus (T2DM) exhibit abnormalities in brain regions in the cerebral cortex. However, the changes of cerebellar anatomical connections in diabetic patients remains unclear. In the current study, diffusion tensor imaging deterministic tractography and statistical analysis were employed to investigate abnormal cerebellar anatomical connections in diabetic patients. This is the first study to investigate the altered cerebellar anatomical connectivity in T2DM patients. Decreased anatomical connections were found in the cerebellar and cerebro-cerebellar circuits of T2DM patients, providing valuable new insights into the potential neuro-pathophysiology of diabetes-related motor and cognitive deficits. Copyright © 2017. Published by Elsevier Inc.

Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish.

PubMed

Aspatwar, Ashok; Tolvanen, Martti E E; Jokitalo, Eija; Parikka, Mataleena; Ortutay, Csaba; Harjula, Sanna-Kaisa E; Rämet, Mika; Vihinen, Mauno; Parkkila, Seppo

2013-02-01

Congenital ataxia and mental retardation are mainly caused by variations in the genes that affect brain development. Recent reports have shown that mutations in the CA8 gene are associated with mental retardation and ataxia in humans and ataxia in mice. The gene product, carbonic anhydrase-related protein VIII (CARP VIII), is predominantly present in cerebellar Purkinje cells, where it interacts with the inositol 1,4,5-trisphosphate receptor type 1, a calcium channel. In this study, we investigated the effects of the loss of function of CARP VIII during embryonic development in zebrafish using antisense morpholino oligonucleotides against the CA8 gene. Knockdown of CA8 in zebrafish larvae resulted in a curved body axis, pericardial edema and abnormal movement patterns. Histologic examination revealed gross morphologic defects in the cerebellar region and in the muscle. Electron microscopy studies showed increased neuronal cell death in developing larvae injected with CA8 antisense morpholinos. These data suggest a pivotal role for CARP VIII during embryonic development. Furthermore, suppression of CA8 expression leads to defects in motor and coordination functions, mimicking the ataxic human phenotype. This work reveals an evolutionarily conserved function of CARP VIII in brain development and introduces a novel zebrafish model in which to investigate the mechanisms of CARP VIII-related ataxia and mental retardation in humans.

Beta-gamma burst stimulations of the inferior olive induce high-frequency oscillations in the deep cerebellar nuclei.

PubMed

Cheron, Julian; Cheron, Guy

2018-02-20

The cerebellum displays various sorts of rhythmic activities covering both low- and high-frequency oscillations. These cerebellar high-frequency oscillations were observed in the cerebellar cortex. Here, we hypothesised that not only is the cerebellar cortex a generator of high-frequency oscillations but also that the deep cerebellar nuclei may also play a similar role. Thus, we analysed local field potentials and single-unit activities in the deep cerebellar nuclei before, during and after electric stimulation in the inferior olive of awake mice. A high-frequency oscillation of 350 Hz triggered by the stimulation of the inferior olive, within the beta-gamma range, was observed in the deep cerebellar nuclei. The amplitude and frequency of the oscillation were independent of the frequency of stimulation. This oscillation emerged during the period of stimulation and persisted after the end of the stimulation. The oscillation coincided with the inhibition of deep cerebellar neurons. As the inhibition of the deep cerebellar nuclei is related to inhibitory inputs from Purkinje cells, we speculate that the oscillation represents the unmasking of the synchronous activation of another subtype of deep cerebellar neuronal subtype, devoid of GABA receptors and under the direct control of the climbing fibres from the inferior olive. Still, the mechanism sustaining this oscillation remains to be deciphered. Our study sheds new light on the role of the olivo-cerebellar loop as the final output control of the intercerebellar circuitry. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Modeled changes of cerebellar activity in mutant mice are predictive of their learning impairments

NASA Astrophysics Data System (ADS)

Badura, Aleksandra; Clopath, Claudia; Schonewille, Martijn; de Zeeuw, Chris I.

2016-11-01

Translating neuronal activity to measurable behavioral changes has been a long-standing goal of systems neuroscience. Recently, we have developed a model of phase-reversal learning of the vestibulo-ocular reflex, a well-established, cerebellar-dependent task. The model, comprising both the cerebellar cortex and vestibular nuclei, reproduces behavioral data and accounts for the changes in neural activity during learning in wild type mice. Here, we used our model to predict Purkinje cell spiking as well as behavior before and after learning of five different lines of mutant mice with distinct cell-specific alterations of the cerebellar cortical circuitry. We tested these predictions by obtaining electrophysiological data depicting changes in neuronal spiking. We show that our data is largely consistent with the model predictions for simple spike modulation of Purkinje cells and concomitant behavioral learning in four of the mutants. In addition, our model accurately predicts a shift in simple spike activity in a mutant mouse with a brainstem specific mutation. This combination of electrophysiological and computational techniques opens a possibility of predicting behavioral impairments from neural activity.

Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1.

PubMed

Kim, Edward; Wang, Yuan; Kim, Sun-Jung; Bornhorst, Miriam; Jecrois, Emmanuelle S; Anthony, Todd E; Wang, Chenran; Li, Yi E; Guan, Jun-Lin; Murphy, Geoffrey G; Zhu, Yuan

2014-12-23

Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities.

Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms

PubMed Central

Haldipur, Parthiv; Dang, Derek; Aldinger, Kimberly A; Janson, Olivia K; Guimiot, Fabien; Adle-Biasette, Homa; Dobyns, William B; Siebert, Joseph R; Russo, Rosa; Millen, Kathleen J

2017-01-01

FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic Foxc1 mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human. DOI: http://dx.doi.org/10.7554/eLife.20898.001 PMID:28092268

Modeled changes of cerebellar activity in mutant mice are predictive of their learning impairments

PubMed Central

Badura, Aleksandra; Clopath, Claudia; Schonewille, Martijn; De Zeeuw, Chris I.

2016-01-01

Translating neuronal activity to measurable behavioral changes has been a long-standing goal of systems neuroscience. Recently, we have developed a model of phase-reversal learning of the vestibulo-ocular reflex, a well-established, cerebellar-dependent task. The model, comprising both the cerebellar cortex and vestibular nuclei, reproduces behavioral data and accounts for the changes in neural activity during learning in wild type mice. Here, we used our model to predict Purkinje cell spiking as well as behavior before and after learning of five different lines of mutant mice with distinct cell-specific alterations of the cerebellar cortical circuitry. We tested these predictions by obtaining electrophysiological data depicting changes in neuronal spiking. We show that our data is largely consistent with the model predictions for simple spike modulation of Purkinje cells and concomitant behavioral learning in four of the mutants. In addition, our model accurately predicts a shift in simple spike activity in a mutant mouse with a brainstem specific mutation. This combination of electrophysiological and computational techniques opens a possibility of predicting behavioral impairments from neural activity. PMID:27805050

The Neuroanatomical Correlates of Training-Related Perceptuo-Reflex Uncoupling in Dancers

PubMed Central

Nigmatullina, Yuliya; Hellyer, Peter J.; Nachev, Parashkev; Sharp, David J.; Seemungal, Barry M.

2015-01-01

Sensory input evokes low-order reflexes and higher-order perceptual responses. Vestibular stimulation elicits vestibular-ocular reflex (VOR) and self-motion perception (e.g., vertigo) whose response durations are normally equal. Adaptation to repeated whole-body rotations, for example, ballet training, is known to reduce vestibular responses. We investigated the neuroanatomical correlates of vestibular perceptuo-reflex adaptation in ballet dancers and controls. Dancers' vestibular-reflex and perceptual responses to whole-body yaw-plane step rotations were: (1) Briefer and (2) uncorrelated (controls' reflex and perception were correlated). Voxel-based morphometry showed a selective gray matter (GM) reduction in dancers' vestibular cerebellum correlating with ballet experience. Dancers' vestibular cerebellar GM density reduction was related to shorter perceptual responses (i.e. positively correlated) but longer VOR duration (negatively correlated). Contrastingly, controls' vestibular cerebellar GM density negatively correlated with perception and VOR. Diffusion-tensor imaging showed that cerebral cortex white matter (WM) microstructure correlated with vestibular perception but only in controls. In summary, dancers display vestibular perceptuo-reflex dissociation with the neuronatomical correlate localized to the vestibular cerebellum. Controls' robust vestibular perception correlated with a cortical WM network conspicuously absent in dancers. Since primary vestibular afferents synapse in the vestibular cerebellum, we speculate that a cerebellar gating of perceptual signals to cortical regions mediates the training-related attenuation of vestibular perception and perceptuo-reflex uncoupling. PMID:24072889

Downbeating nystagmus and muscle spasms in a patient with glutamic-acid decarboxylase antibodies.

PubMed

Ances, Beau M; Dalmau, Josep O; Tsai, Jean; Hasbani, M Josh; Galetta, Steven L

2005-07-01

To report the ophthalmic findings and response to treatment in a patient with glutamic-acid decarboxylase antibodies. Case report. A 55-year-old woman developed progressive, painful, low back muscle spasms, vertical diplopia, downbeating nystagmus, and asymmetric appendicular ataxia. Downbeating nystagmus was present in primary gaze with an alternating skew deviation in lateral gaze. Serum and cerebrospinal fluid GAD antibodies were detected. Treatment with diazepam led to resolution of spasticity, whereas repeated courses of intravenous immunoglobulin improved cerebellar function, including appendicular ataxia and downbeating nystagmus. Patients with GAD antibodies may have elements of both Stiff-person syndrome (muscle rigidity and spasms) and prominent cerebellar dysfunction. Treatment with diazepam rapidly improved Stiff-person symptoms, whereas IVIg was partially effective at the early stage of cerebellar dysfunction.

Cerebellar Abiotrophy Across Domestic Species.

PubMed

Scott, Erica Yuki; Woolard, Kevin Douglas; Finno, Carrie J; Murray, James D

2018-06-01

Cerebellar abiotrophy (CA) is a neurodegenerative disorder affecting the cerebellum and occurs in multiple species. Although CA is well researched in humans and mice, domestic species such as the dog, cat, sheep, cow, and horse receive little recognition. This may be due to few studies addressing the mechanism of CA in these species. However, valuable information can still be extracted from these cases. A review of the clinicohistologic phenotype of CA in these species and determining the various etiologies of CA may aid in determining conserved and required pathways necessary for proper cerebellar development and function. This review outlines research approaches of studies of CA in domestic species, compared to the approaches used in mice, with the objective of comparing CA in domestic species while identifying areas for further research efforts.

BRF1 mutations alter RNA polymerase III–dependent transcription and cause neurodevelopmental anomalies

PubMed Central

Hög, Friederike; Dentici, Maria Lisa; Tan, Perciliz L.; Sowada, Nadine; Medeira, Ana; Gueneau, Lucie; Thiele, Holger; Kousi, Maria; Lepri, Francesca; Wenzeck, Larissa; Blumenthal, Ian; Radicioni, Antonio; Schwarzenberg, Tito Livio; Mandriani, Barbara; Fischetto, Rita; Morris-Rosendahl, Deborah J.; Altmüller, Janine; Reymond, Alexandre; Nürnberg, Peter; Merla, Giuseppe; Dallapiccola, Bruno; Katsanis, Nicholas; Cramer, Patrick; Kubisch, Christian

2015-01-01

RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III–related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development. PMID:25561519

[Acute cerebellar ataxia associated with infectious mononucleosis--a case report and review of the literature].

PubMed

Yabuki, S; Kazahaya, Y; Ikeda, K

1983-04-01

A 20-year-old man, a college student, was admitted to Kochi Municipal Central Hospital with a month's history of slurring of speech and unsteadiness of gait. He had developed fever, sore throat and cervical lymphadenopathy. On admission, the throat was mildly injected, and enlarged lymph nodes were palpable in the lateral cervical regions. His speech was slightly slurred. Bilateral dysmetria, dyssynergia and intention tremor were noted in both extremities. The gait was grossly ataxic. Plantar responses were extensor. Examination of his peripheral blood revealed atypical lymphocytes, and the titer of Paul-Bunnell was 1:16. The CSF protein was 25 mg/dl with normal cell count. Epstein-Barr virus (EBV) antibody titers by indirect immunofluorescence in the serum of the second hospital day were as follows: VCA-IgG was 1:640, VCA-IgM less than 1:10, EBV-EA 1:160, and EBNA less than 1:10, while the CSF-EBV antibody titer was negative. Treatment with prednisolone was started and within 7 days he began to recover. Six weeks after admission he was completely free of neurological symptoms and signs. We also reviewed 18 cases of acute cerebellar ataxia with infectious mononucleosis in the literature. It was postulated that the neurological symptoms complicating infectious mononucleosis were possibly caused by infectious and immuno-allergic mechanisms.

Neural mechanisms underlying spatial realignment during adaptation to optical wedge prisms.

PubMed

Chapman, Heidi L; Eramudugolla, Ranmalee; Gavrilescu, Maria; Strudwick, Mark W; Loftus, Andrea; Cunnington, Ross; Mattingley, Jason B

2010-07-01

Visuomotor adaptation to a shift in visual input produced by prismatic lenses is an example of dynamic sensory-motor plasticity within the brain. Prism adaptation is readily induced in healthy individuals, and is thought to reflect the brain's ability to compensate for drifts in spatial calibration between different sensory systems. The neural correlate of this form of functional plasticity is largely unknown, although current models predict the involvement of parieto-cerebellar circuits. Recent studies that have employed event-related functional magnetic resonance imaging (fMRI) to identify brain regions associated with prism adaptation have discovered patterns of parietal and cerebellar modulation as participants corrected their visuomotor errors during the early part of adaptation. However, the role of these regions in the later stage of adaptation, when 'spatial realignment' or true adaptation is predicted to occur, remains unclear. Here, we used fMRI to quantify the distinctive patterns of parieto-cerebellar activity as visuomotor adaptation develops. We directly contrasted activation patterns during the initial error correction phase of visuomotor adaptation with that during the later spatial realignment phase, and found significant recruitment of the parieto-cerebellar network--with activations in the right inferior parietal lobe and the right posterior cerebellum. These findings provide the first evidence of both cerebellar and parietal involvement during the spatial realignment phase of prism adaptation. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Bisphenol A influences oestrogen- and thyroid hormone-regulated thyroid hormone receptor expression in rat cerebellar cell culture.

PubMed

Somogyi, Virág; Horváth, Tamás L; Tóth, István; Bartha, Tibor; Frenyó, László Vilmos; Kiss, Dávid Sándor; Jócsák, Gergely; Kerti, Annamária; Naftolin, Frederick; Zsarnovszky, Attila

2016-12-01

Thyroid hormones (THs) and oestrogens are crucial in the regulation of cerebellar development. TH receptors (TRs) mediate these hormone effects and are regulated by both hormone families. We reported earlier that THs and oestradiol (E 2 ) determine TR levels in cerebellar cell culture. Here we demonstrate the effects of low concentrations (10 -10 M) of the endocrine disruptor (ED) bisphenol A (BPA) on the hormonal (THs, E 2 ) regulation of TRα,β in rat cerebellar cell culture. Primary cerebellar cell cultures, glia-containing and glia-destroyed, were treated with BPA or a combination of BPA and E 2 and/or THs. Oestrogen receptor and TH receptor mRNA and protein levels were determined by real-time qPCR and Western blot techniques. The results show that BPA alone decreases, while BPA in combination with THs and/or E 2 increases TR mRNA expression. In contrast, BPA alone increased receptor protein expressions, but did not further increase them in combination with THs and/or E 2 . The modulatory effects of BPA were mediated by the glia; however, the degree of changes also depended on the specific hormone ligand used. The results signify the importance of the regulatory mechanisms interposed between transcription and translation and raise the possibility that BPA could act to influence nuclear hormone receptor levels independently of ligand-receptor interaction.

Biohybrid Control of General Linear Systems Using the Adaptive Filter Model of Cerebellum.

PubMed

Wilson, Emma D; Assaf, Tareq; Pearson, Martin J; Rossiter, Jonathan M; Dean, Paul; Anderson, Sean R; Porrill, John

2015-01-01

The adaptive filter model of the cerebellar microcircuit has been successfully applied to biological motor control problems, such as the vestibulo-ocular reflex (VOR), and to sensory processing problems, such as the adaptive cancelation of reafferent noise. It has also been successfully applied to problems in robotics, such as adaptive camera stabilization and sensor noise cancelation. In previous applications to inverse control problems, the algorithm was applied to the velocity control of a plant dominated by viscous and elastic elements. Naive application of the adaptive filter model to the displacement (as opposed to velocity) control of this plant results in unstable learning and control. To be more generally useful in engineering problems, it is essential to remove this restriction to enable the stable control of plants of any order. We address this problem here by developing a biohybrid model reference adaptive control (MRAC) scheme, which stabilizes the control algorithm for strictly proper plants. We evaluate the performance of this novel cerebellar-inspired algorithm with MRAC scheme in the experimental control of a dielectric electroactive polymer, a class of artificial muscle. The results show that the augmented cerebellar algorithm is able to accurately control the displacement response of the artificial muscle. The proposed solution not only greatly extends the practical applicability of the cerebellar-inspired algorithm, but may also shed light on cerebellar involvement in a wider range of biological control tasks.

Effect of antithyroid drug on chick embryos during the last week of development: delayed hatching and decreased cerebellar acetylcholinesterase activity.

PubMed

Haba, Gen; Nishigori, Hidekazu; Tezuka, Yu; Kagami, Keisuke; Sugiyama, Toru; Nishigori, Hideo

2011-11-01

Hypothyroid state during embryogenesis disturbs normal growth and brain development, influencing later life. To evaluate the harmful consequences of the state during embryogenesis using an animal model, we inhibited thyroid hormone biosynthesis in chick embryos by using methimazole (MMI). Typically, embryos were treated with MMI (20 µmol/egg) on day 14, and examined on specific days.  Of the control embryos, 94% hatched on day 21, whereas 0% and 60% of MMI-treated embryos hatched on days 21 and 24, respectively. MMI retarded the rates of bodyweight gain as well as liver and heart development, and delayed hatching. However, the external differences in appearance and differences in the weights of the newly hatched control chicks on day 21 and the MMI-treated chicks on day 24 were less obvious. Embryos treated with MMI exhibited increased mass in their brain parts on day 24. Most notably, the treatment resulted in a 1.35-fold increase in cerebellum weight compared to that of the untreated animals. Acetylcholinesterase activity in the cerebellum on the day of hatching decreased significantly to 0.85-fold that of the untreated controls. Thyroid hormone receptor β mRNA was detected from day 12 and dramatically expressed from day 19 to the day of hatching. The 'fertilized hen's egg-chick embryo-chick system' is an appropriate animal model for investigating the hypothyroid state during embryogenesis. Decreased cerebellar acetylcholinesterase activity after MMI treatment was assumed to relate to a mechanism of motor and cognitive deficits in congenital hypothyroidism. © 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.

Structural and ultrastructural evidence of neurotoxic effects of fried potato chips on rat postnatal development.

PubMed

El-Sayyad, Hassan I; El-Gammal, Hekmat L; Habak, Lotfy A; Abdel-Galil, Heba M; Fernando, Augusta; Gaur, Rajiv L; Ouhtit, Allal

2011-10-01

Acrylamide (ACR), a proved rodent carcinogen and neurotoxic agent, is present in significant quantities in commonly consumed foods such as fried potato chips (FPC) and French fries, raising a health concern worldwide. We investigated and compared the neurotoxic effects of ACR and FPC on postnatal development. Female rats were treated with ACR (30 mg/kg of body weight), fed a diet containing approximately 30% of FPC during pregnancy, or fed a standard diet (control) and their offspring were examined. Female rats treated with ACR or fed a diet containing FPC during pregnancy gave birth to litters with delayed growth and decreased body and brain weights. Light microscopic studies of the cerebellar cortex of treated animals revealed drastic decreases in Purkinje cells and internal granular layers. Different patterns of cell death were detected in Purkinje cells and neurons in the brains of pups born to treated mothers. Ultrastructural analysis of Purkinje cells revealed changes in the endoplasmic reticulum, loss of the normal arrangement of polyribosomes, swollen mitochondria with abnormally differentiated cristae, and an abnormal Golgi apparatus. The gastrocnemius muscle in the ACR and FPC groups showed extensive degeneration of myofibrils as evidenced by poorly differentiated A, H, and Z bands. The present study reveals for the first time that rat fetal exposure to ACR, as a pure compound or from a maternal diet of FPC, causes cerebellar cortical defects and myodegeneration of the gastrocnemius muscle during the postnatal development of pups. These results warrant a systematic study of the health effects of the consumption of FPC and French fries in the general population. Copyright © 2011. Published by Elsevier Inc.

GABAergic neurons in cerebellar interposed nucleus modulate cellular and humoral immunity via hypothalamic and sympathetic pathways.

PubMed

Lu, Jian-Hua; Wang, Xiao-Qin; Huang, Yan; Qiu, Yi-Hua; Peng, Yu-Ping

2015-06-15

Our previous work has shown that cerebellar interposed nucleus (IN) modulates immune function. Herein, we reveal mechanism underlying the immunomodulation. Treatment of bilateral cerebellar IN of rats with 3-mercaptopropionic acid (3-MP), a glutamic acid decarboxylase antagonist that reduces γ-aminobutyric acid (GABA) synthesis, enhanced cellular and humoral immune responses to bovine serum albumin, whereas injection of vigabatrin, a GABA-transaminase inhibitor that inhibits GABA degradation, in bilateral cerebellar IN attenuated the immune responses. The 3-MP or vigabatrin administrations in the cerebellar IN decreased or increased hypothalamic GABA content and lymphoid tissues' norepinephrine content, respectively, but did not alter adrenocortical or thyroid hormone levels in serum. In addition, a direct GABAergic projection from cerebellar IN to hypothalamus was found. These findings suggest that GABAergic neurons in cerebellar IN regulate immune system via hypothalamic and sympathetic pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

Cerebellar mutism--report of four cases.

PubMed

Ozimek, A; Richter, S; Hein-Kropp, C; Schoch, B; Gorissen, B; Kaiser, O; Gizewski, E; Ziegler, W; Timmann, D

2004-08-01

The aim of the present study was to investigate the manifestations of mutism after surgery in children with cerebellar tumors. Speech impairment following cerebellar mutism in children was investigated based on standardized acoustic speech parameters and perceptual criteria. Mutistic and non-mutistic children after cerebellar surgery as well as orthopedic controls were tested pre-and postoperatively. Speech impairment was compared with the localization of cerebellar lesions (i. e. affected lobules and nuclei). Whereas both control groups showed no abnormalities in speech and behavior, the mutistic group could be divided into children with dysarthria in post mutistic phase and children with mainly behavioral disturbances. In the mutistic children involvement of dentate and fastigial nuclei tended to be more frequent and extended than in the nonmutistic cerebellar children. Cerebellar mutism is a complex phenomenon of at least two types. Dysarthric symptoms during resolution of mutism support the anarthria hypothesis, while mainly behavioral changes suggest an explanation independent from speech motor control.

The Cerebellum, Sensitive Periods, and Autism

PubMed Central

Wang, Samuel S.-H.; Kloth, Alexander D.; Badura, Aleksandra

2014-01-01

Cerebellar research has focused principally on adult motor function. However, the cerebellum also maintains abundant connections with nonmotor brain regions throughout postnatal life. Here we review evidence that the cerebellum may guide the maturation of remote nonmotor neural circuitry and influence cognitive development, with a focus on its relationship with autism. Specific cerebellar zones influence neocortical substrates for social interaction, and we propose that sensitive-period disruption of such internal brain communication can account for autism's key features. PMID:25102558

Cerebellar syndrome with hydrocephalus due to Mycoplasma pneumoniae infection.

PubMed Central

Coleman, R. J.; Brown, J. S.; Butler, P.; Swash, M.

