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Kotani, Osamu, Tadaki Suzuki, Masaru Yokoyama, Naoko Iwata-Yoshikawa, Noriko Nakajima, Hironori Sato, Hideki Hasegawa, Fumihiro Taguchi, Hiroyuki Shimizu, and Noriyo Nagata. "Intracerebral Inoculation of Mouse-Passaged Saffold Virus Type 3 Affects Cerebellar Development in Neonatal Mice." Journal of Virology 90, no. 21 (August 31, 2016): 10007–21. http://dx.doi.org/10.1128/jvi.00864-16.
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ABSTRACTSaffold virus (SAFV), a human cardiovirus, is occasionally detected in infants with neurological disorders, including meningitis and cerebellitis. We recently reported that SAFV type 3 isolates infect cerebellar glial cells, but not large neurons, in mice. However, the impact of this infection remained unclear. Here, we determined the neuropathogenesis of SAFV type 3 in the cerebella of neonatal ddY mice by using SAFV passaged in the cerebella of neonatal BALB/c mice. The virus titer in the cerebellum increased following the inoculation of each of five passaged strains. The fifth passaged strain harbored amino acid substitutions in the VP2 (H160R and Q239R) and VP3 (K62M) capsid proteins. Molecular modeling of the capsid proteins suggested that the VP2-H160R and VP3-K62M mutations alter the structural dynamics of the receptor binding surface via the formation of a novel hydrophobic interaction between the VP2 puff B and VP3 knob regions. Compared with the original strain, the passaged strain showed altered growth characteristics in human-derived astroglial cell lines and greater replication in the brains of neonatal mice. In addition, the passaged strain was more neurovirulent than the original strain, while both strains infected astroglial and neural progenitor cells in the mouse brain. Intracerebral inoculation of either the original or the passaged strain affected brain Purkinje cell dendrites, and a high titer of the passaged strain induced cerebellar hypoplasia in neonatal mice. Thus, infection by mouse-passaged SAFV affected cerebellar development in neonatal mice. This animal model contributes to the understanding of the neuropathogenicity of SAFV infections in infants.IMPORTANCESaffold virus (SAFV) is a candidate neuropathogenic agent in infants and children, but the neuropathogenicity of the virus has not been fully elucidated. Recently, we evaluated the pathogenicity of two clinical SAFV isolates in mice. Similar to other neurotropic picornaviruses, these isolates showed mild infectivity of glial and neural progenitor cells, but not of large neurons, in the cerebellum. However, the outcome of this viral infection in the cerebellum has not been clarified. Here, we examined the tropism of SAFV in the cerebellum. We obtained anin vivo-passaged strain from the cerebella of neonatal mice and examined its genome and its neurovirulence in the neonatal mouse brain. The passaged virus showed high infectivity and neurovirulence in the brain, especially the cerebellum, and affected cerebellar development. This unique neonatal mouse model will be helpful for elucidating the neuropathogenesis of SAFV infections occurring early in life.
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Kiffmeyer, Elizabeth A., Jameson A. Cosgrove, Jenna K. Siganos, Heidi E. Bien, Jade E. Vipond, Karisa R. Vogt, and Alexander D. Kloth. "Deficits in Cerebellum-Dependent Learning and Cerebellar Morphology in Male and Female BTBR Autism Model Mice." NeuroSci 3, no. 4 (November 9, 2022): 624–44. http://dx.doi.org/10.3390/neurosci3040045.
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Recently, there has been increased interest in the role of the cerebellum in autism spectrum disorder (ASD). To better understand the pathophysiological role of the cerebellum in ASD, it is necessary to have a variety of mouse models that have face validity for cerebellar disruption in humans. Here, we add to the literature on the cerebellum in mouse models of autism with the characterization of the cerebellum in the idiopathic BTBR T + Itpr3tf/J (BTBR) inbred mouse strain, which has behavioral phenotypes that are reminiscent of ASD in patients. When we examined both male and female BTBR mice in comparison to C57BL/6J (C57) controls, we noted that both sexes of BTBR mice showed motor coordination deficits characteristic of cerebellar dysfunction, but only the male mice showed differences in delay eyeblink conditioning, a cerebellum-dependent learning task that is known to be disrupted in ASD patients. Both male and female BTBR mice showed considerable expansion of, and abnormal foliation in, the cerebellum vermis—including a significant expansion of specific lobules in the anterior cerebellum. In addition, we found a slight but significant decrease in Purkinje cell density in both male and female BTBR mice, irrespective of the lobule. Finally, there was a marked reduction of Purkinje cell dendritic spine density in both male and female BTBR mice. These findings suggest that, for the most part, the BTBR mouse model phenocopies many of the characteristics of the subpopulation of ASD patients that have a hypertrophic cerebellum. We discuss the significance of strain differences in the cerebellum as well as the importance of this first effort to identify both similarities and differences between male and female BTBR mice with regard to the cerebellum.