1990-01-01

A 27 year old woman developed a cerebellar syndrome with serological evidence of recent Mycoplasma pneumoniae infection. The cranial computed tomographic scan showed effacement of the fourth ventricle, enhancement of the basal meninges and hydrocephalus affecting the lateral and third ventricles. Clinical and radiological recovery occurred over 5 weeks. We propose that this was a manifestation of immune-mediated encephalomyelitis induced by the infection rather than direct invasion of the central nervous system. Images Figure 1 PMID:2217014

Hindbrain regional growth in preterm newborns and its impairment in relation to brain injury.

PubMed

Kim, Hosung; Gano, Dawn; Ho, Mai-Lan; Guo, Xiaoyue M; Unzueta, Alisa; Hess, Christopher; Ferriero, Donna M; Xu, Duan; Barkovich, A James

2016-02-01

Premature birth globally affects about 11.1% of all newborns and is a risk factor for neurodevelopmental disability in surviving infants. Histology has suggested that hindbrain subdivisions grow differentially, especially in the third trimester. Prematurity-related brain injuries occurring in this period may selectively affect more rapidly developing areas of hindbrain, thus accompanying region-specific impairments in growth and ultimately neurodevelopmental deficits. The current study aimed to quantify regional growth of the cerebellum and the brainstem in preterm neonates (n = 65 with individually multiple scans). We probed associations of the regional volumes with severity of brain injury. In neonates with no imaging evidence of injury, our analysis using a mixed-effect linear model showed faster growth in the pons and the lateral convexity of anterior/posterior cerebellar lobes. Different patterns of growth impairment were found in relation to early cerebral intraventricular hemorrhage and cerebellar hemorrhage (P < 0.05), likely explaining different mechanisms through which neurogenesis is disrupted. The pattern of cerebellar growth identified in our study agreed excellently with details of cerebellar morphogenesis in perinatal development, which has only been observed in histological data. Our proposed analytic framework may provide predictive imaging biomarkers for neurodevelopmental outcome, enabling early identification and treatment of high-risk patients. Hum Brain Mapp 37:678-688, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Cell proliferation and apoptosis during histogenesis of the guinea pig and rabbit cerebellar cortex.

PubMed

Lossi, Laura; Coli, Alessandra; Giannessi, Elisabetta; Stornelli, Maria Rita; Marroni, Paolo

2002-01-01

Cell proliferation and apoptosis are essential for development of the nervous system. In this study we have investigated the histogenesis of the cerebellar cortex in guinea pig (a precocial species) and rabbit (an altricial species) at different stages of pregnancy and postnatal life. Proliferating cells were identified after labeling with antibodies against the proliferating cell nuclear antigen (PCNA) and/or the Ki-67 antigen. Apoptotic cells were visualized in situ by the TUNEL method and by immunodetection of cleaved caspase 3 and 9. In guinea pigs, both proliferating and apoptotic cells were detected during pre-natal life (E0-E40). Conversely, cell proliferation and apoptosis in rabbits were temporally restricted to early postnatal weeks (P0-P20). In both species cell proliferation was mainly linked to differentiation and migration of the granule cells. In both species, the majority of cells undergoing programmed cell death likely corresponded to granule cells. They were mainly detected in the external granular layer, and were by far more common than previously reported in other locations of the postnatal brain. This study shows that apoptosis is a shared process of cell death during cerebellar development in both altricial and precocial animals, and that there is a direct spatial and temporal correlation between cell proliferation and death in two mammals with different time tables in cerebellar maturation.

Clinical features and natural history of von Hippel-Lindau disease.

PubMed

Maher, E R; Yates, J R; Harries, R; Benjamin, C; Harris, R; Moore, A T; Ferguson-Smith, M A

1990-11-01

The clinical features, age at onset and survival of 152 patients with von Hippel-Lindau disease were studied. Mean age at onset was 26.3 years and 97 per cent of patients had presented by aged 60 years. Retinal angioma was the first manifestation in 65 patients (43 per cent), followed by cerebellar haemangioblastoma (n = 60, 39 per cent) and renal cell carcinoma (n = 15, 10 per cent). Overall, 89 patients (59 per cent) developed a cerebellar haemangioblastoma, 89 (59 per cent) a retinal angioma, 43 (28 per cent) renal cell carcinoma, 20 (13 per cent) spinal haemangioblastoma and 11 (7 per cent) a phaeochromocytoma. Renal, pancreatic and epididymal cysts were frequent findings but their exact incidence was not accurately assessed. Mean age at diagnosis of renal cell carcinoma (44.0 +/- 10.9 years) was significantly older than that for cerebellar haemangioblastoma (29.0 +/- 10.0 years) and retinal angioma (25.4 +/- 12.7 years). The probability of a patient with von Hippel-Lindan disease developing a cerebellar haemangioblastoma, retinal angioma or renal cell carcinoma by age 60 years was 0.84, 0.7 and 0.69, respectively. A comprehensive screening protocol for affected patients and at-risk relatives is presented, based on detailed analysis of age at onset data for each of the major complications. Median actuarial survival was 49 years, with renal cell carcinoma the leading cause of death.

Modality specificity in the cerebro-cerebellar neurocircuitry during working memory.

PubMed

Ng, H B Tommy; Kao, K-L Cathy; Chan, Y C; Chew, Effie; Chuang, K H; Chen, S H Annabel

2016-05-15

Previous studies have suggested cerebro-cerebellar circuitry in working memory. The present fMRI study aims to distinguish differential cerebro-cerebellar activation patterns in verbal and visual working memory, and employs a quantitative analysis to deterimine lateralization of the activation patterns observed. Consistent with Chen and Desmond (2005a,b) predictions, verbal working memory activated a cerebro-cerebellar circuitry that comprised left-lateralized language-related brain regions including the inferior frontal and posterior parietal areas, and subcortically, right-lateralized superior (lobule VI) and inferior cerebellar (lobule VIIIA/VIIB) areas. In contrast, a distributed network of bilateral inferior frontal and inferior temporal areas, and bilateral superior (lobule VI) and inferior (lobule VIIB) cerebellar areas, was recruited during visual working memory. Results of the study verified that a distinct cross cerebro-cerebellar circuitry underlies verbal working memory. However, a neural circuitry involving specialized brain areas in bilateral neocortical and bilateral cerebellar hemispheres subserving visual working memory is observed. Findings are discussed in the light of current models of working memory and data from related neuroimaging studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Abnormal nuclear envelope in the cerebellar Purkinje cells and impaired motor learning in DYT11 myoclonus-dystonia mouse models.

PubMed

Yokoi, Fumiaki; Dang, Mai T; Yang, Guang; Li, Jindong; Doroodchi, Atbin; Zhou, Tong; Li, Yuqing

2012-02-01

Myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonia. DYT11 M-D is caused by mutations in SGCE which codes for ɛ-sarcoglycan. SGCE is maternally imprinted and paternally expressed. Abnormal nuclear envelope has been reported in mouse models of DYT1 generalized torsion dystonia. However, it is not known whether similar alterations occur in DYT11 M-D. We developed a mouse model of DYT11 M-D using paternally inherited Sgce heterozygous knockout (Sgce KO) mice and reported that they had myoclonus and motor coordination and learning deficits in the beam-walking test. However, the specific brain regions that contribute to these phenotypes have not been identified. Since ɛ-sarcoglycan is highly expressed in the cerebellar Purkinje cells, here we examined the nuclear envelope in these cells using a transmission electron microscope and found that they are abnormal in Sgce KO mice. Our results put DYT11 M-D in a growing family of nuclear envelopathies. To analyze the effect of loss of ɛ-sarcoglycan function in the cerebellar Purkinje cells, we produced paternally inherited cerebellar Purkinje cell-specific Sgce conditional knockout (Sgce pKO) mice. Sgce pKO mice showed motor learning deficits, while they did not show abnormal nuclear envelope in the cerebellar Purkinje cells, robust motor deficits, or myoclonus. The results suggest that ɛ-sarcoglycan in the cerebellar Purkinje cells contributes to the motor learning, while loss of ɛ-sarcoglycan in other brain regions may contribute to nuclear envelope abnormality, myoclonus and motor coordination deficits. Copyright © 2011 Elsevier B.V. All rights reserved.

Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics.

PubMed

Fujioka, Shinsuke; Sundal, Christina; Wszolek, Zbigniew K

2013-01-18

Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments.

Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics

PubMed Central

2013-01-01

Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments. PMID:23331413

Adaptive robotic control driven by a versatile spiking cerebellar network.

PubMed

Casellato, Claudia; Antonietti, Alberto; Garrido, Jesus A; Carrillo, Richard R; Luque, Niceto R; Ros, Eduardo; Pedrocchi, Alessandra; D'Angelo, Egidio

2014-01-01

The cerebellum is involved in a large number of different neural processes, especially in associative learning and in fine motor control. To develop a comprehensive theory of sensorimotor learning and control, it is crucial to determine the neural basis of coding and plasticity embedded into the cerebellar neural circuit and how they are translated into behavioral outcomes in learning paradigms. Learning has to be inferred from the interaction of an embodied system with its real environment, and the same cerebellar principles derived from cell physiology have to be able to drive a variety of tasks of different nature, calling for complex timing and movement patterns. We have coupled a realistic cerebellar spiking neural network (SNN) with a real robot and challenged it in multiple diverse sensorimotor tasks. Encoding and decoding strategies based on neuronal firing rates were applied. Adaptive motor control protocols with acquisition and extinction phases have been designed and tested, including an associative Pavlovian task (Eye blinking classical conditioning), a vestibulo-ocular task and a perturbed arm reaching task operating in closed-loop. The SNN processed in real-time mossy fiber inputs as arbitrary contextual signals, irrespective of whether they conveyed a tone, a vestibular stimulus or the position of a limb. A bidirectional long-term plasticity rule implemented at parallel fibers-Purkinje cell synapses modulated the output activity in the deep cerebellar nuclei. In all tasks, the neurorobot learned to adjust timing and gain of the motor responses by tuning its output discharge. It succeeded in reproducing how human biological systems acquire, extinguish and express knowledge of a noisy and changing world. By varying stimuli and perturbations patterns, real-time control robustness and generalizability were validated. The implicit spiking dynamics of the cerebellar model fulfill timing, prediction and learning functions.

Evaluation of the fetal cerebellum by magnetic resonance imaging.

PubMed

Llorens Salvador, R; Viegas Sainz, A; Montoya Filardi, A; Montoliu Fornas, G; Menor Serrano, F

Obstetric protocols dictate that the fetal cerebellum should always be assessed during sonograms during pregnancy. For various reasons, including technical limitations or inconclusive sonographic findings, suspicion of cerebellar abnormalities is one of the most common indications for prenatal magnetic resonance imaging (MRI). Although sonography is the imaging technique of choice to assess the cerebellum, MRI shows the anatomy of the posterior fossa and abnormalities in the development of the fetal cerebellum in greater detail and thus enables a more accurate prenatal diagnosis. We describe and illustrate the normal anatomy of the fetal cerebellum on MRI as well as the different diseases that can affect its development. Moreover, we review the most appropriate terminology to define developmental abnormalities, their differential diagnoses, and the role of MRI in the prenatal evaluation of the posterior fossa. Copyright © 2017 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

[Central hypomyelination, hypogonadotrophic hypogonadism and hypodontia: a new leukodystrophy].

PubMed

Vázquez-López, M; Ruiz-Martín, Y; de Castro-Castro, P; Garzo-Fernández, C; Martín-del Valle, F; Márquez-de la Plata, L

To report one patient with slowly progressive encephalopathy, ataxia, central hypomyelination, hypodontia and hypogonadotropic hypogonadism, the 4H syndrome. This clinical picture has been described recently and there are only four patients reported previously. A girl with a previously normal early psychomotor development, presented a slowly progressive deterioration since 15 months of age. Now, she is 14 years old, and has a severe cerebellar ataxia, with tremor and dysmetria. She can't neither walk nor remain standing alone. She has lost the sphincter control and has an immature expressive language. She has no puberal development and definitive hypodontia of upper central incisors. The brain magnetic resonance imaging shows a diffuse hypomyelination, that is confirmed with diffusion and spectroscopy studies. The hypomyelinating leukoencephalopathies are disorders with abnormally low amount of myelin. The diagnosis is difficult in most of the patients. The hypomyelinating leukoencephalopathies include classic disorders and new leukoencephalopathies, described in the past few years.

Cerebellar Output in Zebrafish: An Analysis of Spatial Patterns and Topography in Eurydendroid Cell Projections

PubMed Central

Heap, Lucy A.; Goh, Chi Ching; Kassahn, Karin S.; Scott, Ethan K.

2013-01-01

The cerebellum is a brain region responsible for motor coordination and for refining motor programs. While a great deal is known about the structure and connectivity of the mammalian cerebellum, fundamental questions regarding its function in behavior remain unanswered. Recently, the zebrafish has emerged as a useful model organism for cerebellar studies, owing in part to the similarity in cerebellar circuits between zebrafish and mammals. While the cell types composing their cerebellar cortical circuits are generally conserved with mammals, zebrafish lack deep cerebellar nuclei, and instead a majority of cerebellar output comes from a single type of neuron: the eurydendroid cell. To describe spatial patterns of cerebellar output in zebrafish, we have used genetic techniques to label and trace eurydendroid cells individually and en masse. We have found that cerebellar output targets the thalamus and optic tectum, and have confirmed the presence of pre-synaptic terminals from eurydendroid cells in these structures using a synaptically targeted GFP. By observing individual eurydendroid cells, we have shown that different medial-lateral regions of the cerebellum have eurydendroid cells projecting to different targets. Finally, we found topographic organization in the connectivity between the cerebellum and the optic tectum, where more medial eurydendroid cells project to the rostral tectum while lateral cells project to the caudal tectum. These findings indicate that there is spatial logic underpinning cerebellar output in zebrafish with likely implications for cerebellar function. PMID:23554587

Challenges in Diagnosis and Treatment of Wernicke Encephalopathy: Report of 2 Cases.

PubMed

Infante, Maria Teresa; Fancellu, Roberto; Murialdo, Alessandra; Barletta, Laura; Castellan, Lucio; Serrati, Carlo

2016-04-01

Wernicke encephalopathy (WE) is a medical emergency caused by thiamine deficiency, characterized by cerebellar ataxia, ophthalmoplegia, and cognitive disturbances that may progress to Korsakoff amnesia. We describe 2 patients with WE who needed high-dose and long-term treatment with thiamine to obtain neurological improvement and recovery. The first patient was a woman diagnosed with non-Hodgkin lymphoma. After a gastrointestinal infection, she developed depression, memory loss, disorientation, behavioral changes, and ataxic paraplegia. Brain magnetic resonance imaging (MRI) showed bilateral alterations in thalamic, frontal, and periaqueductal regions, suggestive of WE. The second patient was a man who lost 10 kg after surgical gastrectomy; he developed diplopia, ophthalmoplegia, cerebellar ataxia, lower limb paresthesias, and amnesia. A brain MRI demonstrated contrast enhancement of mammillary bodies, compatible with WE. The patients were treated with intramuscular (IM) thiamine (1200 mg/d for 2 months and 900 mg/d for a month, respectively) with gradual cognitive and behavioral improvement and brain MRI normalization, while ataxia and oculomotion improved in following months. In both patients, thiamine was gradually reduced to IM 200 mg/d and continued for a year, without clinical relapses. There is no consensus about dosage, frequency, route, and duration of thiamine administration in WE treatment. Based on our cases, we recommend treating patients with WE with higher doses of IM thiamine for a longer time than suggested (900-1200 mg/d for 1-2 months, in our cases) and to gradually reduce dosage after clinical and radiological improvement, maintaining IM 200 mg/d dosage for at least 1 year. © 2016 American Society for Parenteral and Enteral Nutrition.

Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome

PubMed Central

Bodranghien, Florian; Bastian, Amy; Casali, Carlo; Hallett, Mark; Louis, Elan D.; Mariën, Peter; Nowak, Dennis A.; Schmahmann, Jeremy D.; Serrao, Mariano; Steiner, Katharina Marie; Strupp, Michael; Tilikete, Caroline; Timmann, Dagmar; van Dun, Kim

2017-01-01

The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann’s syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor region in lobule VIII, and (c) cognitive and limbic regions located in the posterior lobe (lobule VI, lobule VIIA which includes crus I and crus II, and lobule VIIB). The limbic cerebellum is mainly represented in the posterior vermis. The cortico-ponto-cerebellar and cerebello-thalamocortical loops establish close functional connections between the cerebellum and the supratentorial motor, paralimbic and association cortices, and cerebellar symptoms are associated with a disruption of these loops. PMID:26105056

Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity

PubMed Central

Shaikh, Aasef G.; Hong, Simon; Liao, Ke; Tian, Jing; Solomon, David; Zee, David S.; Leigh, R. John

2010-01-01

The inferior olivary nuclei clearly play a role in creating oculopalatal tremor, but the exact mechanism is unknown. Oculopalatal tremor develops some time after a lesion in the brain that interrupts inhibition of the inferior olive by the deep cerebellar nuclei. Over time the inferior olive gradually becomes hypertrophic and its neurons enlarge developing abnormal soma-somatic gap junctions. However, results from several experimental studies have confounded the issue because they seem inconsistent with a role for the inferior olive in oculopalatal tremor, or because they ascribe the tremor to other brain areas. Here we look at 3D binocular eye movements in 15 oculopalatal tremor patients and compare their behaviour to the output of our recent mathematical model of oculopalatal tremor. This model has two mechanisms that interact to create oculopalatal tremor: an oscillator in the inferior olive and a modulator in the cerebellum. Here we show that this dual mechanism model can reproduce the basic features of oculopalatal tremor and plausibly refute the confounding experimental results. Oscillations in all patients and simulations were aperiodic, with a complicated frequency spectrum showing dominant components from 1 to 3 Hz. The model’s synchronized inferior olive output was too small to induce noticeable ocular oscillations, requiring amplification by the cerebellar cortex. Simulations show that reducing the influence of the cerebellar cortex on the oculomotor pathway reduces the amplitude of ocular tremor, makes it more periodic and pulse-like, but leaves its frequency unchanged. Reducing the coupling among cells in the inferior olive decreases the oscillation’s amplitude until they stop (at ∼20% of full coupling strength), but does not change their frequency. The dual-mechanism model accounts for many of the properties of oculopalatal tremor. Simulations suggest that drug therapies designed to reduce electrotonic coupling within the inferior olive or reduce the disinhibition of the cerebellar cortex on the deep cerebellar nuclei could treat oculopalatal tremor. We conclude that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum. PMID:20080879

Cerebellar Growth Impairment Characterizes School-Aged Children Born Preterm without Perinatal Brain Lesions.

PubMed

Pieterman, K; White, T J; van den Bosch, G E; Niessen, W J; Reiss, I K M; Tibboel, D; Hoebeek, F E; Dudink, J

2018-05-01

Infants born preterm are commonly diagnosed with structural brain lesions known to affect long-term neurodevelopment negatively. Yet, the effects of preterm birth on brain development in the absence of intracranial lesions remain to be studied in detail. In this study, we aim to quantify long term consequences of preterm birth on brain development in this specific group. Neonatal cranial sonography and follow-up T1-weighted MR imaging and DTI were performed to evaluate whether the anatomic characteristics of the cerebrum and cerebellum in a cohort of school-aged children (6-12 years of age) were related to gestational age at birth in children free of brain lesions in the perinatal period. In the cohort consisting of 36 preterm (28-37 weeks' gestational age) and 66 term-born infants, T1-weighted MR imaging and DTI at 6-12 years revealed a reduction of cerebellar white matter volume (β = 0.387, P < .001), altered fractional anisotropy of cerebellar white matter (β = -0.236, P = .02), and a reduction of cerebellar gray and white matter surface area (β = 0.337, P < .001; β = 0.375, P < .001, respectively) in relation to birth age. Such relations were not observed for the cerebral cortex or white matter volume, surface area, or diffusion quantities. The results of our study show that perinatal influences that are not primarily neurologic are still able to disturb long-term neurodevelopment, particularly of the developing cerebellum. Including the cerebellum in future neuroprotective strategies seems therefore essential. © 2018 by American Journal of Neuroradiology.

Cerebellar nodulectomy impairs spatial memory of vestibular and optokinetic stimulation in rabbits.

PubMed

Barmack, N H; Errico, P; Ferraresi, A; Fushiki, H; Pettorossi, V E; Yakhnitsa, V

2002-02-01

Natural vestibular and optokinetic stimulation were used to investigate the possible role of the cerebellar nodulus in the regulation and modification of reflexive eye movements in rabbits. The nodulus and folium 9d of the uvula were destroyed by surgical aspiration. Before and after nodulectomy the vertical and horizontal vestibuloocular reflexes (VVOR, HVOR) were measured during sinusoidal vestibular stimulation about the longitudinal (roll) and vertical (yaw) axes. Although the gain of the HVOR (G(HVOR) = peak eye movement velocity/peak head velocity) was not affected by the nodulectomy, the gain of the VVOR (G(VVOR)) was reduced. The gains of the vertical and horizontal optokinetic reflexes (G(VOKR), G(HOKR)) were measured during monocular, sinusoidal optokinetic stimulation (OKS) about the longitudinal and vertical axes. Following nodulectomy, there was no reduction in G(VOKR) or G(HOKR). Long-term binocular OKS was used to generate optokinetic afternystagmus, OKAN II, that lasts for hours. After OKAN II was induced, rabbits were subjected to static pitch and roll, to determine how the plane and velocity of OKAN II is influenced by a changing vestibular environment. During static pitch, OKAN II slow phase remained aligned with earth-horizontal. This was true for normal and nodulectomized rabbits. During static roll, OKAN II remained aligned with earth-horizontal in normal rabbits. During static roll in nodulectomized rabbits, OKAN II slow phase developed a centripetal vertical drift. We examined the suppression and recovery of G(VVOR) following exposure to conflicting vertical OKS for 10-30 min. This vestibular-optokinetic conflict reduced G(VVOR) in both normal and nodulectomized rabbits. The time course of recovery of G(VVOR) after conflicting OKS was the same before and after nodulectomy. In normal rabbits, the head pitch angle, at which peak OKAN II velocity occurred, corresponded to the head pitch angle maintained during long-term OKS. If the head was maintained in a "pitched-up" or "pitched-down" orientation during long-term OKS, the subsequently measured OKAN II peak velocity occurred at the same orientation. This was not true for nodulectomized rabbits, who had OKAN II peak velocities at head pitch angles independent of those maintained during long-term OKS. We conclude that the nodulus participates in the regulation of compensatory reflexive movements. The nodulus also influences "remembered" head position in space derived from previous optokinetic and vestibular stimulation.

Neural correlates of free recall of "famous events" in a "hypermnestic" individual as compared to an age- and education-matched reference group.

PubMed

Fehr, Thorsten; Staniloiu, Angelica; Markowitsch, Hans J; Erhard, Peter; Herrmann, Manfred

2018-06-19

Memory performance of an individual (within the age range: 50-55 years old) showing superior memory abilities (protagonist PR) was compared to an age- and education-matched reference group in a historical facts ("famous events") retrieval task. Contrasting task versus baseline performance both PR and the reference group showed fMRI activation patterns in parietal and occipital brain regions. The reference group additionally demonstrated activation patterns in cingulate gyrus, whereas PR showed additional widespread activation patterns comprising frontal and cerebellar brain regions. The direct comparison between PR and the reference group revealed larger fMRI contrasts for PR in right frontal, superior temporal and cerebellar brain regions. It was concluded that PR generally recruits brain regions as normal memory performers do, but in a more elaborate way, and furthermore, that he applied a memory-strategy that potentially includes executively driven multi-modal transcoding of information and recruitment of implicit memory resources.

Differentiating Patients with Parkinson's Disease from Normal Controls Using Gray Matter in the Cerebellum.

PubMed

Zeng, Ling-Li; Xie, Liang; Shen, Hui; Luo, Zhiguo; Fang, Peng; Hou, Yanan; Tang, Beisha; Wu, Tao; Hu, Dewen

2017-02-01

Parkinson's disease (PD) is one of the most common neurodegenerative disorders in the world. Previous studies have focused on the basal ganglia and cerebral cortices. To date, the cerebellum has not been systematically investigated in patients with PD. In the current study, 45 probable PD patients and 40 age- and gender-matched healthy controls underwent structural magnetic resonance imaging, and we used support vector machines combining with voxel-based morphometry to explore the cerebellar structural changes in the probable PD patients relative to healthy controls. The results revealed that the gray matter alterations were primarily located within the cerebellar Crus I, implying a possible important role of this region in PD. Furthermore, the gray matter alterations in the cerebellum could differentiate the probable PD patients from healthy controls with accuracies of more than 95 % (p < 0.001, permutation test) via cross-validation, suggesting the potential of analyzing the cerebellum in the clinical diagnosis of PD.

Therapeutic Effect of Steroids in Osmotic Demyelination of Infancy.

PubMed

Bansal, Lalit R

2018-01-01

An 11-month-old male presented with acute gastroenteritis, seizures, and altered mental status. Laboratory workup revealed serum sodium of 177 mmol/L. Magnetic resonance imaging of the brain showed reduced diffusion in the supratentorial white matter, T2 hyperintensities in the left central pons and midbrain, subacute stroke in the right occipital lobe, and bilateral cerebellar hemorrhagic infarcts. The child was presumed to have hypernatremia-induced central pontine and extrapontine myelinolysis. He received 5 days of high-dose methylprednisolone for persistent encephalopathy and spastic quadriparesis with rapid recovery of his cognitive function and neurological examination. The child remained seizure-free and achieved normal development at 3-month and 2-year follow-ups. Osmotic demyelination of infancy may leave children with a significant neurological deficit. For favorable neurological outcome, early steroids should be considered.

Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.

PubMed

Tsai, Peter T; Hull, Court; Chu, YunXiang; Greene-Colozzi, Emily; Sadowski, Abbey R; Leech, Jarrett M; Steinberg, Jason; Crawley, Jacqueline N; Regehr, Wade G; Sahin, Mustafa

2012-08-30

Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.

Cerebellar modulation of frontal cortex dopamine efflux in mice: relevance to autism and schizophrenia.

PubMed

Mittleman, Guy; Goldowitz, Daniel; Heck, Detlef H; Blaha, Charles D

2008-07-01

Cerebellar and frontal cortical pathologies have been commonly reported in schizophrenia, autism, and other developmental disorders. Whether there is a relationship between prefrontal and cerebellar pathologies is unknown. Using fixed potential amperometry, dopamine (DA) efflux evoked by cerebellar or, dentate nucleus electrical stimulation (50 Hz, 200 muA) was recorded in prefrontal cortex of urethane anesthetized lurcher (Lc/+) mice with 100% loss of cerebellar Purkinje cells and wildtype (+/+) control mice. Cerebellar stimulation with 25 and 100 pulses evoked prefrontal cortex DA efflux in +/+ mice that persisted for 12 and 25 s poststimulation, respectively. In contrast, 25 pulse cerebellar stimulation failed to evoke prefrontal cortex DA efflux in Lc/+ mice indicating a dependency on cerebellar Purkinje cell outputs. Dentate nucleus stimulation (25 pulses) evoked a comparable but briefer (baseline recovery within 7 s) increase in prefrontal cortex DA efflux compared to similar cerebellar stimulation in +/+ mice. However, in Lc/+ mice 25 pulse dentate nucleus evoked prefrontal cortex DA efflux was attenuated by 60% with baseline recovery within 4 s suggesting that dentate nucleus outputs to prefrontal cortex remain partially functional. DA reuptake blockade enhanced 100 pulse stimulation evoked prefrontal cortex responses, while serotonin or norepinephrine reuptake blockade were without effect indicating the specificity of the amperometric recordings to DA. Results provide neurochemical evidence that the cerebellum can modulate DA efflux in the prefrontal cortex. Together, these findings may explain why cerebellar and frontal cortical pathologies co-occur, and may provide a mechanism that accounts for the diversity of symptoms common to multiple developmental disorders.

Cerebellar Modulation of Frontal Cortex Dopamine Efflux in Mice: Relevance to Autism and Schizophrenia

PubMed Central

MITTLEMAN, GUY; GOLDOWITZ, DANIEL; HECK, DETLEF H.; BLAHA, CHARLES D.

2013-01-01

Cerebellar and frontal cortical pathologies have been commonly reported in schizophrenia, autism, and other developmental disorders. Whether there is a relationship between prefrontal and cerebellar pathologies is unknown. Using fixed potential amperometry, dopamine (DA) efflux evoked by cerebellar or, dentate nucleus electrical stimulation (50 Hz, 200 μA) was recorded in prefrontal cortex of urethane anesthetized lurcher (Lc/+) mice with 100% loss of cerebellar Purkinje cells and wildtype (+/+) control mice. Cerebellar stimulation with 25 and 100 pulses evoked prefrontal cortex DA efflux in +/+ mice that persisted for 12 and 25 s poststimulation, respectively. In contrast, 25 pulse cerebellar stimulation failed to evoke prefrontal cortex DA efflux in Lc/+ mice indicating a dependency on cerebellar Purkinje cell outputs. Dentate nucleus stimulation (25 pulses) evoked a comparable but briefer (baseline recovery within 7 s) increase in prefrontal cortex DA efflux compared to similar cerebellar stimulation in +/+ mice. However, in Lc/+ mice 25 pulse dentate nucleus evoked prefrontal cortex DA efflux was attenuated by 60% with baseline recovery within 4 s suggesting that dentate nucleus outputs to prefrontal cortex remain partially functional. DA reuptake blockade enhanced 100 pulse stimulation evoked pre-frontal cortex responses, while serotonin or norepinephrine reuptake blockade were without effect indicating the specificity of the amperometric recordings to DA. Results provide neurochemical evidence that the cerebellum can modulate DA efflux in the prefrontal cortex. Together, these findings may explain why cerebellar and frontal cortical pathologies co-occur, and may provide a mechanism that accounts for the diversity of symptoms common to multiple developmental disorders. PMID:18435424

Cerebral blood flow in normal and abnormal sleep and dreaming

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meyer, J.S.; Ishikawa, Y.; Hata, T.

Measurements of regional or local cerebral blood flow (CBF) by the xenon-133 inhalation method and stable xenon computerized tomography CBF (CTCBF) method were made during relaxed wakefulness and different stages of REM and non-REM sleep in normal age-matched volunteers, narcoleptics, and sleep apneics. In the awake state, CBF values were reduced in both narcoleptics and sleep apneics in the brainstem and cerebellar regions. During sleep onset, whether REM or stage I-II, CBF values were paradoxically increased in narcoleptics but decreased severely in sleep apneics, while in normal volunteers they became diffusely but more moderately decreased. In REM sleep and dreamingmore » CBF values greatly increased, particularly in right temporo-parietal regions in subjects experiencing both visual and auditory dreaming.« less

The Pathogenic Role of Low Range Repeats in SCA17.

PubMed

Shin, Jung Hwan; Park, Hyeyoung; Ehm, Gwan Hee; Lee, Woong Woo; Yun, Ji Young; Kim, Young Eun; Lee, Jee-Young; Kim, Han-Joon; Kim, Jong-Min; Jeon, Beom Seok; Park, Sung-Sup

2015-01-01

SCA17 is an autosomal dominant cerebellar ataxia with expansion of the CAG/CAA trinucleotide repeats in the TATA-binding protein (TBP) gene. SCA17 can have various clinical presentations including parkinsonism, ataxia, chorea and dystonia. SCA17 is diagnosed by detecting the expanded CAG repeats in the TBP gene; however, in the literature, pathologic repeat numbers as low as 41 overlap with normal repeat numbers. The subjects in this study included patients with involuntary movement disorders such as cerebellar ataxia, parkinsonism, chorea and dystonia who visited Seoul National University Hospital between Jan. 2006 and Apr. 2014 and were screened for SCA17. Those who were diagnosed with other genetic diseases or nondegenerative diseases were excluded. DNA from healthy subjects who did not have a family history of parkinsonism, ataxia, psychiatric symptoms, chorea or dystonia served as the control. In total, 5242 chromosomes from 2099 patients and 522 normal controls were analyzed. The total number of patients included in the analysis was 2099 (parkinsonism, 1706; ataxia, 345; chorea, 37; and dystonia, 11). In the normal control, up to 44 repeats were found. In the 44 repeat group, there were 7 (0.3%) patients and 1 (0.2%) normal control. In 43 repeat group, there were 8 (0.4%) patients and 2 (0.4%) normal controls. In the 42 repeat group, there were 16 (0.8%) patients and 3 (0.6%) normal controls. In 41 repeat group, there were 48 (2.3%) patients and 8 (1.5%) normal controls. Considering the overlaps and non-significant differences in allelic frequencies between the patients and the normal controls with low-expansions, we could not determine a definitive cutoff value for the pathologic CAG repeat number of SCA17. Because the statistical analysis between the normal controls and patients with low range expansions failed to show any differences so far, we must consider that clinical cases with low range expansions could be idiopathic movement disorders showing coincidental CAG/CAA expansions. Thus, we need to reconsider the pathologic role of low range expansions (41-42). Long term follow up and comprehensive investigations using autopsy and imaging studies in patients and controls with low range expansions are necessary to determine the cutoff value for the pathologic CAG repeat number of SCA17.

Contralateral cortico-ponto-cerebellar pathways reconstruction in humans in vivo: implications for reciprocal cerebro-cerebellar structural connectivity in motor and non-motor areas.

PubMed

Palesi, Fulvia; De Rinaldis, Andrea; Castellazzi, Gloria; Calamante, Fernando; Muhlert, Nils; Chard, Declan; Tournier, J Donald; Magenes, Giovanni; D'Angelo, Egidio; Gandini Wheeler-Kingshott, Claudia A M

2017-10-09

Cerebellar involvement in cognition, as well as in sensorimotor control, is increasingly recognized and is thought to depend on connections with the cerebral cortex. Anatomical investigations in animals and post-mortem humans have established that cerebro-cerebellar connections are contralateral to each other and include the cerebello-thalamo-cortical (CTC) and cortico-ponto-cerebellar (CPC) pathways. CTC and CPC characterization in humans in vivo is still challenging. Here advanced tractography was combined with quantitative indices to compare CPC to CTC pathways in healthy subjects. Differently to previous studies, our findings reveal that cerebellar cognitive areas are reached by the largest proportion of the reconstructed CPC, supporting the hypothesis that a CTC-CPC loop provides a substrate for cerebro-cerebellar communication during cognitive processing. Amongst the cerebral areas identified using in vivo tractography, in addition to the cerebral motor cortex, major portions of CPC streamlines leave the prefrontal and temporal cortices. These findings are useful since provide MRI-based indications of possible subtending connectivity and, if confirmed, they are going to be a milestone for instructing computational models of brain function. These results, together with further multi-modal investigations, are warranted to provide important cues on how the cerebro-cerebellar loops operate and on how pathologies involving cerebro-cerebellar connectivity are generated.

Mechanisms of human cerebellar dysmetria: experimental evidence and current conceptual bases

PubMed Central

Manto, Mario

2009-01-01

The human cerebellum contains more neurons than any other region in the brain and is a major actor in motor control. Cerebellar circuitry is unique by its stereotyped architecture and its modular organization. Understanding the motor codes underlying the organization of limb movement and the rules of signal processing applied by the cerebellar circuits remains a major challenge for the forthcoming decades. One of the cardinal deficits observed in cerebellar patients is dysmetria, designating the inability to perform accurate movements. Patients overshoot (hypermetria) or undershoot (hypometria) the aimed target during voluntary goal-directed tasks. The mechanisms of cerebellar dysmetria are reviewed, with an emphasis on the roles of cerebellar pathways in controlling fundamental aspects of movement control such as anticipation, timing of motor commands, sensorimotor synchronization, maintenance of sensorimotor associations and tuning of the magnitudes of muscle activities. An overview of recent advances in our understanding of the contribution of cerebellar circuitry in the elaboration and shaping of motor commands is provided, with a discussion on the relevant anatomy, the results of the neurophysiological studies, and the computational models which have been proposed to approach cerebellar function. PMID:19364396

[Cerebellar cognitive affective syndrome secondary to a cerebellar tumour].

PubMed

Domínguez-Carral, J; Carreras-Sáez, I; García-Peñas, J J; Fournier-Del Castillo, C; Villalobos-Reales, J

2015-01-01

Cerebellar cognitive affective syndrome is characterized by disturbances of executive function, impaired spatial cognition, linguistic difficulties, and personality change. The case of an 11 year old boy is presented, with behavior problems, learning difficulties and social interaction problems. In the physical examination he had poor visual contact, immature behavior, reduced expressive language and global motor disability with gait dyspraxia, with no defined cerebellar motor signs. In the neuropsychological evaluation he has a full scale overall intellectual quotient of 84, with signs of cerebellar cognitive affective syndrome. A tumour affecting inferior cerebellar vermis was observed in the magnetic resonance imaging, which had not significantly grown during 5 years of follow up. The cerebellum participates in controlling cognitive and affective functions. Cerebellar pathology must be considered in the differential diagnosis of children with cognitive or learning disorder with associated behavioral and emotional components. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

The cerebellum: a neuronal learning machine?

NASA Technical Reports Server (NTRS)

Raymond, J. L.; Lisberger, S. G.; Mauk, M. D.

1996-01-01

Comparison of two seemingly quite different behaviors yields a surprisingly consistent picture of the role of the cerebellum in motor learning. Behavioral and physiological data about classical conditioning of the eyelid response and motor learning in the vestibulo-ocular reflex suggests that (i) plasticity is distributed between the cerebellar cortex and the deep cerebellar nuclei; (ii) the cerebellar cortex plays a special role in learning the timing of movement; and (iii) the cerebellar cortex guides learning in the deep nuclei, which may allow learning to be transferred from the cortex to the deep nuclei. Because many of the similarities in the data from the two systems typify general features of cerebellar organization, the cerebellar mechanisms of learning in these two systems may represent principles that apply to many motor systems.

Questioning the cerebellar doctrine.

PubMed

Galliano, Elisa; De Zeeuw, Chris I

2014-01-01

The basic principles of cerebellar function were originally described by Flourens, Cajal, and Marr/Albus/Ito, and they constitute the pillars of what can be considered to be the classic cerebellar doctrine. In their concepts, the main cerebellar function is to control motor behavior, Purkinje cells are the only cortical neuron receiving and integrating inputs from climbing fiber and mossy-parallel fiber pathways, and plastic modification at the parallel fiber synapses onto Purkinje cells constitutes the substrate of motor learning. Yet, because of recent technical advances and new angles of investigation, all pillars of the cerebellar doctrine now face regular re-examination. In this review, after summarizing the classic concepts and recent disputes, we attempt to synthesize an integrated view and propose a revisited version of the cerebellar doctrine. © 2014 Elsevier B.V. All rights reserved.

Deep brain stimulation or thalamotomy in fragile X-associated tremor/ataxia syndrome? Case report.

PubMed

Tamás, Gertrúd; Kovács, Norbert; Varga, Noémi Ágnes; Barsi, Péter; Erőss, Loránd; Molnár, Mária Judit; Balás, István

2016-01-01

We present the case of a 66-year-old man who has been treated for essential tremor since the age of 58. He developed mild cerebellar gait ataxia seven years after tremor onset. Moderate, global brain atrophy was identified on MRI scans. At the age of 68, only temporary tremor relief could be achieved by bilateral deep brain stimulation of the ventral intermedius nucleus of the thalamus. Bilateral stimulation of the subthalamic nucleus also resulted only in transient improvement. In the meantime, progressive gait ataxia and tetraataxia developed accompanied by other cerebellar symptoms, such as nystagmus and scanning speech. These correlated with progressive development of bilateral symmetric hyperintensity of the middle cerebellar peduncles on T2 weighted MRI scans. Genetic testing revealed premutation of the FMR1 gene, establishing the diagnosis of fragile X-associated tremor/ataxia syndrome. Although this is a rare disorder, it should be taken into consideration during preoperative evaluation of essential tremor. Postural tremor ceased two years later after thalamotomy on the left side, while kinetic tremor of the right hand also improved. Copyright © 2016 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Increased cerebellar PET glucose metabolism corresponds to ataxia in Wernicke-Korsakoff syndrome.

PubMed

Fellgiebel, Andreas; Siessmeier, Thomas; Winterer, Georg; Lüddens, Hartmut; Mann, Klaus; Schmidt, Lutz G; Bartenstein, Peter

2004-01-01

To investigate a possible relationship between cerebellar glucose metabolism and recovery from ataxia in the first months of acute Wernicke-Korsakoff syndrome. Two cases of alcoholic Wernicke-Korsakoff syndrome were followed up with the clinical status and cerebral glucose metabolism over a 4- and 9-month period. Initially both patients showed severe ataxia and elevated cerebellar glucose metabolism that decreased corresponding to the restitution of stance and gait. Increased cerebellar glucose metabolism at the onset of the illness may reflect the reorganization process of disturbed motor skills and may indicate cerebellar plasticity.

Promoting Motor Cortical Plasticity with Acute Aerobic Exercise: A Role for Cerebellar Circuits

PubMed Central

Mang, Cameron S.; Brown, Katlyn E.; Neva, Jason L.; Snow, Nicholas J.; Campbell, Kristin L.; Boyd, Lara A.

2016-01-01

Acute aerobic exercise facilitated long-term potentiation-like plasticity in the human primary motor cortex (M1). Here, we investigated the effect of acute aerobic exercise on cerebellar circuits, and their potential contribution to altered M1 plasticity in healthy individuals (age: 24.8 ± 4.1 years). In Experiment   1, acute aerobic exercise reduced cerebellar inhibition (CBI) (n = 10, p = 0.01), elicited by dual-coil paired-pulse transcranial magnetic stimulation. In Experiment   2, we evaluated the facilitatory effects of aerobic exercise on responses to paired associative stimulation, delivered with a 25 ms (PAS25) or 21 ms (PAS21) interstimulus interval (n = 16 per group). Increased M1 excitability evoked by PAS25, but not PAS21, relies on trans-cerebellar sensory pathways. The magnitude of the aerobic exercise effect on PAS response was not significantly different between PAS protocols (interaction effect: p = 0.30); however, planned comparisons indicated that, relative to a period of rest, acute aerobic exercise enhanced the excitatory response to PAS25 (p = 0.02), but not PAS21 (p = 0.30). Thus, the results of these planned comparisons indirectly provide modest evidence that modulation of cerebellar circuits may contribute to exercise-induced increases in M1 plasticity. The findings have implications for developing aerobic exercise strategies to “prime” M1 plasticity for enhanced motor skill learning in applied settings. PMID:27127659

Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1

PubMed Central

Kim, Edward; Wang, Yuan; Kim, Sun-Jung; Bornhorst, Miriam; Jecrois, Emmanuelle S; Anthony, Todd E; Wang, Chenran; Li, Yi E; Guan, Jun-Lin; Murphy, Geoffrey G; Zhu, Yuan

2014-01-01

Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities. DOI: http://dx.doi.org/10.7554/eLife.05151.001 PMID:25535838

A new myohaptic instrument to assess wrist motion dynamically.

PubMed

Manto, Mario; Van Den Braber, Niels; Grimaldi, Giuliana; Lammertse, Piet

2010-01-01

The pathophysiological assessment of joint properties and voluntary motion in neurological patients remains a challenge. This is typically the case in cerebellar patients, who exhibit dysmetric movements due to the dysfunction of cerebellar circuitry. Several tools have been developed, but so far most of these tools have remained confined to laboratories, with a lack of standardization. We report on a new device which combines the use of electromyographic (EMG) sensors with haptic technology for the dynamic investigation of wrist properties. The instrument is composed of a drivetrain, a haptic controller and a signal acquisition unit. Angular accuracy is 0.00611 rad, nominal torque is 6 N·m, maximal rotation velocity is 34.907 rad/sec, with a range of motion of -1.0472 to +1.0472 rad. The inertia of the motor and handgrip is 0.004 kg·m2. This is the first standardized myohaptic instrument allowing the dynamic characterization of wrist properties, including under the condition of artificial damping. We show that cerebellar patients are unable to adapt EMG activities when faced with an increase in damping while performing fast reversal movements. The instrument allows the extraction of an electrophysiological signature of a cerebellar deficit.

Effect of edaravone on acute brainstem-cerebellar infarction with vertigo and sudden hearing loss.

PubMed

Inoue, Yuta; Yabe, Takao; Okada, Kazunari; Nakamura, Yuka

2014-06-01

We report 2 cases with acute brainstem and brainstem-cerebellar infarction showed improvement of their signs and symptoms after administration of edaravone. Case 1, a 74-year-old woman who experienced sudden vertigo, also had dysarthria and left hemiplegia. Magnetic resonance imaging (MRI) showed an abnormal region in the right ventrolateral medulla oblongata. The patient's vertigo and hemiplegia improved completely after treatment. Case 2, a 50-year-old man who experienced sudden vertigo and sensorineural hearing loss (SNHL), developed dysarthria after admission. MRI revealed acute infarction in the right cerebellar hemisphere. Magnetic resonance angiography revealed dissection of the basilar artery and occlusion of the right anterior inferior cerebellar artery. The patient's vertigo and hearing remarkably improved. We have described 2 patients whose early symptoms were vertigo and sudden SNHL, but who were later shown to have ischemic lesions of the central nervous system. Edaravone is neuroprotective drug with free radical-scavenging actions. Free radicals in the ear are responsible for ischemic damage. Edaravone, a free radical scavenger, may be useful in the treatment of vertigo and SNHL. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Distinguishing spinocerebellar ataxia with pure cerebellar manifestation from multiple system atrophy (MSA-C) through saccade profiles.

PubMed

Terao, Yasuo; Fukuda, Hideki; Tokushige, Shin-Ichi; Inomata-Terada, Satomi; Yugeta, Akihiro; Hamada, Masashi; Ugawa, Yoshikazu

2017-01-01

Patients with spinocerebellar ataxia with pure cerebellar presentation (SCD) and multiple system atrophy (MSA-C) show similar symptoms at early stages, although cerebellofugal pathology predominates in SCD, and cerebellopetal pathology in MSA-C. We studied whether saccade velocity profiles, which reflect the accelerating and braking functions of the cerebellum, can differentiate these two disorders. We recorded visually guided (VGS) and memory guided saccades (MGS) in 29 MSA-C patients, 12 SCD patients, and 92 age-matched normal subjects, and compared their amplitude, peak velocity and duration (accelerating and decelerating phases). Hypometria predominated in VGS and MGS of MSA-C, whereas hypometria was less marked in SCD, with hypermetria frequently noted in MGS. Peak velocity was reduced, and deteriorated with advancing disease both in SCD and MSA-C groups at smaller target eccentricities. The deceleration phase was prolonged in SCD compared to MSA-C and normal groups at larger target eccentricities, which deteriorated with advancing disease. Saccades in MSA-C were characterized by a more prominent acceleration deficit and those in SCD by a more prominent braking defect, possibly caused by the cerebellopetal and cerebellofugal pathologies, respectively. Saccade profiles provide important information regarding the accelerating and braking signals of the cerebellum in spinocerebellar ataxia. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Comparison of Automated Brain Volume Measures obtained with NeuroQuant and FreeSurfer.