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Geminiani, Alice, Claudia Casellato, Alberto Antonietti, Egidio D’Angelo, and Alessandra Pedrocchi. "A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies." International Journal of Neural Systems 28, no. 05 (April 19, 2018): 1750017. http://dx.doi.org/10.1142/s0129065717500174.
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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.
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Pollok, Bettina, Joachim Gross, Daniel Kamp, and Alfons Schnitzler. "Evidence for Anticipatory Motor Control within a Cerebello-Diencephalic-Parietal Network." Journal of Cognitive Neuroscience 20, no. 5 (May 2008): 828–40. http://dx.doi.org/10.1162/jocn.2008.20506.
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The posterior parietal cortex and the cerebellum are assumed to contribute to anticipatory motor control. Thus, it is reasonable that these areas act as a functional unit. To identify a neural signature of anticipatory motor control, 11 healthy volunteers performed a bimanual finger-tapping task with respect to isochronous (i.e., regular) and randomized (i.e., irregular) auditory pacing. Neuromagnetic activity was recorded using a 122-channel whole-head neuromagnetometer. Functional interaction between spatially distributed brain areas was determined by measures of tap-related phase synchronization. Assuming that (i) the cerebellum predicts sensory events by an internal model and (ii) the PPC maintains this prediction, we hypothesized that functional interaction between both structures varies depending on the predictability of the pacing signal. During isochronous pacing, functional connectivity within a cerebello-diencephalic-parietal network before tap onset was evident, suggesting anticipatory motor control. During randomized pacing, however, functional connectivity after tap onset was increased within a parietal-cerebellar loop, suggesting mismatch detection and update of the internal model. Data of the present study imply that anticipatory motor control is implemented in a network-like manner. Our data agree well with the hypothesis that functional connectivity in a cerebello-diencephalic-parietal loop might be crucial for anticipatory motor control, whereas parietal-cerebellar interaction might be critical for feedback processing.
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Omotoso, Gabriel Olaiya, Leviticus Oghenevurinrin Arietarhire, Ileje Inelo Ukwubile, and Ismail Temitayo Gbadamosi. "The Protective Effect of Kolaviron on Molecular, Cellular, and Behavioral Characterization of Cerebellum in the Rat Model of Demyelinating Diseases." Basic and Clinical Neuroscience Journal 11, no. 5 (September 1, 2020): 609–18. http://dx.doi.org/10.32598/bcn.9.10.300.
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Introduction: This study aimed at assessing the protective mechanisms of Kolaviron (KV) on the cerebellum in a rat model of demyelination. Methods: Twenty-eight male Wistar rats were used in the present study. They were randomly divided into 4 groups of 7 rats. Group A (control) received corn oil (0.5 mL/kg/d); group B received 0.2% Cuprizone (CPZ); group C was treated with 200 mg/kg/d of KV, and group D received 0.2% CPZ and 200 mg/kg/d KV for 6 weeks. CPZ powder was mixed with the regular diet while KV was dissolved in corn oil and administered orally. A behavioral test was conducted at the termination of the experiment. Thereafter, the animals were sacrificed and their brains were removed with the excision of the cerebellum. A part of the cerebelli underwent tissue processing with a series of 5 µm thick sections cut from paraffin blocks for histological and immunohistochemical assessment. Besides, the remaining cerebellar tissues were homogenized for the spectrophotometric assays of Oxidative Stress (OS) parameters. Results: The current research findings revealed minimal weight gain following CPZ treatment, but significant weight increase in KV-treated rats. CPZ treatment was associated with a reduction in the number of the line crossed, rearing frequency, rearing duration, center square entry, and center square duration; however, it increased the freezing time, i.e. significantly reversed in the KV-treated animals. Oxidative markers, such as Superoxide Dismutase (SOD) and GPx were reduced in CPZ-treated rats with elevated MDA levels. However, these data were significantly reversed by the co-administration of CPZ and KV. At the tissue level, the cerebellar cortex was characterized by poorly defined layers, cryptic granules, as well as chromatolysis and pyknotic Purkinje cells with the evidence of hypertrophic astrogliosis. Conclusion: CPZ treatment significantly depressed locomotor and exploratory activities. Furthermore, it increased OS and cerebellar toxicity. However, KV intervention significantly enhanced behavioral functions and ameliorated CPZ-induced cerebellar degeneration. Moreover, it considerably regulated OS markers in the cerebellum of the rat model of demyelinating diseases.