PubMed

Ochs, Alfred L; Ross, David E; Zannoni, Megan D; Abildskov, Tracy J; Bigler, Erin D

2015-01-01

To examine intermethod reliabilities and differences between FreeSurfer and the FDA-cleared congener, NeuroQuant, both fully automated methods for structural brain MRI measurements. MRI scans from 20 normal control subjects, 20 Alzheimer's disease patients, and 20 mild traumatically brain-injured patients were analyzed with NeuroQuant and with FreeSurfer. Intermethod reliability was evaluated. Pairwise correlation coefficients, intraclass correlation coefficients, and effect size differences were computed. NeuroQuant versus FreeSurfer measures showed excellent to good intermethod reliability for the 21 regions evaluated (r: .63 to .99/ICC: .62 to .99/ES: -.33 to 2.08) except for the pallidum (r/ICC/ES = .31/.29/-2.2) and cerebellar white matter (r/ICC/ES = .31/.31/.08). Volumes reported by NeuroQuant were generally larger than those reported by FreeSurfer with the whole brain parenchyma volume reported by NeuroQuant 6.50% larger than the volume reported by FreeSurfer. There was no systematic difference in results between the 3 subgroups. NeuroQuant and FreeSurfer showed good to excellent intermethod reliability in volumetric measurements for all brain regions examined with the only exceptions being the pallidum and cerebellar white matter. This finding was robust for normal individuals, patients with Alzheimer's disease, and patients with mild traumatic brain injury. Copyright © 2015 by the American Society of Neuroimaging.

Do the cerebellar tonsils move during flexion and extension of the neck in patients with Chiari I malformation? A radiological study with clinical implications.

PubMed

Tubbs, R Shane; Kirkpatrick, Christina M; Rizk, Elias; Chern, Joshua J; Oskouian, Rod J; Oakes, W Jerry

2016-03-01

In the past, diagnosis of the Chiari I malformation has primarily been made on midsagittal MRI. We hypothesized that based on the frequent presentation of opisthotonos in patients with hindbrain hernia (primarily Chiari II malformation but sometimes Chiari I malformation) that the hyperextension might be a compensatory technique used by such patients to bring the cerebellar tonsils up out of the cervical spine. This prospective study reviewed imaging of patients with Chiari I malformation who underwent flexion/extension MRI for evaluation of their hindbrain herniation. Age-matched controls were used for comparison. In general, there was elevation of the cerebellar tonsils with extension and increased descent with flexion of the cervical spine. In 72 % of patients, flexion of the neck resulted in descent of the cerebellar tonsils. In 64 % of patients, extension of the neck resulted in ascent of the cerebellar tonsils. In the 14 patients with an associated syrinx, 71 % were found to have caudal movement of the cerebellar tonsils with neck flexion, and only 43 % were observed to have any movement of the cerebellar tonsils in neck extension compared to patients without a syrinx where ascent of the tonsils was seen in only nine during neck extension. Two patients were observed to have the reverse finding of ascent of the cerebellar tonsils with neck flexion and descent of the cerebellar tonsils with neck extension. Five patients had no movement of the cerebellar tonsils in either flexion or extension of the neck, and one of these had a small syrinx. Although minimal and not in all patients, we observed elevation of the herniated cerebellar tonsils with extension of the cervical spine in patients with Chiari I malformation. This finding provides evidence as to why some patients with hindbrain herniation present with opisthotonos and supports earlier findings that CSF flow is reduced at the craniocervical junction in flexion in patients with Chiari I malformation.

Functional topography of the cerebellum for motor and cognitive tasks: an fMRI study

PubMed Central

Stoodley, Catherine J.; Valera, Eve M.; Schmahmann, Jeremy D.

2011-01-01

Anatomical, clinical and imaging findings suggest that the cerebellum is engaged in cognitive and affective functions as well as motor control. Evidence from converging modalities also indicates that there is a functional topography in the human cerebellum for overt control of movement vs. higher functions, such that the cerebellum can be divided into zones depending on connectivity with sensorimotor vs. multimodal association cortices. Using functional MRI, we show that regions active during overt movement differ from those involved in higher-level language, spatial processing and working memory tasks. Nine healthy participants each completed five tasks in order to determine the relative activation patterns for the different paradigms. Right-handed finger-tapping activated right cerebellar lobules IV-V and VIII, consistent with descriptions of the cerebellar homunculi. Verb generation engaged right cerebellar lobules VI-Crus I and a second cluster in lobules VIIB-VIIIA. Mental rotation activation peaks were localized to medial left cerebellar lobule VII (Crus II). A 2-back working memory task activated bilateral regions of lobules VI-VII. Viewing arousing vs. neutral images did not reliably activate the cerebellum or cerebral limbic areas in this study. The cerebellar functional topography identified in this study reflects the involvement of different cerebro-cerebellar circuits depending on the demands of the task being performed: overt movement activated sensorimotor cortices along with contralateral cerebellar lobules IV-VI and VIII, whereas more cognitively demanding tasks engaged prefrontal and parietal cortices along with cerebellar lobules VI and VII. These findings provide further support for a cerebellar role in both motor and cognitive tasks, and better establish the existence of functional subregions in the cerebellum. Future studies are needed to determine the exact contribution of the cerebellum – and different cerebro-cerebellar circuits – to task performance. PMID:21907811

Principal Component Analysis of Cerebellar Shape on MRI Separates SCA Types 2 and 6 into Two Archetypal Modes of Degeneration

PubMed Central

Jung, Brian C.; Choi, Soo I.; Du, Annie X.; Cuzzocreo, Jennifer L.; Geng, Zhuo Z.; Ying, Howard S.; Perlman, Susan L.; Toga, Arthur W.; Prince, Jerry L.

2014-01-01

Although “cerebellar ataxia” is often used in reference to a disease process, presumably there are different underlying pathogenetic mechanisms for different subtypes. Indeed, spinocerebellar ataxia (SCA) types 2 and 6 demonstrate complementary phenotypes, thus predicting a different anatomic pattern of degeneration. Here, we show that an unsupervised classification method, based on principal component analysis (PCA) of cerebellar shape characteristics, can be used to separate SCA2 and SCA6 into two classes, which may represent disease-specific archetypes. Patients with SCA2 (n=11) and SCA6 (n=7) were compared against controls (n=15) using PCA to classify cerebellar anatomic shape characteristics. Within the first three principal components, SCA2 and SCA6 differed from controls and from each other. In a secondary analysis, we studied five additional subjects and found that these patients were consistent with the previously defined archetypal clusters of clinical and anatomical characteristics. Secondary analysis of five subjects with related diagnoses showed that disease groups that were clinically and pathophysiologically similar also shared similar anatomic characteristics. Specifically, Archetype #1 consisted of SCA3 (n=1) and SCA2, suggesting that cerebellar syndromes accompanied by atrophy of the pons may be associated with a characteristic pattern of cerebellar neurodegeneration. In comparison, Archetype #2 was comprised of disease groups with pure cerebellar atrophy (episodic ataxia type 2 (n=1), idiopathic late-onset cerebellar ataxias (n=3), and SCA6). This suggests that cerebellar shape analysis could aid in discriminating between different pathologies. Our findings further suggest that magnetic resonance imaging is a promising imaging biomarker that could aid in the diagnosis and therapeutic management in patients with cerebellar syndromes. PMID:22258915

Restoring Cognitive Functions Using Non-Invasive Brain Stimulation Techniques in Patients with Cerebellar Disorders

PubMed Central

Pope, Paul A.; Miall, R. Chris

2014-01-01

Numerous studies have highlighted the possibility of modulating the excitability of cerebro–cerebellar circuits bi-directionally using transcranial electrical brain stimulation, in a manner akin to that observed using magnetic stimulation protocols. It has been proposed that cerebellar stimulation activates Purkinje cells in the cerebellar cortex, leading to inhibition of the dentate nucleus, which exerts a tonic facilitatory drive onto motor and cognitive regions of cortex through a synaptic relay in the ventral–lateral thalamus. Some cerebellar deficits present with cognitive impairments if damage to non-motor regions of the cerebellum disrupts the coupling with cerebral cortical areas for thinking and reasoning. Indeed, white matter changes in the dentato–rubral tract correlate with cognitive assessments in patients with Friedreich ataxia, suggesting that this pathway is one component of the anatomical substrate supporting a cerebellar contribution to cognition. An understanding of the physiology of the cerebro–cerebellar pathway previously helped us to constrain our interpretation of results from two recent studies in which we showed cognitive enhancements in healthy participants during tests of arithmetic after electrical stimulation of the cerebellum, but only when task demands were high. Others studies have also shown how excitation of the prefrontal cortex can enhance performance in a variety of working memory tasks. Thus, future efforts might be guided toward neuro-enhancement in certain patient populations, using what is commonly termed “non-invasive brain stimulation” as a cognitive rehabilitation tool to modulate cerebro–cerebellar circuits, or for stimulation over the cerebral cortex to compensate for decreased cerebellar drive to this region. This article will address these possibilities with a review of the relevant literature covering ataxias and cerebellar cognitive affective disorders, which are characterized by thalamo–cortical disturbances. PMID:24765079

Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia.

PubMed

Lin, Hong; Magrane, Jordi; Clark, Elisia M; Halawani, Sarah M; Warren, Nathan; Rattelle, Amy; Lynch, David R

2017-12-19

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with progressive ataxia that affects both the peripheral and central nervous system (CNS). While later CNS neuropathology involves loss of large principal neurons and glutamatergic and GABAergic synaptic terminals in the cerebellar dentate nucleus, early pathological changes in FRDA cerebellum remain largely uncharacterized. Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model. At asymptomatic ages, VGLUT1 levels in cerebellar homogenates are significantly decreased, whereas VGLUT2 (SLC17A6) levels are significantly increased, in KIKO mice compared with age-matched controls. Additionally, GAD65 (GAD2) levels are significantly increased, while GAD67 (GAD1) levels remain unaltered. This suggests early VGLUT1-specific synaptic input deficits, and dysregulation of VGLUT2 and GAD65 synaptic inputs, in the cerebellum of asymptomatic KIKO mice. Immunohistochemistry and electron microscopy further show specific reductions of VGLUT1-containing PF presynaptic terminals in the cerebellar molecular layer, demonstrating PF synaptic input deficiency in asymptomatic and symptomatic KIKO mice. Moreover, the parvalbumin levels in cerebellar homogenates and Purkinje neurons are significantly reduced, but preserved in other interneurons of the cerebellar molecular layer, suggesting specific parvalbumin dysregulation in Purkinje neurons of these mice. Furthermore, a moderate loss of large principal neurons is observed in the dentate nucleus of asymptomatic KIKO mice, mimicking that of FRDA patients. Our findings thus identify early VGLUT1-specific PF synaptic input deficits and dysregulated cerebellar circuit as potential mediators of cerebellar dysfunction in KIKO mice, reflecting developmental features of FRDA in this mouse model. © 2017. Published by The Company of Biologists Ltd.

Healthy and pathological cerebellar Spiking Neural Networks in Vestibulo-Ocular Reflex.

PubMed

Antonietti, Alberto; Casellato, Claudia; Geminiani, Alice; D'Angelo, Egidio; Pedrocchi, Alessandra

2015-01-01

Since the Marr-Albus model, computational neuroscientists have been developing a variety of models of the cerebellum, with different approaches and features. In this work, we developed and tested realistic artificial Spiking Neural Networks inspired to this brain region. We tested in computational simulations of the Vestibulo-Ocular Reflex protocol three different models: a network equipped with a single plasticity site, at the cortical level; a network equipped with a distributed plasticity, at both cortical and nuclear levels; a network with a pathological plasticity mechanism at the cortical level. We analyzed the learning performance of the three different models, highlighting the behavioral differences among them. We proved that the model with a distributed plasticity produces a faster and more accurate cerebellar response, especially during a second session of acquisition, compared with the single plasticity model. Furthermore, the pathological model shows an impaired learning capability in Vestibulo-Ocular Reflex acquisition, as found in neurophysiological studies. The effect of the different plasticity conditions, which change fast and slow dynamics, memory consolidation and, in general, learning capabilities of the cerebellar network, explains differences in the behavioral outcome.

Story time turbocharger? Child engagement during shared reading and cerebellar activation and connectivity in preschool-age children listening to stories.

PubMed

Hutton, John S; Phelan, Kieran; Horowitz-Kraus, Tzipi; Dudley, Jonathan; Altaye, Mekibib; DeWitt, Thomas; Holland, Scott K

2017-01-01

Expanding behavioral and neurobiological evidence affirms benefits of shared (especially parent-child) reading on cognitive development during early childhood. However, the majority of this evidence involves factors under caregiver control, the influence of those intrinsic to the child, such as interest or engagement in reading, largely indirect or unclear. The cerebellum is increasingly recognized as playing a "smoothing" role in higher-level cognitive processing and learning, via feedback loops with language, limbic and association cortices. We utilized functional MRI to explore the relationship between child engagement during a mother-child reading observation and neural activation and connectivity during a story listening task, in a sample of 4-year old girls. Children exhibiting greater interest and engagement in the narrative showed increased activation in right-sided cerebellar association areas during the task, and greater functional connectivity between this activation cluster and language and executive function areas. Our findings suggest a potential cerebellar "boost" mechanism responsive to child engagement level that may contribute to emergent literacy development during early childhood, and synergy between caregiver and child factors during story sharing.

Neurosurgical treatment of low-grade cerebellar astrocytoma in children and adolescents: a single consecutive institutional series of 100 patients.

PubMed

Due-Tønnessen, Bernt Johan; Lundar, Tryggve; Egge, Arild; Scheie, David

2013-03-01

The objective of this study was to delineate the long-term results of surgical treatment of pediatric low-grade cerebellar astrocytoma. One hundred consecutive children and adolescents (0-19 years old) who underwent primary tumor resection for a low-grade cerebellar astrocytoma during the years 1980-2011 were included in this retrospective study on surgical morbidity, mortality rate, academic achievement, and/or work participation. Gross motor function and activities of daily living were scored according to the Barthel Index. Of the 100 patients, 61 children were in the 1st decade, and 39 were 10-19 years old. The male/female ratio was 1.13:1 (53 males, 47 females). No patients were lost to follow-up. There were no deaths in this series and all 100 patients are currently alive. In 29 patients, the follow-up duration was less than 10 years, in 37 it was between 10 and 19 years, and in 34 it was between 20 and 31 years. The Barthel Index was 100 (normal) in 97 patients, 90 in 2 patients, and 40 in the last patient. A total of 113 tumor resections were performed. Two patients underwent further tumor resection due to MRI-confirmed residual tumor demonstrated on the immediate postoperative MR image (obtained the day after the initial procedure). Furthermore, 9 children underwent repeat tumor resection after MRI-confirmed progressive tumor recurrence up to 10 years after the initial operation. Two of these patients also underwent a third resection, without subsequent radiation therapy, and have experienced 8 and 12 years of tumor-free follow-up thereafter, respectively. A total of 15% of the patients required treatment for persistent hydrocephalus. Low-grade cerebellar astrocytoma is a surgical disease, in need of long-term follow-up, but with excellent long-term results. Nine percent of the children in this study underwent repeated surgery due to progressive tumor recurrence, and 15% were treated for persistent hydrocephalus.

Inositol Hexakisphosphate Kinase-3 Regulates the Morphology and Synapse Formation of Cerebellar Purkinje Cells via Spectrin/Adducin

PubMed Central

Fu, Chenglai; Xu, Jing; Li, Ruo-Jing; Crawford, Joshua A.; Khan, A. Basit; Ma, Ting Martin; Cha, Jiyoung Y.; Snowman, Adele M.; Pletnikov, Mikhail V.

2015-01-01

The inositol hexakisphosphate kinases (IP6Ks) are the principal enzymes that generate inositol pyrophosphates. There are three IP6Ks (IP6K1, 2, and 3). Functions of IP6K1 and IP6K2 have been substantially delineated, but little is known of IP6K3's role in normal physiology, especially in the brain. To elucidate functions of IP6K3, we generated mice with targeted deletion of IP6K3. We demonstrate that IP6K3 is highly concentrated in the brain in cerebellar Purkinje cells. IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin, whose mutual interactions are perturbed in IP6K3-null mutants. Consequently, IP6K3 knock-out cerebella manifest abnormalities in Purkinje cell structure and synapse number, and the mutant mice display deficits in motor learning and coordination. Thus, IP6K3 is a major determinant of cytoskeletal disposition and function of cerebellar Purkinje cells. SIGNIFICANCE STATEMENT We identified and cloned a family of three inositol hexakisphosphate kinases (IP6Ks) that generate the inositol pyrophosphates, most notably 5-diphosphoinositol pentakisphosphate (IP7). Of these, IP6K3 has been least characterized. In the present study we generated IP6K3 knock-out mice and show that IP6K3 is highly expressed in cerebellar Purkinje cells. IP6K3-deleted mice display defects of motor learning and coordination. IP6K3-null mice manifest aberrations of Purkinje cells with a diminished number of synapses. IP6K3 interacts with the cytoskeletal proteins spectrin and adducin whose altered disposition in IP6K3 knock-out mice may mediate phenotypic features of the mutant mice. These findings afford molecular/cytoskeletal mechanisms by which the inositol polyphosphate system impacts brain function. PMID:26245967

Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out.

PubMed

Yokoi, Fumiaki; Dang, Mai Tu; Li, Yuqing

2012-05-01

Early-onset generalized torsion dystonia (dystonia 1) is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most patients have a 3-base pair deletion (ΔGAG) in one allele of DYT1, corresponding to a loss of a glutamic acid residue (ΔE) in the C-terminal region of the protein. Functional alterations in basal ganglia circuits and the cerebellum have been reported in dystonia. Pharmacological manipulations or mutations in genes that result in functional alterations of the cerebellum have been reported to have dystonic symptoms and have been used as phenotypic rodent models. Additionally, structural lesions in the abnormal cerebellar circuits, such as cerebellectomy, have therapeutic effects in these models. A previous study has shown that the Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits in the beam-walking test. Both Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 Purkinje cell-specific knockout (Dyt1 pKO) mice exhibit dendritic alterations of cerebellar Purkinje cells. Here, Dyt1 pKO mice exhibited significantly less slip numbers in the beam-walking test, suggesting better motor performance than control littermates, and normal gait. Furthermore, Dyt1 ΔGAG KI/Dyt1 pKO double mutant mice exhibited significantly lower numbers of slips than Dyt1 ΔGAG heterozygous KI mice, suggesting Purkinje-cell specific knockout of Dyt1 wild-type (WT) allele in Dyt1 ΔGAG heterozygous KI mice rescued the motor deficits. The results suggest that molecular lesions of torsinA in Purkinje cells by gene therapy or intervening in the signaling pathway downstream of the cerebellar Purkinje cells may rescue motor symptoms in dystonia 1. Copyright © 2012 Elsevier B.V. All rights reserved.

Apparent diffusion coefficient mapping in medulloblastoma predicts non-infiltrative surgical planes.

PubMed

Marupudi, Neena I; Altinok, Deniz; Goncalves, Luis; Ham, Steven D; Sood, Sandeep

2016-11-01

An appropriate surgical approach for posterior fossa lesions is to start tumor removal from areas with a defined plane to where tumor is infiltrating the brainstem or peduncles. This surgical approach minimizes risk of damage to eloquent areas. Although magnetic resonance imaging (MRI) is the current standard preoperative imaging obtained for diagnosis and surgical planning of pediatric posterior fossa tumors, it offers limited information on the infiltrative planes between tumor and normal structures in patients with medulloblastomas. Because medulloblastomas demonstrate diffusion restriction on apparent diffusion coefficient map (ADC map) sequences, we investigated the role of ADC map in predicting infiltrative and non-infiltrative planes along the brain stem and/or cerebellar peduncles by medulloblastomas prior to surgery. Thirty-four pediatric patients with pathologically confirmed medulloblastomas underwent surgical resection at our facility from 2004 to 2012. An experienced pediatric neuroradiologist reviewed the brain MRIs/ADC map, assessing the planes between the tumor and cerebellar peduncles/brain stem. An independent evaluator documented surgical findings from operative reports for comparison to the radiographic findings. The radiographic findings were statistically compared to the documented intraoperative findings to determine predictive value of the test in identifying tumor infiltration of the brain stem cerebellar peduncles. Twenty-six patients had preoperative ADC mapping completed and thereby, met inclusion criteria. Mean age at time of surgery was 8.3 ± 4.6 years. Positive predictive value of ADC maps to predict tumor invasion of the brain stem and cerebellar peduncles ranged from 69 to 88 %; negative predictive values ranged from 70 to 89 %. Sensitivity approached 93 % while specificity approached 78 %. ADC maps are valuable in predicting the infiltrative and non-infiltrative planes along the tumor and brain stem interface in medulloblastomas. Inclusion and evaluation of ADC maps in preoperative evaluation can assist in surgical resection planning in patients with medulloblastoma.

Quantitative assessment of cerebral blood flow in genetically confirmed spinocerebellar ataxia type 6.

PubMed

Honjo, Kie; Ohshita, Tomohiko; Kawakami, Hideshi; Naka, Hiromitsu; Imon, Yukari; Maruyama, Hirofumi; Mimori, Yasuyo; Matsumoto, Masayasu

2004-06-01

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia caused by CAG trinucleotide expansion. The characteristics of regional cerebral blood flow (rCBF) in SCA6 patients have not been established, whereas it has been reported that decreased rCBF in the cerebrum seems to be a remote effect of cerebellar impairment in other cerebellar disorders. To clarify the characteristics of rCBF, including cerebro-cerebellar relationship, and its correlation with clinical manifestations in patients with genetically confirmed SCA6 using quantitative assessment of rCBF by brain single-photon emission computed tomography (SPECT). Technetium Tc 99m ethyl cysteinate dimer SPECT study using a Patlak plot. Patients Hiroshima University Hospital, Hiroshima, Japan. Ten patients with SCA6 and 9 healthy controls. Main Outcome Measure The rCBF of the cerebellar vermis, cerebellar hemisphere, and frontal lobes. In SCA6 patients, rCBF was decreased only in the cerebellar vermis and hemisphere compared with healthy controls, and this was inversely correlated with duration of illness. The rCBF in the frontal lobes was slightly correlated with duration of illness without statistical significance. The rCBF in the vermis was inversely correlated with severity of dysarthria, but there was no significant correlation with CAG repeated expansions. Decrease in rCBF was found only in the cerebellum and was associated with duration of illness, dysarthria and ataxia, and cerebellar atrophy. No remote effect of cerebellar hypoperfusion was found in the SCA6 patients.

Humor and laughter in patients with cerebellar degeneration.

PubMed

Frank, B; Propson, B; Göricke, S; Jacobi, H; Wild, B; Timmann, D

2012-06-01

Humor is a complex behavior which includes cognitive, affective and motor responses. Based on observations of affective changes in patients with cerebellar lesions, the cerebellum may support cerebral and brainstem areas involved in understanding and appreciation of humorous stimuli and expression of laughter. The aim of the present study was to examine if humor appreciation, perception of humorous stimuli, and the succeeding facial reaction differ between patients with cerebellar degeneration and healthy controls. Twenty-three adults with pure cerebellar degeneration were compared with 23 age-, gender-, and education-matched healthy control subjects. No significant difference in humor appreciation and perception of humorous stimuli could be found between groups using the 3 Witz-Dimensionen Test, a validated test asking for funniness and aversiveness of jokes and cartoons. Furthermore, while observing jokes, humorous cartoons, and video sketches, facial expressions of subjects were videotaped and afterwards analysed using the Facial Action Coding System. Using depression as a covariate, the number, and to a lesser degree, the duration of facial expressions during laughter were reduced in cerebellar patients compared to healthy controls. In sum, appreciation of humor appears to be largely preserved in patients with chronic cerebellar degeneration. Cerebellar circuits may contribute to the expression of laughter. Findings add to the literature that non-motor disorders in patients with chronic cerebellar disease are generally mild, but do not exclude that more marked disorders may show up in acute cerebellar disease and/or in more specific tests of humor appreciation.

The cerebellum: a new key structure in the navigation system

PubMed Central

Rochefort, Christelle; Lefort, Julie M.; Rondi-Reig, Laure

2013-01-01

Early investigations of cerebellar function focused on motor learning, in particular on eyeblink conditioning and adaptation of the vestibulo-ocular reflex, and led to the general view that cerebellar long-term depression (LTD) at parallel fiber (PF)–Purkinje cell (PC) synapses is the neural correlate of cerebellar motor learning. Thereafter, while the full complexity of cerebellar plasticities was being unraveled, cerebellar involvement in more cognitive tasks—including spatial navigation—was further investigated. However, cerebellar implication in spatial navigation remains a matter of debate because motor deficits frequently associated with cerebellar damage often prevent the dissociation between its role in spatial cognition from its implication in motor function. Here, we review recent findings from behavioral and electrophysiological analyses of cerebellar mutant mouse models, which show that the cerebellum might participate in the construction of hippocampal spatial representation map (i.e., place cells) and thereby in goal-directed navigation. These recent advances in cerebellar research point toward a model in which computation from the cerebellum could be required for spatial representation and would involve the integration of multi-source self-motion information to: (1) transform the reference frame of vestibular signals and (2) distinguish between self- and externally-generated vestibular signals. We eventually present herein anatomical and functional connectivity data supporting a cerebello-hippocampal interaction. Whilst a direct cerebello-hippocampal projection has been suggested, recent investigations rather favor a multi-synaptic pathway involving posterior parietal and retrosplenial cortices, two regions critically involved in spatial navigation. PMID:23493515

Diagnostic Yield and Safety of Cerebellar and Brainstem Parenchymal Biopsy.

PubMed

Tobin, W Oliver; Meyer, Fredric B; Keegan, B Mark

2015-12-01

We aimed to determine the diagnostic yield and safety of posterior fossa parenchymal biopsy. One-hundred-thirty-six patients who underwent 137 posterior fossa (brainstem or cerebellar) parenchymal biopsies at Mayo Clinic (Rochester, Minnesota, USA) between 1996 and 2009 were identified by chart review. Case histories; radiologic, surgical, and pathologic reports; and safety outcomes were assessed. Posterior fossa parenchymal biopsies were performed on 78 male and 58 female patients of median age 47 years (interquartile range 28-61). Preoperative clinical diagnosis in the majority of cases was of a malignant neoplasm. Glial neoplasm (51%) was the most common finding followed by lymphoma (7%) and neurosarcoidosis (7%). Normal tissue or nonspecific changes were observed in 28 cases (20%). Three deaths occurred: 2 at the time of biopsy (1%) and 1 due to underlying disease. All deaths occurred in patients who had a cerebellar biopsy. Transient neurologic deficits occurred in 15 patients (11%): worsening of presenting symptoms (4), cardiac arrhythmia (3), vertigo (2), diplopia (2), ataxia (3), seizure (1), decreased consciousness (1), and limb numbness (3). Sustained neurologic deficits occurred in 3 patients: fourth nerve palsy (1), hemiparesis (1), and facial numbness (1). The diagnostic yield of posterior fossa parenchymal biopsy in Mayo Clinic patients with diverse pathologies was 80%. The complication rate was 11% with the majority being transient, but 2 deaths were attributed to biopsy. Evaluation of the diagnostic yield and complication rate at individual neurosurgical centers is needed to determine generalizability of these results. Copyright © 2015 Elsevier Inc. All rights reserved.

Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age: A case report.

PubMed

Hwang, Yun Tae; Aliaga, Solange Mabel; Arpone, Marta; Francis, David; Li, Xin; Chong, Belinda; Slater, Howard Robert; Rogers, Carolyn; Bretherton, Lesley; Hunter, Matthew; Heard, Robert; Godler, David Eugeny

2016-12-01

CGG repeat expansion >200 within FMR1, termed full mutation (FM), has been associated with promoter methylation, consequent silencing of gene expression and fragile X syndrome (FXS)-a common cause of intellectual disability and co-morbid autism. Unmethylated premutation (55-199 repeats) and FM alleles have been associated with fragile X related tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder. Here we present a 33-year-old male with FXS, with white matter changes and progressive deterioration in gait with cerebellar signs consistent with probable FXTAS; there was no evidence of any other cerebellar pathology. We show that he has tissue mosaicism in blood, saliva, and buccal samples for the size and methylation of his expanded alleles and a de novo, unmethylated microdeletion. This microdeletion involves a ∼80 bp sequence in the FMR1 promoter as well as complete loss of the CGG repeat in a proportion of cells. Despite FMR1 mRNA levels in blood within the normal range, the methylation and CGG sizing results are consistent with the diagnosis of concurrent FXS and probable FXTAS. The demonstrated presence of unmethylated FM alleles would explain the manifestation of milder than expected cognitive and behavioral impairments and early onset of cerebellar ataxia. Our case suggests that individuals with FXS, who manifest symptoms of FXTAS, may benefit from more detailed laboratory testing. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Anti-Hu Antibody Associated Paraneoplastic Cerebellar Degeneration in Head and Neck Cancer.

PubMed

Huemer, Florian; Melchardt, Thomas; Tränkenschuh, Wolfgang; Neureiter, Daniel; Moser, Gerhard; Magnes, Teresa; Weiss, Lukas; Schlattau, Alexander; Hufnagl, Clemens; Ricken, Gerda; Höftberger, Romana; Greil, Richard; Egle, Alexander

2015-12-22

Paraneoplastic syndromes are most frequently associated with small cell lung carcinoma, hematologic and gynecologic malignancies while reports in head and neck cancer are rare. We present the case of a 60-year old female patient who developed paraneoplastic cerebellar degeneration upon locoregional recurrence of a poorly differentiated spindle cell carcinoma of the nasal cavity and paranasal sinus. The neurological symptoms, especially ataxia, stabilized after resection of tumor recurrence and concomitant chemoradiotherapy whereas anti-Hu-antibodies remained positive. Despite the unfavorable prognosis of paraneoplastic neurological disorders associated with onconeural antibodies, the patient achieved long-standing stabilization of neurological symptoms. We report the first patient with anti-Hu antibodies and paraneoplastic cerebellar degeneration associated with a spindle cell carcinoma of the head and neck. We recommend that evaluation of neurological symptoms in patients with this tumor entity should also include paraneoplastic syndromes as differential diagnoses and suggest early extensive screening for onconeural antibodies.

Transient mutism and pathologic laughter in the course of cerebellitis.

PubMed

Dimova, Petia S; Bojinova, Veneta S; Milanov, Ivan G

2009-07-01

The phenomenon of cerebellar mutism with subsequent dysarthria is most commonly described as a part of posterior fossa syndrome after surgery for neoplasms in childhood. Pathologic laughter, on the other hand, is observed primarily in various neurologic diseases in adults. In the present case, a child manifested transient mutism and pathologic laughter during a severe cerebellitis. Headache, vertigo, and impaired consciousness developed during an acute respiratory infection. Thereafter, severe ataxia, mutism, and involuntary laughter became the main clinical features, as well as pyramidal signs. Magnetic resonance imaging revealed cerebellar swelling and T(2) hyperintensity. During steroid treatment, a gradual vanishing of the pathologic laughter and improvement of the motor and speech functions occurred. Recovery was slow and incomplete, and follow-up magnetic resonance imaging showed cerebellar atrophy. This case confirms that mutism is a rare, but possible, manifestation in acute parainfectious cerebellitis and provides a novel example of pathologic laughter during this disease in childhood.

Transcranial cerebellar direct current stimulation and transcutaneous spinal cord direct current stimulation as innovative tools for neuroscientists

PubMed Central

Priori, Alberto; Ciocca, Matteo; Parazzini, Marta; Vergari, Maurizio; Ferrucci, Roberta

2014-01-01

Two neuromodulatory techniques based on applying direct current (DC) non-invasively through the skin, transcranial cerebellar direct current stimulation (tDCS) and transcutaneous spinal DCS, can induce prolonged functional changes consistent with a direct influence on the human cerebellum and spinal cord. In this article we review the major experimental works on cerebellar tDCS and on spinal tDCS, and their preliminary clinical applications. Cerebellar tDCS modulates cerebellar motor cortical inhibition, gait adaptation, motor behaviour, and cognition (learning, language, memory, attention). Spinal tDCS influences the ascending and descending spinal pathways, and spinal reflex excitability. In the anaesthetised mouse, DC stimulation applied under the skin along the entire spinal cord may affect GABAergic and glutamatergic systems. Preliminary clinical studies in patients with cerebellar disorders, and in animals and patients with spinal cord injuries, have reported beneficial effects. Overall the available data show that cerebellar tDCS and spinal tDCS are two novel approaches for inducing prolonged functional changes and neuroplasticity in the human cerebellum and spinal cord, and both are new tools for experimental and clinical neuroscientists. PMID:24907311

Incidence and anatomy of gaze-evoked nystagmus in patients with cerebellar lesions.

PubMed

Baier, Bernhard; Dieterich, Marianne

2011-01-25

Disorders of gaze-holding--organized by a neural network located in the brainstem or the cerebellum--may lead to nystagmus. Based on previous animal studies it was concluded that one key player of the cerebellar part of this gaze-holding neural network is the flocculus. Up to now, in humans there are no systematic studies in patients with cerebellar lesions examining one of the most common forms of nystagmus: gaze-evoked nystagmus (GEN). The aim of our present study was to clarify which cerebellar structures are involved in the generation of GEN. Twenty-one patients with acute unilateral cerebellar stroke were analyzed by means of modern MRI-based voxel-wise lesion-behavior mapping. Our data indicate that cerebellar structures such as the vermal pyramid, the uvula, and the tonsil, but also parts of the biventer lobule and the inferior semilunar lobule, were affected in horizontal GEN. It seems that these structures are part of a gaze-holding neural integrator control system. Furthermore, GEN might present a diagnostic sign pointing toward ipsilesionally located lesions of midline and lower cerebellar structures.

Hypersomnia due to injury of the ventral ascending reticular activating system following cerebellar herniation: A case report.

PubMed

Jang, Sung Ho; Chang, Chul Hoon; Jung, Young Jin; Kwon, Hyeok Gyu

2017-01-01

We report on a patient with hypersomnia who showed injury of the lower ascending reticular activating system (ARAS) following cerebellar herniation due to a cerebellar infarct, detected on diffusion tensor tractography (DTT). A 53-year-old male patient was diagnosed as a left cerebellar infarct, and underwent decompressive suboccipital craniectomy due to brain edema at 2 days after the onset of a cerebellar infarct. Three weeks after onset when the patient started rehabilitation, he showed hypersomnia without impairment of consciousness; he fell asleep most of daytime without external stimulation and showed an abnormal score on the Epworth Sleepiness Scale: 15 (full score: 24, cut off for hypersomnia: 10). On 3-week DTT, narrowing of the upper portion of the lower ventral ARAS between the pontine reticular formation and the hypothalamus was observed on both sides. In addition, partial tearing was observed in the middle portion of the right lower ventral ARAS. In conclusion, we found injury of the lower ventral ARAS in a patient with hypersomnia following cerebellar herniation due to a cerebellar infarct.

Thyroid hormone and cerebellar development.

PubMed

Anderson, Grant W

2008-01-01

Thyroid hormone (TH) plays a key role in mammalian brain development. The developing brain is sensitive to both TH deficiency and excess. Brain development in the absence of TH results in motor skill deficiencies and reduced intellectual development. These functional abnormalities can be attributed to maldevelopment of specific cell types and regions of the brain including the cerebellum. TH functions at the molecular level by regulating gene transcription. Therefore, understanding how TH regulates cerebellar development requires identification of TH-regulated gene targets and the cells expressing these genes. Additionally, the process of TH-dependent regulation of gene expression is tightly controlled by mechanisms including regulation of TH transport, TH metabolism, toxicologic inhibition of TH signaling, and control of the nuclear TH response apparatus. This review will describe the functional, cellular, and molecular effects of TH deficit in the developing cerebellum and emphasize the most recent findings regarding TH action in this important brain region.

Differential Motor and Prefrontal Cerebello-Cortical Network Development: Evidence from Multimodal Neuroimaging

PubMed Central

Bernard, Jessica A.; Orr, Joseph M.; Mittal, Vijay A.

2015-01-01

While our understanding of cerebellar structural development through adolescence and young adulthood has expanded, we still lack knowledge of the developmental patterns of cerebellar networks during this critical portion of the lifespan. Volume in lateral posterior cerebellar regions associated with cognition and the prefrontal cortex develops more slowly, reaching their peak volume in adulthood, particularly as compared to motor Lobule V. We predicted that resting state functional connectivity of the lateral posterior regions would show a similar pattern of development during adolescence and young adulthood. That is, we expected to see changes over time in Crus I and Crus II connectivity with the cortex, but no changes in Lobule V connectivity. Additionally, we were interested in how structural connectivity changes in cerebello-thalamo-cortical white matter are related to changes in functional connectivity. A sample of 23 individuals between 12 and 21 years old underwent neuroimaging scans at baseline and 12-months later. Functional networks of Crus I and Crus II showed significant connectivity decreases over 12-months, though there were no differences in Lobule V. Furthermore, these functional connectivity changes were correlated with increases in white matter structural integrity in the corresponding cerebello-thalamo-cortical white matter tract. We suggest that these functional network changes are due to both later pruning in the prefrontal cortex as well as further development of the white matter tracts linking these brain regions. PMID:26391125

Oligodendrocytes as Regulators of Neuronal Networks during Early Postnatal Development

PubMed Central

Ramos, Maria; Ikrar, Taruna; Kinoshita, Chisato; De Mei, Claudia; Tirotta, Emanuele; Xu, Xiangmin; Borrelli, Emiliana

2011-01-01

Oligodendrocytes are the glial cells responsible for myelin formation. Myelination occurs during the first postnatal weeks and, in rodents, is completed during the third week after birth. Myelin ensures the fast conduction of the nerve impulse; in the adult, myelin proteins have an inhibitory role on axon growth and regeneration after injury. During brain development, oligodendrocytes precursors originating in multiple locations along the antero-posterior axis actively proliferate and migrate to colonize the whole brain. Whether the initial interactions between oligodendrocytes and neurons might play a functional role before the onset of myelination is still not completely elucidated. In this article, we addressed this question by transgenically targeted ablation of proliferating oligodendrocytes during cerebellum development. Interestingly, we show that depletion of oligodendrocytes at postnatal day 1 (P1) profoundly affects the establishment of cerebellar circuitries. We observed an impressive deregulation in the expression of molecules involved in axon growth, guidance and synaptic plasticity. These effects were accompanied by an outstanding increase of neurofilament staining observed 4 hours after the beginning of the ablation protocol, likely dependent from sprouting of cerebellar fibers. Oligodendrocyte ablation modifies localization and function of ionotropic glutamate receptors in Purkinje neurons. These results show a novel oligodendrocyte function expressed during early postnatal brain development, where these cells participate in the formation of cerebellar circuitries, and influence its development. PMID:21589880

Dynamic balance in children with attention-deficit hyperactivity disorder and its relationship with cognitive functions and cerebellum.

PubMed

Goetz, Michal; Schwabova, Jaroslava Paulasova; Hlavka, Zdenek; Ptacek, Radek; Surman, Craig Bh

2017-01-01

Attention-deficit hyperactivity disorder (ADHD) is linked to the presence of motor deficiencies, including balance deficits. The cerebellum serves as an integrative structure for balance control and is also involved in cognition, including timing and anticipatory regulation. Cerebellar development may be delayed in children and adolescents with ADHD, and inconsistent reaction time is commonly seen in ADHD. We hypothesized that dynamic balance deficits would be present in children with ADHD and they would correlate with attention and cerebellar functions. Sixty-two children with ADHD and no other neurological conditions and 62 typically developing (TD) children were examined with five trials of the Phyaction Balance Board, an electronic balancing platform. Cerebellar clinical symptoms were evaluated using an international ataxia rating scale. Conners' Continuous Performance Test was used to evaluate patterns of reaction. Children with ADHD had poorer performance on balancing tasks, compared to TD children ( P <0.001). They exhibited significantly greater sway amplitudes than TD children ( P <0.001) in all of the five balancing trials. The effect size of the difference between the groups increased continuously from the first to the last trial. Balance score in both groups was related to the variation in the reaction time, including reaction time standard error ( r =0.25; P =0.0409, respectively, r =0.31; P =0.0131) and Variability of Standard Error ( r =0.28; P =0.0252, respectively, r =0.41; P <0.001). The burden of cerebellar symptoms was strongly related to balance performance in both groups ( r =0.50, P <0.001; r =0.49, P =0.001). This study showed that ADHD may be associated with poor dynamic balance control. Furthermore, we showed that maintaining balance correlates with neuropsychological measures of consistency of reaction time. Balance deficits and impaired cognitive functioning could reflect a common cerebellar dysfunction in ADHD children.

Ethanol impairs activation of retinoic acid receptors in cerebellar granule cells in a rodent model of fetal alcohol spectrum disorders.

PubMed

Kumar, Ambrish; Singh, Chandra K; DiPette, Donald D; Singh, Ugra S

2010-05-01

Ethanol is the main addictive and neurotoxic constituent of alcohol. Ethanol exposure during embryonic development causes dysfunction of the central nervous system (CNS) and leads to fetal alcohol spectrum disorders. The cerebellum is one of the CNS regions that are particularly vulnerable to ethanol toxic effects. Retinoic acid (RA) is a physiologically active metabolite of vitamin A that is locally synthesized in the cerebellum. Studies have shown that RA is required for neuronal development, but it remains unknown if ethanol impairs RA signaling and thus induces neuronal malformations. In this study, we tested the hypothesis that ethanol impairs the expression and activation of RA receptors in cerebellum and in cerebellar granule cells. The cerebellum of ethanol unexposed and exposed pups was used to study the expression of retinoic acid receptors (RARs or RXRs) by immunohistochemistry and by Western blot analysis. We also studied the effect of ethanol on expression of RA receptors in the cerebellar granule cells. Activation of RA receptors (DNA-binding activities) in response to high-dose ethanol was determined by electrophoretic mobility shift and supershift assays. Findings from these studies demonstrated that ethanol exposure reduced the expression of RARalpha/gamma while it increased the expression of RXRalpha/gamma in the cerebellum and in cerebellar granule neurons. Immuno-histological studies further strengthened the expression pattern of RA receptors in response to ethanol. The DNA-binding activity of RARs was reduced, while DNA-binding activity of RXRs was increased in response to ethanol exposure. For the first time, our studies have demonstrated that high-dose ethanol affects the expression and activation of RA receptors, which could impair the signaling events and induce harmful effects on the survival and differentiation of cerebellar granule cells. Taken together, these findings could provide insight into the treatment options for brain defects caused by excessive ethanol exposure, such as in Fetal Alcohol Spectrum Disorders.

Dynamic balance in children with attention-deficit hyperactivity disorder and its relationship with cognitive functions and cerebellum

PubMed Central

Goetz, Michal; Schwabova, Jaroslava Paulasova; Hlavka, Zdenek; Ptacek, Radek; Surman, Craig BH

2017-01-01

Background Attention-deficit hyperactivity disorder (ADHD) is linked to the presence of motor deficiencies, including balance deficits. The cerebellum serves as an integrative structure for balance control and is also involved in cognition, including timing and anticipatory regulation. Cerebellar development may be delayed in children and adolescents with ADHD, and inconsistent reaction time is commonly seen in ADHD. We hypothesized that dynamic balance deficits would be present in children with ADHD and they would correlate with attention and cerebellar functions. Methods Sixty-two children with ADHD and no other neurological conditions and 62 typically developing (TD) children were examined with five trials of the Phyaction Balance Board, an electronic balancing platform. Cerebellar clinical symptoms were evaluated using an international ataxia rating scale. Conners’ Continuous Performance Test was used to evaluate patterns of reaction. Results Children with ADHD had poorer performance on balancing tasks, compared to TD children (P<0.001). They exhibited significantly greater sway amplitudes than TD children (P<0.001) in all of the five balancing trials. The effect size of the difference between the groups increased continuously from the first to the last trial. Balance score in both groups was related to the variation in the reaction time, including reaction time standard error (r =0.25; P=0.0409, respectively, r =0.31; P=0.0131) and Variability of Standard Error (r =0.28; P=0.0252, respectively, r =0.41; P<0.001). The burden of cerebellar symptoms was strongly related to balance performance in both groups (r =0.50, P<0.001; r =0.49, P=0.001). Conclusion This study showed that ADHD may be associated with poor dynamic balance control. Furthermore, we showed that maintaining balance correlates with neuropsychological measures of consistency of reaction time. Balance deficits and impaired cognitive functioning could reflect a common cerebellar dysfunction in ADHD children. PMID:28356743

A left cerebellar pathway mediates language in prematurely-born young adults

PubMed Central

Constable, R. Todd; Vohr, Betty R.; Scheinost, Dustin; Benjamin, Jennifer R.; Fulbright, Robert K.; Lacadie, Cheryl; Schneider, Karen C.; Katz, Karol H.; Zhang, Heping; Papademetris, Xenophon; Ment, Laura R.

2012-01-01

Preterm (PT) subjects are at risk for developmental delay, and task-based studies suggest that developmental disorders may be due to alterations in neural connectivity. Since emerging data imply the importance of right cerebellar function for language acquisition in typical development, we hypothesized that PT subjects would have alternate areas of cerebellar connectivity, and that these areas would be responsible for differences in cognitive outcomes between PT subjects and term controls at age 20 years. Nineteen PT and 19 term control young adults were prospectively studied using resting-state functional MRI (fMRI) to create voxel-based contrast maps reflecting the functional connectivity of each tissue element in the grey matter through analysis of the intrinsic connectivity contrast degree (ICC-d). Left cerebellar ICC-d differences between subjects identified a region of interest that was used for subsequent seed-based connectivity analyses. Subjects underwent standardized language testing, and correlations with cognitive outcomes were assessed. There were no differences in gender, hand preference, maternal education, age at study, or Peabody Picture Vocabulary Test (PPVT) scores. Functional connectivity (FcMRI) demonstrated increased tissue connectivity in the biventer, simple and quadrangular lobules of the L cerebellum (p<0.05) in PTs compared to term controls; seed-based analyses from these regions demonstrated alterations in connectivity from L cerebellum to both R and L inferior frontal gyri (IFG) in PTs compared to term controls. For PTs but not term controls, there were significant positive correlations between these connections and PPVT scores (R IFG: r=0.555, p=0.01; L IFG: r=0.454, p=0.05), as well as Verbal Comprehension Index (VCI) scores (R IFG: r=0.472, p=0.04). These data suggest the presence of a left cerebellar language circuit in PT subjects at young adulthood. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain. PMID:22982585

Proximal dentatothalamocortical tract involvement in posterior fossa syndrome

PubMed Central

Phillips, Nicholas S.; Laningham, Fred H.; Patay, Zoltan; Gajjar, Amar; Wallace, Dana; Boop, Frederick; Sanford, Robert; Ness, Kirsten K.; Ogg, Robert J.

2009-01-01

Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, –71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates –24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome. PMID:19805491

Post-operative paediatric cerebellar mutism syndrome: time to move beyond structural MRI.

PubMed

Toescu, Sebastian M; Hettige, Samantha; Phipps, Kim; Smith, R J Paul; Haffenden, Verity; Clark, Chris; Hayward, Richard; Mankad, Kshitij; Aquilina, Kristian

2018-06-20

To determine the value of structural magnetic resonance imaging (MRI) in predicting post-operative paediatric cerebellar mutism syndrome (pCMS) in children undergoing surgical treatment for medulloblastoma. Retrospective cohort study design. Electronic/paper case note review of all children with medulloblastoma presenting to Great Ormond Street Hospital between 2003 and 2013. The diagnosis of pCMS was established through a scoring system incorporating mutism, ataxia, behavioural disturbance and cranial nerve deficits. MRI scans performed at three time points were assessed by neuroradiologists blinded to the diagnosis of pCMS. Of 56 children included, 12 (21.4%) developed pCMS as judged by a core symptom of mutism. pCMS was more common in those aged 5 or younger. There was no statistically significant difference in pre-operative distortion or signal change of the dentate or red nuclei or superior cerebellar peduncles (SCPs) between those who did and did not develop pCMS. In both early (median 5 days) and late (median 31 months) post-operative scans, T2-weighted signal change in SCPs was more common in the pCMS group (p = 0.040 and 0.046 respectively). Late scans also showed statistically significant signal change in the dentate nuclei (p = 0.024). The development of pCMS could not be linked to any observable changes on pre-operative structural MRI scans. Post-operative T2-weighted signal change in the SCPs and dentate nuclei underlines the role of cerebellar efferent injury in pCMS. Further research using advanced quantitative MRI sequences is warranted given the inability of conventional pre-surgical MRI to predict pCMS.

Chronic pharmacological blockade of the Na+ /Ca2+ exchanger modulates the growth and development of the Purkinje cell dendritic arbor in mouse cerebellar slice cultures.

PubMed

Sherkhane, Pradeep; Kapfhammer, Josef P

2017-09-01

The Na + /Ca 2+ exchanger (NCX) is a bidirectional plasma membrane antiporter involved in Ca 2+ homeostasis in eukaryotes. NCX has three isoforms, NCX1-3, and all of them are expressed in the cerebellum. Immunostaining on cerebellar slice cultures indicates that NCX is widely expressed in the cerebellum, including expression in Purkinje cells. The pharmacological blockade of the forward mode of NCX (Ca 2+ efflux mode) by bepridil moderately inhibited growth and development of Purkinje cell dendritic arbor in cerebellar slice cultures. However, the blockade of the reverse mode (Ca 2+ influx mode) by KB-R7943 severely reduced the dendritic arbor and induced a morphological change with thickened distal dendrites. The effect of KB-R7943 on dendritic growth was unrelated to the activity of voltage-gated calcium channels and was also apparent in the absence of bioelectrical activity indicating that it was mediated by NCX expressed in Purkinje cells. We have used additional NCX inhibitors including CB-DMB, ORM-10103, SEA0400, YM-244769, and SN-6 which have higher specificity for NCX isoforms and target either the forward, reverse, or both modes. These inhibitors caused a strong dendritic reduction similar to that seen with KB-R7943, but did not elicit thickening of distal dendrites. Our findings indicate that disturbance of the NCX-dependent calcium transport in Purkinje cells induces a reduction of dendritic arbor, which is presumably caused by changes in the calcium handling, and underline the importance of the calcium equilibrium for the dendritic development in cerebellar Purkinje cells. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The improvement of movement and speech during rapid eye movement sleep behaviour disorder in multiple system atrophy.

PubMed

De Cock, Valérie Cochen; Debs, Rachel; Oudiette, Delphine; Leu, Smaranda; Radji, Fatai; Tiberge, Michel; Yu, Huan; Bayard, Sophie; Roze, Emmanuel; Vidailhet, Marie; Dauvilliers, Yves; Rascol, Olivier; Arnulf, Isabelle

2011-03-01

Multiple system atrophy is an atypical parkinsonism characterized by severe motor disabilities that are poorly levodopa responsive. Most patients develop rapid eye movement sleep behaviour disorder. Because parkinsonism is absent during rapid eye movement sleep behaviour disorder in patients with Parkinson's disease, we studied the movements of patients with multiple system atrophy during rapid eye movement sleep. Forty-nine non-demented patients with multiple system atrophy and 49 patients with idiopathic Parkinson's disease were interviewed along with their 98 bed partners using a structured questionnaire. They rated the quality of movements, vocal and facial expressions during rapid eye movement sleep behaviour disorder as better than, equal to or worse than the same activities in an awake state. Sleep and movements were monitored using video-polysomnography in 22/49 patients with multiple system atrophy and in 19/49 patients with Parkinson's disease. These recordings were analysed for the presence of parkinsonism and cerebellar syndrome during rapid eye movement sleep movements. Clinical rapid eye movement sleep behaviour disorder was observed in 43/49 (88%) patients with multiple system atrophy. Reports from the 31/43 bed partners who were able to evaluate movements during sleep indicate that 81% of the patients showed some form of improvement during rapid eye movement sleep behaviour disorder. These included improved movement (73% of patients: faster, 67%; stronger, 52%; and smoother, 26%), improved speech (59% of patients: louder, 55%; more intelligible, 17%; and better articulated, 36%) and normalized facial expression (50% of patients). The rate of improvement was higher in Parkinson's disease than in multiple system atrophy, but no further difference was observed between the two forms of multiple system atrophy (predominant parkinsonism versus cerebellar syndrome). Video-monitored movements during rapid eye movement sleep in patients with multiple system atrophy revealed more expressive faces, and movements that were faster and more ample in comparison with facial expression and movements during wakefulness. These movements were still somewhat jerky but lacked any visible parkinsonism. Cerebellar signs were not assessable. We conclude that parkinsonism also disappears during rapid eye movement sleep behaviour disorder in patients with multiple system atrophy, but this improvement is not due to enhanced dopamine transmission because these patients are not levodopa-sensitive. These data suggest that these movements are not influenced by extrapyramidal regions; however, the influence of abnormal cerebellar control remains unclear. The transient disappearance of parkinsonism here is all the more surprising since no treatment (even dopaminergic) provides a real benefit in this disabling disease.

Subgroup Specific Alternative Splicing in Medulloblastoma

PubMed Central

Kloosterhof, Nanne K; Northcott, Paul A; Yu, Emily PY; Shih, David; Peacock, John; Grajkowska, Wieslawa; van Meter, Timothy; Eberhart, Charles G; Pfister, Stefan; Marra, Marco A; Weiss, William A; Scherer, Stephen W; Rutka, James T; French, Pim J; Taylor, Michael D

2014-01-01

Medulloblastoma is comprised of four distinct molecular variants: WNT, SHH, Group 3, and Group 4. We analyzed alternative splicing usage in 14 normal cerebellar samples and 103 medulloblastomas of known subgroup. Medulloblastoma samples have a statistically significant increase in alternative splicing as compared to normal fetal cerebella (2.3-times; P<6.47E-8). Splicing patterns are distinct and specific between molecular subgroups. Unsupervised hierarchical clustering of alternative splicing events accurately assigns medulloblastomas to their correct subgroup. Subgroup-specific splicing and alternative promoter usage was most prevalent in Group 3 (19.4%) and SHH (16.2%) medulloblastomas, while observed less frequently in WNT (3.2%), and Group 4 (9.3%) tumors. Functional annotation of alternatively spliced genes reveals over-representation of genes important for neuronal development. Alternative splicing events in medulloblastoma may be regulated in part by the correlative expression of antisense transcripts, suggesting a possible mechanism affecting subgroup specific alternative splicing. Our results identify additional candidate markers for medulloblastoma subgroup affiliation, further support the existence of distinct subgroups of the disease, and demonstrate an additional level of transcriptional heterogeneity between medulloblastoma subgroups. PMID:22358458

Magnetic resonance imaging depiction of acquired Dyke-Davidoff-Masson syndrome with crossed cerebro-cerebellar diaschisis: Report of two cases.

PubMed

Gupta, Ranjana; Joshi, Sandeep; Mittal, Amit; Luthra, Ishita; Mittal, Puneet; Verma, Vibha

2015-01-01

Acquired Dyke-Davidoff-Masson syndrome, also known as hemispheric atrophy, is characterized by loss of volume of one cerebral hemisphere from an insult in early life. Crossed cerebellar diaschisis refers to dysfunction/atrophy of cerebellar hemisphere which is secondary to contralateral supratentorial insult. We describe magnetic resonance imaging findings in two cases of acquired Dyke-Davidoff-Masson syndrome with crossed cerebro-cerebellar diaschisis.

Dose-related cerebellar abnormality in rats with prenatal exposure to X-irradiation by magnetic resonance imaging volumetric analysis.

PubMed

Sawada, Kazuhiko; Saito, Shigeyoshi; Horiuchi-Hirose, Miwa; Mori, Yuki; Yoshioka, Yoshichika; Murase, Kenya

2013-09-01

Cerebellar abnormalities in 4-week-old rats with a single whole body X-irradiation at a dose of 0.5, 1.0, or 1.5 Gy on embryonic day (ED) 15 were examined by magnetic resonance imaging (MRI) volumetry. A 3D T2 W-MRI anatomical sequence with high-spatial resolution at 11.7-tesla was acquired from the fixed rat heads. By MRI volumetry, whole cerebellar volumes decreased dose-dependently. Multiple linear regression analysis revealed that the cortical volume (standardized β=0.901; P<0.001) was a major explanatory variable for the whole cerebellar volume, whereas both volumes of the white matter and deep cerebellar nuclei also decreased depending on the X-irradiation dose. The present MRI volumetric analysis revealed a dose-related cerebellar cortical hypoplasia by prenatal exposure to X-irradiation on E15. © 2013 The Authors. Congenital Anomalies © 2013 Japanese Teratology Society.

Gaze‐evoked nystagmus induced by alcohol intoxication

PubMed Central

Tarnutzer, Alexander A.; Straumann, Dominik; Ramat, Stefano; Bertolini, Giovanni

2017-01-01

Key points The cerebellum is the core structure controlling gaze stability. Chronic cerebellar diseases and acute alcohol intoxication affect cerebellar function, inducing, among others, gaze instability as gaze‐evoked nystagmus.Gaze‐evoked nystagmus is characterized by increased centripetal eye‐drift. It is used as an important diagnostic sign for patients with cerebellar degeneration and to assess the ‘driving while intoxicated’ condition.We quantified the effect of alcohol on gaze‐holding using an approach allowing, for the first time, the comparison of deficits induced by alcohol intoxication and cerebellar degeneration.Our results showed that alcohol intoxication induces a two‐fold increase of centripetal eye‐drift.We establish analysis techniques for using controlled alcohol intake as a model to support the study of cerebellar deficits.The observed similarity between the effect of alcohol and the clinical signs observed in cerebellar patients suggests a possible pathomechanism for gaze‐holding deficits. Abstract Gaze‐evoked nystagmus (GEN) is an ocular‐motor finding commonly observed in cerebellar disease, characterized by increased centripetal eye‐drift with centrifugal correcting saccades at eccentric gaze. With cerebellar degeneration being a rare and clinically heterogeneous disease, data from patients are limited. We hypothesized that a transient inhibition of cerebellar function by defined amounts of alcohol may provide a suitable model to study gaze‐holding deficits in cerebellar disease. We recorded gaze‐holding at varying horizontal eye positions in 15 healthy participants before and 30 min after alcohol intake required to reach 0.6‰ blood alcohol content (BAC). Changes in ocular‐motor behaviour were quantified measuring eye‐drift velocity as a continuous function of gaze eccentricity over a large range (±40 deg) of horizontal gaze angles and characterized using a two‐parameter tangent model. The effect of alcohol on gaze stability was assessed analysing: (1) overall effects on the gaze‐holding system, (2) specific effects on each eye and (3) differences between gaze angles in the temporal and nasal hemifields. For all subjects, alcohol consumption induced gaze instability, causing a two‐fold increase [2.21 (0.55), median (median absolute deviation); P = 0.002] of eye‐drift velocity at all eccentricities. Results were confirmed analysing each eye and hemifield independently. The alcohol‐induced transient global deficit in gaze‐holding matched the pattern previously described in patients with late‐onset cerebellar degeneration. Controlled intake of alcohol seems a suitable disease model to study cerebellar GEN. With alcohol resulting in global cerebellar hypofunction, we hypothesize that patients matching the gaze‐holding behaviour observed here suffered from diffuse deficits in the gaze‐holding system as well. PMID:27981586

Recommendations for the management of cerebral and cerebellar infarction with swelling: a statement for healthcare professionals from the American Heart Association/American Stroke Association.

PubMed

Wijdicks, Eelco F M; Sheth, Kevin N; Carter, Bob S; Greer, David M; Kasner, Scott E; Kimberly, W Taylor; Schwab, Stefan; Smith, Eric E; Tamargo, Rafael J; Wintermark, Max

2014-04-01

There are uncertainties surrounding the optimal management of patients with brain swelling after an ischemic stroke. Guidelines are needed on how to manage this major complication, how to provide the best comprehensive neurological and medical care, and how to best inform families facing complex decisions on surgical intervention in deteriorating patients. This scientific statement addresses the early approach to the patient with a swollen ischemic stroke in a cerebral or cerebellar hemisphere. The writing group used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge. The panel reviewed the most relevant articles on adults through computerized searches of the medical literature using MEDLINE, EMBASE, and Web of Science through March 2013. The evidence is organized within the context of the American Heart Association framework and is classified according to the joint American Heart Association/American College of Cardiology Foundation and supplementary American Heart Association Stroke Council methods of classifying the level of certainty and the class and level of evidence. The document underwent extensive American Heart Association internal peer review. Clinical criteria are available for hemispheric (involving the entire middle cerebral artery territory or more) and cerebellar (involving the posterior inferior cerebellar artery or superior cerebellar artery) swelling caused by ischemic infarction. Clinical signs that signify deterioration in swollen supratentorial hemispheric ischemic stroke include new or further impairment of consciousness, cerebral ptosis, and changes in pupillary size. In swollen cerebellar infarction, a decrease in level of consciousness occurs as a result of brainstem compression and therefore may include early loss of corneal reflexes and the development of miosis. Standardized definitions should be established to facilitate multicenter and population-based studies of incidence, prevalence, risk factors, and outcomes. Identification of patients at high risk for brain swelling should include clinical and neuroimaging data. If a full resuscitative status is warranted in a patient with a large territorial stroke, admission to a unit with neurological monitoring capabilities is needed. These patients are best admitted to intensive care or stroke units attended by skilled and experienced physicians such as neurointensivists or vascular neurologists. Complex medical care includes airway management and mechanical ventilation, blood pressure control, fluid management, and glucose and temperature control. In swollen supratentorial hemispheric ischemic stroke, routine intracranial pressure monitoring or cerebrospinal fluid diversion is not indicated, but decompressive craniectomy with dural expansion should be considered in patients who continue to deteriorate neurologically. There is uncertainty about the efficacy of decompressive craniectomy in patients ≥60 years of age. In swollen cerebellar stroke, suboccipital craniectomy with dural expansion should be performed in patients who deteriorate neurologically. Ventriculostomy to relieve obstructive hydrocephalus after a cerebellar infarct should be accompanied by decompressive suboccipital craniectomy to avoid deterioration from upward cerebellar displacement. In swollen hemispheric supratentorial infarcts, outcome can be satisfactory, but one should anticipate that one third of patients will be severely disabled and fully dependent on care even after decompressive craniectomy. Surgery after a cerebellar infarct leads to acceptable functional outcome in most patients. Swollen cerebral and cerebellar infarcts are critical conditions that warrant immediate, specialized neurointensive care and often neurosurgical intervention. Decompressive craniectomy is a necessary option in many patients. Selected patients may benefit greatly from such an approach, and although disabled, they may be functionally independent.

Anterior spinal and bulbar artery supply to the posterior inferior cerebellar artery revealed by a ruptured aneurysm: case report.

PubMed

Gabrieli, Joseph; Sourour, Nader-Antoine; Chauvet, Dorian; Di Maria, Federico; Chiras, Jacques; Clarençon, Frédéric

2017-02-01

The posterior inferior cerebellar artery (PICA) is a vessel located between the intra- and extracranial circulation. The artery is characterized by a complex embryological development and numerous anatomical variants. The authors present a case of the PICA supplied by both a hypertrophic anterior spinal artery and a hypoplastic bulbar artery. This unusual arrangement somehow completes the list of previously published variants, and the spontaneous rupture of a related aneurysm confirmed the fragility of this network. The authors discuss anatomical and treatment considerations.

Neurodevelopmental malformations of the cerebellar vermis in genetically engineered rats

EPA Science Inventory

The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformati...

Automated MRI Cerebellar Size Measurements Using Active Appearance Modeling

PubMed Central

Price, Mathew; Cardenas, Valerie A.; Fein, George

2014-01-01

Although the human cerebellum has been increasingly identified as an important hub that shows potential for helping in the diagnosis of a large spectrum of disorders, such as alcoholism, autism, and fetal alcohol spectrum disorder, the high costs associated with manual segmentation, and low availability of reliable automated cerebellar segmentation tools, has resulted in a limited focus on cerebellar measurement in human neuroimaging studies. We present here the CATK (Cerebellar Analysis Toolkit), which is based on the Bayesian framework implemented in FMRIB’s FIRST. This approach involves training Active Appearance Models (AAM) using hand-delineated examples. CATK can currently delineate the cerebellar hemispheres and three vermal groups (lobules I–V, VI–VII, and VIII–X). Linear registration with the low-resolution MNI152 template is used to provide initial alignment, and Point Distribution Models (PDM) are parameterized using stellar sampling. The Bayesian approach models the relationship between shape and texture through computation of conditionals in the training set. Our method varies from the FIRST framework in that initial fitting is driven by 1D intensity profile matching, and the conditional likelihood function is subsequently used to refine fitting. The method was developed using T1-weighted images from 63 subjects that were imaged and manually labeled: 43 subjects were scanned once and were used for training models, and 20 subjects were imaged twice (with manual labeling applied to both runs) and used to assess reliability and validity. Intraclass correlation analysis shows that CATK is highly reliable (average test-retest ICCs of 0.96), and offers excellent agreement with the gold standard (average validity ICC of 0.87 against manual labels). Comparisons against an alternative atlas-based approach, SUIT (Spatially Unbiased Infratentorial Template), that registers images with a high-resolution template of the cerebellum, show that our AAM approach offers superior reliability and validity. Extensions of CATK to cerebellar hemisphere parcels is envisioned. PMID:25192657

The Sleeping Cerebellum.

PubMed

Canto, Cathrin B; Onuki, Yoshiyuki; Bruinsma, Bastiaan; van der Werf, Ysbrand D; De Zeeuw, Chris I

2017-05-01

We sleep almost one-third of our lives and sleep plays an important role in critical brain functions like memory formation and consolidation. The role of sleep in cerebellar processing, however, constitutes an enigma in the field of neuroscience; we know little about cerebellar sleep-physiology, cerebro-cerebellar interactions during sleep, or the contributions of sleep to cerebellum-dependent memory consolidation. Likewise, we do not understand why cerebellar malfunction can lead to changes in the sleep-wake cycle and sleep disorders. In this review, we evaluate how sleep and cerebellar processing may influence one another and highlight which scientific routes and technical approaches could be taken to uncover the mechanisms underlying these interactions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Oculomotor Deficits in Aryl Hydrocarbon Receptor Null Mouse

PubMed Central

Chevallier, Aline; Mialot, Antoine; Petit, Jean-Maurice; Fernandez-Salguero, Pedro; Barouki, Robert

2013-01-01

The Aryl hydrocarbon Receptor or AhR, a ligand-activated transcription factor, is known to mediate the toxic and carcinogenic effects of various environmental pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). Recent studies in Caenorhabditis elegans and Drosophila melanogaster show that the orthologs of the AhR are expressed exclusively in certain types of neurons and are implicated in the development and the homeostasis of the central nervous system. While physiological roles of the AhR were demonstrated in the mammalian heart, liver and gametogenesis, its ontogenic expression and putative neural functions remain elusive. Here, we report that the constitutive absence of the AhR in adult mice (AhR−/−) leads to abnormal eye movements in the form of a spontaneous pendular horizontal nystagmus. To determine if the nystagmus is of vestibular, visual, or cerebellar origin, gaze stabilizing reflexes, namely vestibulo-ocular and optokinetic reflexes (VOR and OKR), were investigated. The OKR is less effective in the AhR−/− mice suggesting a deficit in the visuo-motor circuitry, while the VOR is mildly affected. Furthermore, the AhR is expressedin the retinal ganglion cells during the development, however electroretinograms revealed no impairment of retinal cell function. The structure of the cerebellum of the AhR−/− mice is normal which is compatible with the preserved VOR adaptation, a plastic process dependent on cerebellar integrity. Finally, intoxication with TCDD of control adults did not lead to any abnormality of the oculomotor control. These results demonstrate that the absence of the AhR leads to acquired central nervous system deficits in the adults. Given the many common features between both AhR mouse and human infantile nystagmus syndromes, the AhR−/− mice might give insights into the developmental mechanisms which lead to congenital eye disorders. PMID:23301081

Epidermal growth factor receptor expression is related to post-mitotic events in cerebellar development: regulation by thyroid hormone.

PubMed

Carrasco, Emilce; Blum, Mariann; Weickert, Cynthia Shannon; Casper, Diana

2003-01-10

It has been established that thyroid hormone and neurotrophic factors both orchestrate developmental events in the brain. However, it is not clear how these two influences are related. In this study, we investigated the effects of thyroid hormone on cerebellar development and the coincident expression of transforming growth factor-alpha (TGF-alpha), a ligand in the epidermal growth factor (EGF) family, and the epidermal growth factor receptor (EGFR). Profiles of thyroid hormone expression were measured in postnatal animals and were found to peak at postnatal day 15 (P15). These levels dropped below detectable levels when mice were made hypothyroid with propylthiouracil (PTU). TGF-alpha and EGFR expression, as determined by RNAse protection assay, was maximal at P6 in normal animals, but remained low in hypothyroid animals, suggesting that thyroid hormone was responsible for their induction. In situ hybridization and immunohistochemical analysis of EGFR expression revealed that this receptor was present on granule cells within the inner zone of the external granule cell layer (EGL), suggesting that EGFR-ligands were not inducing granule cell proliferation. The persistence of EGFR expression on migrating granule cells and subsequent down-regulation of expression in the internal granule cell layer (IGL) implicates a role for EGFR-ligands in differentiation and/or migration. In hypothyroid animals, we observed a delayed progression of granule cell migration, consistent with the persistence of EGFR labeling in the EGL, and in the 'pile-up' of labeled cells at the interface between the molecular layer and the Purkinje cell layer. Taken together, these results implicate thyroid hormone in the coordinated expression of TGF-alpha and EGFR, which are positioned to play a role in post-mitotic developmental events in the cerebellum.

Modelling the electric field and the current density generated by cerebellar transcranial DC stimulation in humans.

PubMed

Parazzini, Marta; Rossi, Elena; Ferrucci, Roberta; Liorni, Ilaria; Priori, Alberto; Ravazzani, Paolo

2014-03-01

Transcranial Direct Current Stimulation (tDCS) over the cerebellum (or cerebellar tDCS) modulates working memory, changes cerebello-brain interaction, and affects locomotion in humans. Also, the use of tDCS has been proposed for the treatment of disorders characterized by cerebellar dysfunction. Nonetheless, the electric field (E) and current density (J) spatial distributions generated by cerebellar tDCS are unknown. This work aimed to estimate E and J distributions during cerebellar tDCS. Computational electromagnetics techniques were applied in three human realistic models of different ages and gender. The stronger E and J occurred mainly in the cerebellar cortex, with some spread (up to 4%) toward the occipital cortex. Also, changes by ±1cm in the position of the active electrode resulted in a small effect (up to 4%) in the E and J spatial distribution in the cerebellum. Finally, the E and J spreads to the brainstem and the heart were negligible, thus further supporting the safety of this technique. Despite inter-individual differences, our modeling study confirms that the cerebellum is the structure mainly involved by cerebellar tDCS. Modeling approach reveals that during cerebellar tDCS the current spread to other structures outside the cerebellum is unlike to produce functional effects. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Real-time cerebellar neuroprosthetic system based on a spiking neural network model of motor learning.

PubMed

Xu, Tao; Xiao, Na; Zhai, Xiaolong; Kwan Chan, Pak; Tin, Chung

2018-02-01

Damage to the brain, as a result of various medical conditions, impacts the everyday life of patients and there is still no complete cure to neurological disorders. Neuroprostheses that can functionally replace the damaged neural circuit have recently emerged as a possible solution to these problems. Here we describe the development of a real-time cerebellar neuroprosthetic system to substitute neural function in cerebellar circuitry for learning delay eyeblink conditioning (DEC). The system was empowered by a biologically realistic spiking neural network (SNN) model of the cerebellar neural circuit, which considers the neuronal population and anatomical connectivity of the network. The model simulated synaptic plasticity critical for learning DEC. This SNN model was carefully implemented on a field programmable gate array (FPGA) platform for real-time simulation. This hardware system was interfaced in in vivo experiments with anesthetized rats and it used neural spikes recorded online from the animal to learn and trigger conditioned eyeblink in the animal during training. This rat-FPGA hybrid system was able to process neuronal spikes in real-time with an embedded cerebellum model of ~10 000 neurons and reproduce learning of DEC with different inter-stimulus intervals. Our results validated that the system performance is physiologically relevant at both the neural (firing pattern) and behavioral (eyeblink pattern) levels. This integrated system provides the sufficient computation power for mimicking the cerebellar circuit in real-time. The system interacts with the biological system naturally at the spike level and can be generalized for including other neural components (neuron types and plasticity) and neural functions for potential neuroprosthetic applications.

New supervised learning theory applied to cerebellar modeling for suppression of variability of saccade end points.

PubMed

Fujita, Masahiko

2013-06-01

A new supervised learning theory is proposed for a hierarchical neural network with a single hidden layer of threshold units, which can approximate any continuous transformation, and applied to a cerebellar function to suppress the end-point variability of saccades. In motor systems, feedback control can reduce noise effects if the noise is added in a pathway from a motor center to a peripheral effector; however, it cannot reduce noise effects if the noise is generated in the motor center itself: a new control scheme is necessary for such noise. The cerebellar cortex is well known as a supervised learning system, and a novel theory of cerebellar cortical function developed in this study can explain the capability of the cerebellum to feedforwardly reduce noise effects, such as end-point variability of saccades. This theory assumes that a Golgi-granule cell system can encode the strength of a mossy fiber input as the state of neuronal activity of parallel fibers. By combining these parallel fiber signals with appropriate connection weights to produce a Purkinje cell output, an arbitrary continuous input-output relationship can be obtained. By incorporating such flexible computation and learning ability in a process of saccadic gain adaptation, a new control scheme in which the cerebellar cortex feedforwardly suppresses the end-point variability when it detects a variation in saccadic commands can be devised. Computer simulation confirmed the efficiency of such learning and showed a reduction in the variability of saccadic end points, similar to results obtained from experimental data.

A computational framework for the detection of subcortical brain dysmaturation in neonatal MRI using 3D Convolutional Neural Networks.

PubMed

Ceschin, Rafael; Zahner, Alexandria; Reynolds, William; Gaesser, Jenna; Zuccoli, Giulio; Lo, Cecilia W; Gopalakrishnan, Vanathi; Panigrahy, Ashok

2018-05-21

Deep neural networks are increasingly being used in both supervised learning for classification tasks and unsupervised learning to derive complex patterns from the input data. However, the successful implementation of deep neural networks using neuroimaging datasets requires adequate sample size for training and well-defined signal intensity based structural differentiation. There is a lack of effective automated diagnostic tools for the reliable detection of brain dysmaturation in the neonatal period, related to small sample size and complex undifferentiated brain structures, despite both translational research and clinical importance. Volumetric information alone is insufficient for diagnosis. In this study, we developed a computational framework for the automated classification of brain dysmaturation from neonatal MRI, by combining a specific deep neural network implementation with neonatal structural brain segmentation as a method for both clinical pattern recognition and data-driven inference into the underlying structural morphology. We implemented three-dimensional convolution neural networks (3D-CNNs) to specifically classify dysplastic cerebelli, a subset of surface-based subcortical brain dysmaturation, in term infants born with congenital heart disease. We obtained a 0.985 ± 0. 0241-classification accuracy of subtle cerebellar dysplasia in CHD using 10-fold cross-validation. Furthermore, the hidden layer activations and class activation maps depicted regional vulnerability of the superior surface of the cerebellum, (composed of mostly the posterior lobe and the midline vermis), in regards to differentiating the dysplastic process from normal tissue. The posterior lobe and the midline vermis provide regional differentiation that is relevant to not only to the clinical diagnosis of cerebellar dysplasia, but also genetic mechanisms and neurodevelopmental outcome correlates. These findings not only contribute to the detection and classification of a subset of neonatal brain dysmaturation, but also provide insight to the pathogenesis of cerebellar dysplasia in CHD. In addition, this is one of the first examples of the application of deep learning to a neuroimaging dataset, in which the hidden layer activation revealed diagnostically and biologically relevant features about the clinical pathogenesis. The code developed for this project is open source, published under the BSD License, and designed to be generalizable to applications both within and beyond neonatal brain imaging. Copyright © 2018 Elsevier Inc. All rights reserved.

Coexistance of cerebral sinovenous thrombosis and Dandy Walker malformation in newborn.

PubMed

Gverić-Ahmetasević, Snjezana; Colić, Ana; Gverić, Tugomir; Gasparović, Vesna Elvedi; Pavlisa, Goran; Ozretić, David

2011-01-01

Cerebral sinovenous thrombosis in neonatal period may cause neurological impairment, epilepsy, and lead to stroke. It is caused primarily by coagulopathy of numerous reasons, occasionally perinatal asphyxia, traumatic delivery and hyperhomocysteinemia. Dandy-Walker malformation is characterized by agenesis or hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle, and enlargement of the posterior fossa. Dandy-Walker malformation, variant, and mega cisterna magna represent a spectrum of developmental anomalies. Insults to developing cerebellar hemispheres and the fourth ventricle are believed to be the cause of malformation. Our patient was born from noncomplicated pregnancy, noncomplicated nontraumatic vaginal delivery at term, excellent Apgar scores, without peculiarities in clinical status. She was brest-fed by the 42nd hour of life when she had rightsided seizures during sleep that repeated for five times in next 24 hours. Brain Ultrasound (US) revealed clot in left lateral ventricle, slight dilatation of left ventricle, both sided periventricular echodensity, ischemia, slight enlargement of forth ventricle and a bit smaller cerebellum. There was no visible flow through left transverse, superior sagittal and straight sinus. Magnetic Resonance (MRI) confirmed the finding and showed thrombosis of left and right transverse venous sinuses and confluence of sinuses. Electroencephalogram (EEG) showed leftsided focal changes. The newborn was treated with phenobarbiton for 8 days and had no convulsions during that period. All coagulation parameters, homocistein, lipoproteins (a) and D-dimers were normal. There were no mutations on FV R506Q, PT 20210A, MTHFR 677C/T. No antiphospholipides were found. Heart US showed no structural anomalies. No other patology or risk factors were present at the time. Before discharge, US showed hydrocephalus. Flow in affected sinuses was visible with color Doppler. MRI showed recanalization of affected sinuses, also hydrocephalus and presentation of Dandy Walker On EEG there was borderline finding. Due to progression of hydrocephalus ventriculo-peritoneal shunt was placed. In age of 1 year EEG was slower for age but without focus. Neurological development was normal for age. The question is whether this child had intrauterine insult and inception of Dandy Walker with further postnatal progress of thrombosis and evolution to full picture of Dandy Walker with hydrocephalus OR thrombosis that led to development of hydrocephalus and Dandy Walker malformation in this child were accidental coexistance.

A Cerebellar Tremor in a Patient with Human Immunodeficiency Virus-1 Associated with Progressive Multifocal Leukoencephalopathy

PubMed Central

Kim, Hee-Jin; Lee, Jae-Jung; Lee, Phil Hyu

2009-01-01

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by JC virus infection in oligodendrocytes, especially in patients with acquired immunodeficiency syndrome (AIDS). Movement disorders associated with PML are very rare. Here, we report a case of PML in an AIDS patient who presented with a cerebellar tremor, caused by lesions in the cerebellar outflow tract. A cerebellar tremor can be a rare clinical manifestation in patients with PML. PMID:24868366

"Acquired" Dandy-Walker malformation and cerebellar hemorrhage: Usefulness of serial MRI.

PubMed

Pichiecchio, Anna; Decio, Alice; Di Perri, Carol; Parazzini, Cecilia; Rossi, Andrea; Signorini, Sabrina

2016-01-01

Neuroimaging plays a fundamental role in the diagnosis of Dandy Walker malformation (DWM), a posterior fossa anomaly that is usually associated with genetic abnormalities, but may rarely be ascribed to acquired causes. Here, we report the clinical history and neuroimaging studies of a child with a complex cardiac malformation, developmental delay, and oculomotor anomalies whose neuroimaging findings were consistent with an acquired form of DWM. Fetal MRI at gestational weeks 27 and 31 showed cerebellar and vermis hypoplasia and fourth ventricle enlargement, together with hemosiderin deposits on the cerebellar hemispheric surface, but without significant vermian rotation. Postnatal MRIs at 5 days and 13 months revealed progressive counter-clockwise rotation of the hypoplastic cerebellar vermis with cystic dilation of the fourth ventricle, eventually leading to a full-blown DWM. This case strengthens the opinion that DWM is a heterogeneous condition, and may support the hypothesis that acquired meningeal abnormalities in the form of cortico-pial hemosiderosis may play a role in the development of DWM. This case also demonstrates that serial neuroimaging plays a key role in the correct diagnosis of posterior fossa malformations, whose prognosis is difficult to establish on second trimester fetal MRI and requires longer clinical follow-up. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Synaptic pathology in the cerebellar dentate nucleus in chronic multiple sclerosis.

PubMed

Albert, Monika; Barrantes-Freer, Alonso; Lohrberg, Melanie; Antel, Jack P; Prineas, John W; Palkovits, Miklós; Wolff, Joachim R; Brück, Wolfgang; Stadelmann, Christine

2017-11-01

In multiple sclerosis, cerebellar symptoms are associated with clinical impairment and an increased likelihood of progressive course. Cortical atrophy and synaptic dysfunction play a prominent role in cerebellar pathology and although the dentate nucleus is a predilection site for lesion development, structural synaptic changes in this region remain largely unexplored. Moreover, the mechanisms leading to synaptic dysfunction have not yet been investigated at an ultrastructural level in multiple sclerosis. Here, we report on synaptic changes of dentate nuclei in post-mortem cerebella of 16 multiple sclerosis patients and eight controls at the histological level as well as an electron microscopy evaluation of afferent synapses of the cerebellar dentate and pontine nuclei of one multiple sclerosis patient and one control. We found a significant reduction of afferent dentate synapses in multiple sclerosis, irrespective of the presence of demyelination, and a close relationship between glial processes and dentate synapses. Ultrastructurally, we show autophagosomes containing degradation products of synaptic vesicles within dendrites, residual bodies within intact-appearing axons and free postsynaptic densities opposed to astrocytic appendages. Our study demonstrates loss of dentate afferent synapses and provides, for the first time, ultrastructural evidence pointing towards neuron-autonomous and neuroglia-mediated mechanisms of synaptic degradation in chronic multiple sclerosis. © 2016 International Society of Neuropathology.

Synchrony and neural coding in cerebellar circuits

PubMed Central

Person, Abigail L.; Raman, Indira M.

2012-01-01

The cerebellum regulates complex movements and is also implicated in cognitive tasks, and cerebellar dysfunction is consequently associated not only with movement disorders, but also with conditions like autism and dyslexia. How information is encoded by specific cerebellar firing patterns remains debated, however. A central question is how the cerebellar cortex transmits its integrated output to the cerebellar nuclei via GABAergic synapses from Purkinje neurons. Possible answers come from accumulating evidence that subsets of Purkinje cells synchronize their firing during behaviors that require the cerebellum. Consistent with models predicting that coherent activity of inhibitory networks has the capacity to dictate firing patterns of target neurons, recent experimental work supports the idea that inhibitory synchrony may regulate the response of cerebellar nuclear cells to Purkinje inputs, owing to the interplay between unusually fast inhibitory synaptic responses and high rates of intrinsic activity. Data from multiple laboratories lead to a working hypothesis that synchronous inhibitory input from Purkinje cells can set the timing and rate of action potentials produced by cerebellar nuclear cells, thereby relaying information out of the cerebellum. If so, then changing spatiotemporal patterns of Purkinje activity would allow different subsets of inhibitory neurons to control cerebellar output at different times. Here we explore the evidence for and against the idea that a synchrony code defines, at least in part, the input–output function between the cerebellar cortex and nuclei. We consider the literature on the existence of simple spike synchrony, convergence of Purkinje neurons onto nuclear neurons, and intrinsic properties of nuclear neurons that contribute to responses to inhibition. Finally, we discuss factors that may disrupt or modulate a synchrony code and describe the potential contributions of inhibitory synchrony to other motor circuits. PMID:23248585

Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder

PubMed Central

Rogers, Tiffany D.; Dickson, Price E.; McKimm, Eric; Heck, Detlef H.; Goldowitz, Dan; Blaha, Charles D.; Mittleman, Guy

2013-01-01

Imaging, clinical and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area [VTA] and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50% in wildtype and 20-30% in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15% in wildtype and 40% in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways. PMID:23436049

Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder.

PubMed

Rogers, Tiffany D; Dickson, Price E; McKimm, Eric; Heck, Detlef H; Goldowitz, Dan; Blaha, Charles D; Mittleman, Guy

2013-08-01

Imaging, clinical, and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area (VTA) and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50 % in wildtype and 20-30 % in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15 % in wildtype and 40 % in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways.

Failure of Fixation Suppression of Spontaneous Nystagmus in Cerebellar Infarction: Frequency, Pattern, and a Possible Structure.

PubMed

Kim, Hyun-Ah; Yi, Hyon-Ah; Lee, Hyung

2016-04-01

To investigate the frequency and pattern of failure of the fixation suppression (FFS) of spontaneous nystagmus (SN) in unilateral cerebellar infarction, and to identify the structure responsible for FFS, 29 patients with acute, mainly unilateral, isolated cerebellar infarction who had SN with a predominantly horizontal component were enrolled in this study. The ocular fixation index (OFI) was defined as the mean slow phase velocity (SPV) of the horizontal component of SN with fixation divided by the mean SPV of the horizontal component of SN without fixation. The OFI from age- and sex-matched patients with vestibular neuritis was calculated and used as the control data. The FFS of SN was only found in less than half (41 %, 12/29) of the patients. Approximately 65 % (n = 7) of the patients with isolated anterior inferior cerebellar artery territory cerebellar infarction showed FFS, whereas only a quarter (n = 3) of the patients with isolated posterior inferior cerebellar artery (PICA) territory cerebellar infarction showed FFS. The proportion of gaze-evoked nystagmus (6/12 [50 %] vs. 2/17 [12 %], p = 0.04) and deficient gain of ipsilesional pursuit (10/12 [83 %] vs. 6/17 [35 %], p = 0.05) was more frequent in the FFS group than in the group without FFS. Lesion subtraction analysis in isolated PICA territory cerebellar infarction revealed that the nodulus was commonly damaged in patients with FFS, compared to that of patients without FFS. Our study shows that FFS of SN due to acute cerebellar infarction is less common than previously thought and the nodulus may be an important structure for the suppression of SN in humans.

Morphological and Biochemical Features of Cerebellar Cortex After Exposure to Zinc Oxide Nanoparticles: Possible Protective Role of Curcumin.

PubMed

Amer, Mona G; Karam, Rehab A

2018-03-25

Zinc oxide nanoparticles (ZnONPs) are widely used in the last decades. Therefore, investigation of its neurotoxic effect is important. This work aimed to investigate the potential adverse effects of ZnONPs on rat's cerebellar cortex and the possible neuroprotective role of curcumin (Cur). Forty male albino rats were randomly divided into four equal groups. Two groups were injected with ZnONPs and one group was previously received Cur before ZnONPs. At the end of the experiment, cerebellar tissue samples were prepared for histological, morphometric, immunohistochemical study, and tissue levels of oxidative stress markers and cytokine analysis. cerebellar damage is clearly visible with ZnONPs. Degeneration, loss, disorganization of cerebellar neurons was observed. Histopathological degeneration of Purkinje and granular cells together with loss of Nissl substance, astrocyte gliosis, and affection of cerebellar blood brain barrier were detected. Moreover, an apoptotic marker (caspase-3) was significantly expressed in Purkinje and granular layers together with elevated gene expression of P53 and COX-2 in cerebellar tissue of ZnONPs intoxicated group. Astrocyte gliosis and inflammatory markers IL-1, IL-6, and TNF-α were expressed significantly in ZnONPs intoxicated cerebellum. These changes were associated with evidence of cerebellar oxidative stress. Strikingly, treatment with Cur together with ZnONPs recorded morphological improvement, with increased number of Purkinje cells and decreased caspase +ve cells. These findings were confirmed by morphometric and statistical analysis. Cur ameliorates the deterious effect of ZnONPs on the cerebellar cortex through its antioxidant, antiapoptotic, and anti-inflammatory efficacies. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Motor cortex plasticity can indicate vulnerability to motor fluctuation and high L-DOPA need in drug-naïve Parkinson's disease.

PubMed

Kishore, Asha; James, Praveen; Krishnan, Syam; Yahia-Cherif, Lydia; Meunier, Sabine; Popa, Traian

2017-02-01

Motor cortex plasticity is reported to be decreased in Parkinson's disease in studies which pooled patients in various stages of the disease. Whether the early decrease in plasticity is related to the motor signs or is linked to the future development of motor complications of treatment is unclear. The aim of the study was to test if motor cortex plasticity and its cerebellar modulation are impaired in treatment-naïve Parkinson's disease, are related to the motor signs of the disease and predict occurrence of motor complications of treatment. Twenty-nine denovo patients with Parkinson's disease were longitudinally assessed for motor complications for four years. Using transcranial magnetic stimulation, the plasticity of the motor cortex and its cerebellar modulation were measured (response to paired-associative stimulation alone or preceded by 2 active cerebellar stimulation protocols), both in the untreated state and after a single dose of L-DOPA. Twenty-six matched, healthy volunteers were tested, only without L-DOPA. Patients and healthy controls had similar proportions of responders and non-responders to plasticity induction. In the untreated state, the more efficient was the cerebellar modulation of motor cortex plasticity, the lower were the bradykinesia and rigidity scores. The extent of the individual plastic response to paired associative stimulation could indicate a vulnerability to develop early motor fluctuation but not dyskinesia. Measuring motor cortex plasticity in denovo Parkinson's disease could be a neurophysiological parameter that may help identify patients with greater propensity for early motor fluctuations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Developmental Injury to the Cerebellar Cortex Following Hydroxyurea Treatment in Early Postnatal Life: An Immunohistochemical and Electron Microscopic Study.

PubMed

Martí, Joaquín; Molina, Vanesa; Santa-Cruz, M C; Hervás, José P

2017-02-01

Postnatal development of the cerebellar cortex was studied in rats administered with a single dose (2 mg/g) of the cytotoxic agent hydroxyurea (HU) on postnatal day (P) 9 and collected at appropriate times ranging from 6 h to 45 days. Quantification of several parameters such as the density of pyknotic, mitotic, BrdU-positive, and vimentin-stained cells revealed that HU compromises the survival of the external granular layer (EGL) cells. Moreover, vimentin immunocytochemistry revealed overexpression and thicker immunoreactive glial processes in HU-treated rats. On the other hand, we also show that HU leads to the activation of apoptotic cellular events, resulting in a substantial number of dying EGL cells, as revealed by TUNEL staining and at the electron microscope level. Additionally, we quantified several features of the cerebellar cortex of rats exposed to HU in early postnatal life and collected in adulthood. Data analysis indicated that the analyzed parameters were less pronounced in rats administered with this agent. Moreover, we observed several alterations in the cerebellar cortex cytoarchitecture of rats injected with HU. Anomalies included ectopic placement of Purkinje cells and abnormities in the dendritic arbor of these macroneurons. Ectopic granule cells were also found in the molecular layer. These findings provide a clue for investigating the mechanisms of HU-induced toxicity during the development of the central nervous system. Our results also suggest that it is essential to avoid underestimating the adverse effects of this hydroxylated analog of urea when administered during early postnatal life.

Acute bilateral cerebellar infarction in the territory of the medial branches of posterior inferior cerebellar arteries.

PubMed

Gurer, G; Sahin, G; Cekirge, S; Tan, E; Saribas, O

2001-10-01

The most frequent type of cerebellar infarcts involved the posterior inferior cerebellar artery (PICA) and superior cerebellar artery territories but bilateral involvement of lateral or medial branches of PICA is extremely rare. In this report, we present a 55-year-old male who admitted to hospital with vomiting, nausea and dizziness. On examination left-sided hemiparesia and ataxic gait were detected. Infarct on bilateral medial branch of PICA artery territories was found out with cranial magnetic resonance imaging (MRI) technique and 99% stenosis of the left vertebral artery was found out with digital subtraction arteriography. The patient was put on heparin treatment. After 3 weeks, his complaints and symptoms had disappeared except for mild gait ataxia.

Gaze-evoked nystagmus induced by alcohol intoxication.

PubMed

Romano, Fausto; Tarnutzer, Alexander A; Straumann, Dominik; Ramat, Stefano; Bertolini, Giovanni

2017-03-15

The cerebellum is the core structure controlling gaze stability. Chronic cerebellar diseases and acute alcohol intoxication affect cerebellar function, inducing, among others, gaze instability as gaze-evoked nystagmus. Gaze-evoked nystagmus is characterized by increased centripetal eye-drift. It is used as an important diagnostic sign for patients with cerebellar degeneration and to assess the 'driving while intoxicated' condition. We quantified the effect of alcohol on gaze-holding using an approach allowing, for the first time, the comparison of deficits induced by alcohol intoxication and cerebellar degeneration. Our results showed that alcohol intoxication induces a two-fold increase of centripetal eye-drift. We establish analysis techniques for using controlled alcohol intake as a model to support the study of cerebellar deficits. The observed similarity between the effect of alcohol and the clinical signs observed in cerebellar patients suggests a possible pathomechanism for gaze-holding deficits. Gaze-evoked nystagmus (GEN) is an ocular-motor finding commonly observed in cerebellar disease, characterized by increased centripetal eye-drift with centrifugal correcting saccades at eccentric gaze. With cerebellar degeneration being a rare and clinically heterogeneous disease, data from patients are limited. We hypothesized that a transient inhibition of cerebellar function by defined amounts of alcohol may provide a suitable model to study gaze-holding deficits in cerebellar disease. We recorded gaze-holding at varying horizontal eye positions in 15 healthy participants before and 30 min after alcohol intake required to reach 0.6‰ blood alcohol content (BAC). Changes in ocular-motor behaviour were quantified measuring eye-drift velocity as a continuous function of gaze eccentricity over a large range (±40 deg) of horizontal gaze angles and characterized using a two-parameter tangent model. The effect of alcohol on gaze stability was assessed analysing: (1) overall effects on the gaze-holding system, (2) specific effects on each eye and (3) differences between gaze angles in the temporal and nasal hemifields. For all subjects, alcohol consumption induced gaze instability, causing a two-fold increase [2.21 (0.55), median (median absolute deviation); P = 0.002] of eye-drift velocity at all eccentricities. Results were confirmed analysing each eye and hemifield independently. The alcohol-induced transient global deficit in gaze-holding matched the pattern previously described in patients with late-onset cerebellar degeneration. Controlled intake of alcohol seems a suitable disease model to study cerebellar GEN. With alcohol resulting in global cerebellar hypofunction, we hypothesize that patients matching the gaze-holding behaviour observed here suffered from diffuse deficits in the gaze-holding system as well. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Genetics Home Reference: Gordon Holmes syndrome

MedlinePlus

... production of hormones that direct sexual development (hypogonadotropic hypogonadism). Many affected individuals have a delay in development ... a lack of RNF216 protein function causes hypogonadotropic hypogonadism or cerebellar ataxia. The PNPLA6 gene provides instructions ...

Relationships between regional cerebellar volume and sensorimotor and cognitive function in young and older adults

PubMed Central

Bernard, Jessica A.; Seidler, Rachael D.

2013-01-01

The cerebellum has been implicated in both sensorimotor and cognitive function, but is known to undergo volumetric declines with advanced age. Individual differences in regional cerebellar volume may therefore provide insight into performance variability across the lifespan, as has been shown with other brain structures and behaviors. Here, we investigated whether there are regional age differences in cerebellar volume in young and older adults, and whether these volumes explain, in part, individual differences in sensorimotor and cognitive task performance. We found that older adults had smaller cerebellar volume than young adults; specifically, lobules in the anterior cerebellum were more impacted by age. Multiple regression analyses for both age groups revealed associations between sensorimotor task performance in several domains (balance, choice reaction time, and timing) and regional cerebellar volume. There were also relationships with working memory, but none with measures of general cognitive or executive function. Follow-up analyses revealed several differential relationships with age between regional volume and sensorimotor performance. These relationships were predominantly selective to cerebellar regions that have been implicated in cognitive functions. Therefore, it may be the cognitive aspects of sensorimotor task performance that are best explained by individual differences in regional cerebellar volumes. In sum, our results demonstrate the importance of regional cerebellar volume with respect to both sensorimotor and cognitive performance, and we provide additional insight into the role of the cerebellum in age-related performance declines. PMID:23625382

Localization of organ-specific antigens in the nervous system of the rat.

PubMed

Weinrauder, H; Lach, B

1977-08-16

Localization of organ-specific brain antigens in the central nervous system of the rat has been studied by means of indirect immunofluorescence. Rabbit antiserum against homogenate of rat brain, previously absorbed with normal serum and homogenates of rat organs (kidney, liver, spleen), reacted with the water-soluble antigens of rat brain prepared by extraction with phosphate buffer (pH 7.3) and ultracentrifugation at 50 000 X g to give one band in the immunodiffusion test and 2--3 precipitation arcs in immunoelectrophoresis. There was also a positive reaction with peripheral nerve. The antigen was detectable in all regions of the CNS. Cells with distinct cytoplasmic immunofluorescence were most frequently observed in cerebellar white matter, pons, cerebellar pedunculi, longitudinal tracts of the brain stem. Positive immunofluorecence reaction has appeared in the outer plexiform layer and granular layer of the retina, satelite cells of the spinal root ganglia and Schwann cells. A similar reaction was observed in human, mouse and guinea pig brain slices. Both the morphological and immunochemical reactions are indicative of glial localization of this antigen.

Story time turbocharger? Child engagement during shared reading and cerebellar activation and connectivity in preschool-age children listening to stories

PubMed Central

Phelan, Kieran; Horowitz-Kraus, Tzipi; Dudley, Jonathan; Altaye, Mekibib; DeWitt, Thomas; Holland, Scott K.

2017-01-01

Expanding behavioral and neurobiological evidence affirms benefits of shared (especially parent-child) reading on cognitive development during early childhood. However, the majority of this evidence involves factors under caregiver control, the influence of those intrinsic to the child, such as interest or engagement in reading, largely indirect or unclear. The cerebellum is increasingly recognized as playing a “smoothing” role in higher-level cognitive processing and learning, via feedback loops with language, limbic and association cortices. We utilized functional MRI to explore the relationship between child engagement during a mother-child reading observation and neural activation and connectivity during a story listening task, in a sample of 4-year old girls. Children exhibiting greater interest and engagement in the narrative showed increased activation in right-sided cerebellar association areas during the task, and greater functional connectivity between this activation cluster and language and executive function areas. Our findings suggest a potential cerebellar “boost” mechanism responsive to child engagement level that may contribute to emergent literacy development during early childhood, and synergy between caregiver and child factors during story sharing. PMID:28562619

Importance of genetics in fetal alcohol effects: null mutation of the nNOS gene worsens alcohol-induced cerebellar neuronal losses and behavioral deficits

PubMed Central

Bonthius, Daniel J.; Winters, Zachary; Karacay, Bahri; Bousquet, Samantha Larimer; Bonthius, Daniel J.

2014-01-01

The cerebellum is a major target of alcohol-induced damage in the developing brain. However, the cerebella of some children are much more seriously affected than others by prenatal alcohol exposure. As a consequence of in utero alcohol exposure, some children have substantial reductions in cerebellar volume and corresponding neurodevelopmental problems, including microencephaly, ataxia, and balance deficits, while other children who were exposed to similar alcohol quantities are spared. One factor that likely plays a key role in determining the impact of alcohol on the fetal cerebellum is genetics. However, no specific gene variant has yet been identified that worsens cerebellar function as a consequence of developmental alcohol exposure. Previous studies have revealed that mice carrying a homozygous mutation of the gene for neuronal nitric oxide synthase (nNOS−/− mice) have more severe acute alcohol-induced neuronal losses from the cerebellum than wild type mice. Therefore, the goals of this study were to determine whether alcohol induces more severe cerebellum-based behavioral deficits in nNOS−/− mice than in wild type mice and to determine whether these worsened behavior deficits are associated with worsened cerebellar neuronal losses. nNOS−/− mice and their wild type controls received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days 4–9. In adulthood, the mice underwent behavioral testing, followed by neuronal quantification. Alcohol caused dose-related deficits in rotarod and balance beam performance in both nNOS−/− and wild type mice. However, the alcohol-induced behavioral deficits were substantially worse in the nNOS−/− mice than in wild type. Likewise, alcohol exposure led to losses of Purkinje cells and cerebellar granule cells in mice of both genotypes, but the cell losses were more severe in the nNOS−/− mice than in wild type. Behavioral performances were correlated with neuronal number in the nNOS−/− mice, but not in wild type. Thus, homozygous mutation of the nNOS gene increases vulnerability to alcohol-induced cerebellar dysfunction and neuronal loss. nNOS is the first gene identified whose mutation worsens alcohol-induced cerebellar behavioral deficits. PMID:25511929

The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice.

PubMed

Bausch, Anne E; Dieter, Rebekka; Nann, Yvette; Hausmann, Mario; Meyerdierks, Nora; Kaczmarek, Leonard K; Ruth, Peter; Lukowski, Robert

2015-07-01

Kcnt1 encoded sodium-activated potassium channels (Slack channels) are highly expressed throughout the brain where they modulate the firing patterns and general excitability of many types of neurons. Increasing evidence suggests that Slack channels may be important for higher brain functions such as cognition and normal intellectual development. In particular, recent findings have shown that human Slack mutations produce very severe intellectual disability and that Slack channels interact directly with the Fragile X mental retardation protein (FMRP), a protein that when missing or mutated results in Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism in humans. We have now analyzed a recently developed Kcnt1 null mouse model in several behavioral tasks to assess which aspects of memory and learning are dependent on Slack. We demonstrate that Slack deficiency results in mildly altered general locomotor activity, but normal working memory, reference memory, as well as cerebellar control of motor functions. In contrast, we find that Slack channels are required for cognitive flexibility, including reversal learning processes and the ability to adapt quickly to unfamiliar situations and environments. Our data reveal that hippocampal-dependent spatial learning capabilities require the proper function of Slack channels. © 2015 Bausch et al.; Published by Cold Spring Harbor Laboratory Press.

The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice

PubMed Central

Bausch, Anne E.; Dieter, Rebekka; Nann, Yvette; Hausmann, Mario; Meyerdierks, Nora; Kaczmarek, Leonard K.

2015-01-01

Kcnt1 encoded sodium-activated potassium channels (Slack channels) are highly expressed throughout the brain where they modulate the firing patterns and general excitability of many types of neurons. Increasing evidence suggests that Slack channels may be important for higher brain functions such as cognition and normal intellectual development. In particular, recent findings have shown that human Slack mutations produce very severe intellectual disability and that Slack channels interact directly with the Fragile X mental retardation protein (FMRP), a protein that when missing or mutated results in Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism in humans. We have now analyzed a recently developed Kcnt1 null mouse model in several behavioral tasks to assess which aspects of memory and learning are dependent on Slack. We demonstrate that Slack deficiency results in mildly altered general locomotor activity, but normal working memory, reference memory, as well as cerebellar control of motor functions. In contrast, we find that Slack channels are required for cognitive flexibility, including reversal learning processes and the ability to adapt quickly to unfamiliar situations and environments. Our data reveal that hippocampal-dependent spatial learning capabilities require the proper function of Slack channels. PMID:26077685

Imbalance in Multiple Sclerosis: A Result of Slowed Spinal Somatosensory Conduction

PubMed Central

Cameron, Michelle H.; Horak, Fay B.; Herndon, Robert R.; Bourdette, Dennis

2009-01-01

Balance problems and falls are common in people with multiple sclerosis (MS) but their cause and nature are not well understood. It is known that MS affects many areas of the central nervous system that can impact postural responses to maintain balance, including the cerebellum and the spinal cord. Cerebellar balance disorders are associated with normal latencies but reduced scaling of postural responses. We therefore examined the latency and scaling of automatic postural responses, and their relationship to somatosensory evoked potentials (SSEPs), in 10 people with MS and imbalance and 10 age-, sex-matched, healthy controls. The latency and scaling of postural responses to backward surface translations of 5 different velocities and amplitudes, and the latency of spinal and supraspinal somatosensory conduction, were examined. Subjects with MS had large, but very delayed automatic postural response latencies compared to controls (161ms ± 31 vs 102 ± 21, p < 0.01) and these postural response latencies correlated with the latencies of their spinal SSEPs (r=0.73, p< 0.01). Subjects with MS also had normal or excessive scaling of postural response amplitude to perturbation velocity and amplitude. Longer latency postural responses were associated with less velocity scaling and more amplitude scaling. Balance deficits in people with MS appear to be caused by slowed spinal somatosensory conduction and not by cerebellar involvement. People with MS appear to compensate for their slowed spinal somatosensory conduction by increasing the amplitude scaling and the magnitude of their postural responses. PMID:18570015

Eye hyperdeviation in mouse cerebellar mutants is comparable to the gravity-dependent component of human downbeat nystagmus.

PubMed

Stahl, John S; Oommen, Brian S

2008-01-01

Humans with cerebellar degeneration commonly exhibit downbeat nystagmus (DBN). DBN has gravity-independent and -dependent components, and the latter has been proposed to reflect hyperactive tilt maculo-ocular reflexes (tilt-MOR). Mice with genetically determined cerebellar ataxia do not exhibit DBN, but they do exhibit tonic hyperdeviation of the eyes, which we have proposed to be the DBN equivalent. As such, the tilt-MOR might be predicted to be hyperactive in these mutant mice. We measured the tilt-MOR in 10 normal C57BL/6 mice and in 6 tottering, a mutant exhibiting ataxia and ocular motor abnormalities due to mutation of the P/Q calcium channel. Awake mice were placed in body orientations spanning 360 degrees about the pitch axis. The absolute, equilibrium vertical angular deviations of one eye were measured using infrared videooculography. In both strains, eye elevation varied quasi-sinusoidally with tilt angle in the range of 90 degrees nose-up to 90 degrees nose-down. Beyond this range the eye returned to a neutral position. Deviation over +/-30 degrees of tilt was an approximately linear function of the projection of the gravity vector into the animal's horizontal plane, and can thus be summarized by its slope (sensitivity). Sensitivity measured 14.9 degrees/g for C57BL/6 and 20.3 degrees/g for tottering, a statistically significant difference. Thus the pitch otolithic reflex of the ataxic mutants is hyperactive relative to controls and could explain tonic hyperdeviation of the eyes, consistent with the idea that the tonic hyperdeviation is analogous to DBN.

Acute cerebellar ataxia and infectious mononucleosis.

PubMed Central

Wadhwa, N. K.; Ghose, R. R.

1983-01-01

A 28-year-old man, who presented with acute cerebellar ataxia, was found to have haematological features of infectious mononucleosis. There was serological evidence of recent infection with Epstein-Barr virus. It is speculated that cerebellar dysfunction results from virus-induced inflammatory changes within the central nervous system. PMID:6312442

Learning of Sensory Sequences in Cerebellar Patients

ERIC Educational Resources Information Center

Frings, Markus; Boenisch, Raoul; Gerwig, Marcus; Diener, Hans-Christoph; Timmann, Dagmar

2004-01-01

A possible role of the cerebellum in detecting and recognizing event sequences has been proposed. The present study sought to determine whether patients with cerebellar lesions are impaired in the acquisition and discrimination of sequences of sensory stimuli of different modalities. A group of 26 cerebellar patients and 26 controls matched for…

Incidence of Dysarthria in Children with Cerebellar Tumors: A Prospective Study

ERIC Educational Resources Information Center

Richter, S.; Schoch, B.; Ozimek, A.; Gorissen, B.; Hein-Kropp, C.; Kaiser, O.; Hovel, M.; Wieland, R.; Gizewski, E.; Timmann, D.

2005-01-01

The present study investigated dysarthric symptoms in children with cerebellar tumors. Ten children with cerebellar tumors and 10 orthopedic control children were tested prior and one week after surgery. Clinical dysarthric symptoms were quantified in spontaneous speech. Syllable durations were analyzed in syllable repetition and sentence…

Cerebellar abiotrophy in a family of Border Collie dogs.

PubMed

Sandy, J R; Slocombe, R E; Mitten, R W; Jedwab, D

2002-11-01

Cerebellar abiotrophies have a nonsex-linked, autosomal, recessively inherited basis in a number of species, and lesions typically reflect profound and progressive loss of Purkinje cells. In this report, an unusual form of abiotrophy is described for two sibling Border Collies. Extensive loss of the cerebellar granular cell layer was present with relative sparing of Purkinje cells of two female pups. The biochemical basis for this form of cerebellar abiotrophy is unknown, but the lack of disease in other siblings supports an autosomal recessive mode of inheritance.

Heat stroke induced cerebellar dysfunction: A “forgotten syndrome”

PubMed Central

Kosgallana, Athula D; Mallik, Shreyashee; Patel, Vishal; Beran, Roy G

2013-01-01

We report a case of heat stroke induced acute cerebellar dysfunction, a rare neurological disease characterized by gross cerebellar dysfunction with no acute radiographic changes, in a 61 years old ship captain presenting with slurred speech and gait ataxia. A systematic review of the literature on heat stroke induced cerebellar dysfunction was performed, with a focus on investigations, treatment and outcomes. After review of the literature and detailed patient investigation it was concluded that this patient suffered heat stroke at a temperature less than that quoted in the literature. PMID:24340279

Paraneoplastic cerebellar ataxia and the paraneoplastic syndromes

PubMed Central

Afzal, Sadaf; Recio, Maria

2015-01-01

Paraneoplastic cerebellar ataxia, also known as paraneoplastic cerebellar degeneration, is one of the wide array of paraneoplastic neurological syndromes in which neurological symptoms are indirectly caused by an underlying malignancy, most commonly gynecological, breast, or lung cancer or Hodgkin's lymphoma. We describe a patient with severe cerebellar dysfunction attributed to a paraneoplastic neurological syndrome. The case highlights the need to look for paraneoplastic syndromes—both to discover malignancies early, at a treatable stage, and, as in our case, to address very distressing symptoms for the patient's relief even if the malignancy is not curable. PMID:25829659

Cerebellum tunes the excitability of the motor system: evidence from peripheral motor axons.

PubMed

Nodera, Hiroyuki; Manto, Mario

2014-12-01

Cerebellum is highly connected with the contralateral cerebral cortex. So far, the motor deficits observed in acute focal cerebellar lesions in human have been mainly explained on the basis of a disruption of the cerebello-thalamo-cortical projections. Cerebellar circuits have also numerous anatomical and functional interactions with brainstem nuclei and projects also directly to the spinal cord. Cerebellar lesions alter the excitability of peripheral motor axons as demonstrated by peripheral motor threshold-tracking techniques in cerebellar stroke. The biophysical changes are correlated with the functional scores. Nerve excitability measurements represent an attractive tool to extract the rules underlying the tuning of excitability of the motor pathways by the cerebellum and to discover the contributions of each cerebellar nucleus in this key function, contributing to early plasticity and sensorimotor learning.

[Cerebellar atrophy in Minamata disease: comparison with spino-cerebellar degeneration on MR images].

PubMed

Ikeda, O; Okajima, T; Korogi, Y; Kitajima, M; Uchino, M; Takahasi, M

1997-02-01

We evaluated atrophic patterns of the cerebellar vermis in seven patients with Minamata disease (MD) and nine patients with spino-cerebellar degeneration (SCD) on MR images. Twenty-five control subjects were also examined. The cerebellar vermis was divided into superior, middle, and inferior parts by the primary fissure and the prepyramidal fissure on the median sagittal T1-weighted MR image. The length and area of each part were measured. In the patients with SCD, there were no significant differences in the degree of atrophy among the three parts. However, MR images of the patients with MD showed more severe atrophy in the middle and inferior parts than in the superior part. Atrophy of the superior part was less frequently observed in MD patients.

Anticoagulation therapy is harmful to large-sized cerebellar infarction.

PubMed

Zhang, She-Qing; Wang, Wei; Ma, Xiao-Long; Xia, Yu-Ye; Liu, Ai-Jun

2014-09-01

Anticoagulants are commonly used to treat ischemic stroke. Its impact on cerebellar infarction has not been fully understood. In the clinical study, we reviewed a consecutive series of patients with large-sized cerebellar infarction (diameter > 3 cm, n = 30) treated with or without anticoagulation. In animal study, cerebellar infarction operation was performed in 12 Cynomolgus monkeys. Then the animals were administrated with low molecular weight heparin (LMWH) or vehicle for 14 days. Six patients died during the following treatment. All the subjects that died received anticoagulation therapy, while nobody in the survival group received such a therapy. Compared with sham-operated animals, all monkeys with cerebellar infarction have obvious neurological deficits. The number and size of the Purkinje cells in the cerebellar area were also reduced. Two animals in the LMWH group (33%) died, while all animals in the vehicle control group survived. Compared with the vehicle group, the neurological score in the LMWH group was significantly increased (P < 0.05). The water content in the cerebella was also significantly higher (P < 0.05). Edema, hemorrhage, and subarachnoid hemorrhage occurred in the cerebella as well as brainstem of all the LMWH treated animals. These results indicated the harmful effects of anticoagulation therapy on large-sized cerebellar infarction. © 2014 John Wiley & Sons Ltd.

Aberrant cerebellar connectivity in bipolar disorder with psychosis.

PubMed

Shinn, Ann K; Roh, Youkyung S; Ravichandran, Caitlin T; Baker, Justin T; Öngür, Dost; Cohen, Bruce M

2017-07-01

The cerebellum, which modulates affect and cognition in addition to motor functions, may contribute substantially to the pathophysiology of mood and psychotic disorders, such as bipolar disorder. A growing literature points to cerebellar abnormalities in bipolar disorder. However, no studies have investigated the topographic representations of resting state cerebellar networks in bipolar disorder, specifically their functional connectivity to cerebral cortical networks. Using a well-defined cerebral cortical parcellation scheme as functional connectivity seeds, we compared ten cerebellar resting state networks in 49 patients with bipolar disorder and a lifetime history of psychotic features and 55 healthy control participants matched for age, sex, and image signal-to-noise ratio. Patients with psychotic bipolar disorder showed reduced cerebro-cerebellar functional connectivity in somatomotor A, ventral attention, salience, and frontoparietal control A and B networks relative to healthy control participants. These findings were not significantly correlated with current symptoms. Patients with psychotic bipolar disorder showed evidence of cerebro-cerebellar dysconnectivity in selective networks. These disease-related changes were substantial and not explained by medication exposure or substance use. Therefore, they may be mechanistically relevant to the underlying susceptibility to mood dysregulation and psychosis. Cerebellar mechanisms deserve further exploration in psychiatric conditions, and this study's findings may have value in guiding future studies on pathophysiology and treatment of mood and psychotic disorders, in particular.

Cerebellum engages in automation of verb-generation skill.

PubMed

Yang, Zhi; Wu, Paula; Weng, Xuchu; Bandettini, Peter A

2014-03-01

Numerous studies have shown cerebellar involvement in item-specific association, a form of explicit learning. However, very few have demonstrated cerebellar participation in automation of non-motor cognitive tasks. Applying fMRI to a repeated verb-generation task, we sought to distinguish cerebellar involvement in learning of item-specific noun-verb association and automation of verb generation skill. The same set of nouns was repeated in six verb-generation blocks so that subjects practiced generating verbs for the nouns. The practice was followed by a novel block with a different set of nouns. The cerebellar vermis (IV/V) and the right cerebellar lobule VI showed decreased activation following practice; activation in the right cerebellar Crus I was significantly lower in the novel challenge than in the initial verb-generation task. Furthermore, activation in this region during well-practiced blocks strongly correlated with improvement of behavioral performance in both the well-practiced and the novel blocks, suggesting its role in the learning of general mental skills not specific to the practiced noun-verb pairs. Therefore, the cerebellum processes both explicit verbal associative learning and automation of cognitive tasks. Different cerebellar regions predominate in this processing: lobule VI during the acquisition of item-specific association, and Crus I during automation of verb-generation skills through practice.

The Usefulness of the TOAST Classification and Prognostic Significance of Pyramidal Symptoms During the Acute Phase of Cerebellar Ischemic Stroke.

PubMed

Dziadkowiak, Edyta; Chojdak-Łukasiewicz, Justyna; Guziński, Maciej; Noga, Leszek; Paradowski, Bogusław

2016-04-01

Cerebellar stroke is a rare condition with very nonspecific clinical features. The symptoms in the acute phase could imitate acute peripheral vestibular disorders or a brainstem lesion. The aim of this study was to assess the usefulness of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification in cerebellar stroke and the impact of clinical features on the prognosis. We retrospectively analyzed 107 patients with diagnosed ischemic cerebellar infarction. We studied the clinical features and compared them based on the location of the ischemic lesion and its distribution in the posterior interior cerebellar artery (PICA), superior cerebellar artery (SCA), and anterior inferior cerebellar artery (AICA) territories. According to the TOAST classification, stroke was more prevalent in atrial fibrillation (26/107) and when the lesion was in the PICA territory (39/107). Pyramidal signs occurred in 29/107 of patients and were more prevalent when the lesion was distributed in more than two vascular regions (p = 0.00640). Mortality was higher among patients with ischemic lesion caused by cardiac sources (p = 0.00094) and with pyramidal signs (p = 0.00640). The TOAST classification is less useful in assessing supratentorial ischemic infarcts. Cardioembolic etiology, location of the ischemic lesion, and pyramidal signs support a negative prognosis.

What Do We Know About the Influence of the Cerebellum on Walking Ability? Promising Findings from Transcranial Alternating Current Stimulation.

PubMed

Naro, Antonino; Milardi, Demetrio; Cacciola, Alberto; Russo, Margherita; Sciarrone, Francesca; La Rosa, Gianluca; Bramanti, Alessia; Bramanti, Placido; Calabrò, Rocco Salvatore

2017-08-01

Several cerebellar functions related to upper limb motor control have been studied using non-invasive brain stimulation paradigms. We have recently shown that transcranial alternating current stimulation (tACS) may be a promising approach in shaping the plasticity of cerebellum-brain pathways in a safe and effective manner. This study aimed to assess whether cerebellar tACS at different frequencies may tune M1-leg excitability and modify gait control in healthy human subjects. To this end, we tested the effects of different cerebellar tACS frequencies over the right cerebellar hemisphere (at 10, 50, and 300 Hz, besides a sham-tACS) on M1-leg excitability, cerebellum-brain inhibition (CBI), and gait parameters in a sample of 25 healthy volunteers. Fifty and 300 Hz tACS differently modified M1-leg excitability and CBI from both lower limbs, without significant gait perturbations. We hypothesize that tACS aftereffect may depend on a selective entrainment of distinct cerebellar networks related to lower limb motor functions. Therefore, cerebellar tACS might represent a useful tool to modulate walking training in people with cerebellum-related gait impairment, given that tACS may potentially reset abnormal cerebellar circuitries.