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Kim, Jusik, Keeeun Kim, Jung-soon Mo, and Youngsoo Lee. "Atm deficiency in the DNA polymerase β null cerebellum results in cerebellar ataxia and Itpr1 reduction associated with alteration of cytosine methylation." Nucleic Acids Research 48, no. 7 (March 3, 2020): 3678–91. http://dx.doi.org/10.1093/nar/gkaa140.
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Abstract Genomic instability resulting from defective DNA damage responses or repair causes several abnormalities, including progressive cerebellar ataxia, for which the molecular mechanisms are not well understood. Here, we report a new murine model of cerebellar ataxia resulting from concomitant inactivation of POLB and ATM. POLB is one of key enzymes for the repair of damaged or chemically modified bases, including methylated cytosine, but selective inactivation of Polb during neurogenesis affects only a subpopulation of cortical interneurons despite the accumulation of DNA damage throughout the brain. However, dual inactivation of Polb and Atm resulted in ataxia without significant neuropathological defects in the cerebellum. ATM is a protein kinase that responds to DNA strand breaks, and mutations in ATM are responsible for Ataxia Telangiectasia, which is characterized by progressive cerebellar ataxia. In the cerebella of mice deficient for both Polb and Atm, the most downregulated gene was Itpr1, likely because of misregulated DNA methylation cycle. ITPR1 is known to mediate calcium homeostasis, and ITPR1 mutations result in genetic diseases with cerebellar ataxia. Our data suggest that dysregulation of ITPR1 in the cerebellum could be one of contributing factors to progressive ataxia observed in human genomic instability syndromes.
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Knolle, Franziska, Erich Schröger, Pamela Baess, and Sonja A. Kotz. "The Cerebellum Generates Motor-to-Auditory Predictions: ERP Lesion Evidence." Journal of Cognitive Neuroscience 24, no. 3 (March 2012): 698–706. http://dx.doi.org/10.1162/jocn_a_00167.
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Forward predictions are crucial in motor action (e.g., catching a ball, or being tickled) but may also apply to sensory or cognitive processes (e.g., listening to distorted speech or to a foreign accent). According to the “internal forward model,” the cerebellum generates predictions about somatosensory consequences of movements. These predictions simulate motor processes and prepare respective cortical areas for anticipated sensory input. Currently, there is very little evidence that a cerebellar forward model also applies to other sensory domains. In the current study, we address this question by examining the role of the cerebellum when auditory stimuli are anticipated as a consequence of a motor act. We applied an N100 suppression paradigm and compared the ERP in response to self-initiated with the ERP response to externally produced sounds. We hypothesized that sensory consequences of self-initiated sounds are precisely predicted and should lead to an N100 suppression compared with externally produced sounds. Moreover, if the cerebellum is involved in the generation of a motor-to-auditory forward model, patients with focal cerebellar lesions should not display an N100 suppression effect. Compared with healthy controls, patients showed a largely attenuated N100 suppression effect. The current results suggest that the cerebellum forms not only motor-to-somatosensory predictions but also motor-to-auditory predictions. This extends the cerebellar forward model to other sensory domains such as audition.
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Liu, Qi, Chang Liu, Yu Chen, and Yumei Zhang. "Cognitive Dysfunction following Cerebellar Stroke: Insights Gained from Neuropsychological and Neuroimaging Research." Neural Plasticity 2022 (April 15, 2022): 1–11. http://dx.doi.org/10.1155/2022/3148739.
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Although the cerebellum has been consistently noted in the process of cognition, the pathophysiology of this link is still under exploration. Cerebellar stroke, in which the lesions are focal and limited, provides an appropriate clinical model disease for studying the role of the cerebellum in the cognitive process. This review article targeting the cerebellar stroke population (1) describes a cognitive impairment profile, (2) identifies the cerebellar structural alterations linked to cognition, and (3) reveals possible mechanisms of cerebellar cognition using functional neuroimaging. The data indicates the disruption of the cerebro-cerebellar loop in cerebellar stroke and its contribution to cognitive dysfunctions. And the characteristic of cognitive deficits are mild, span a broad spectrum, dominated by executive impairment. The consideration of these findings could contribute to deeper and more sophisticated insights into the cognitive function of the cerebellum and might provide a novel approach to cognitive rehabilitation. The goal of this review is to spread awareness of cognitive impairments in cerebellar disorders.
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Kurtaj, Lavdim, Vjosa Shatri, and Ilir Limani. "Cerebellar Model Controller with new Model of Granule Cell-golgi Cell Building Blocks and Two-phase Learning Acquires Multitude of Generalization Capabilities in Controlling Robot Joint without Exponential Growth in Complexity." International Journal of Electrical and Computer Engineering (IJECE) 8, no. 6 (December 1, 2018): 4292. http://dx.doi.org/10.11591/ijece.v8i6.pp4292-4309.
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Processing in the cerebellum is roughly described as feed forward processing of incoming information over three layers of the cerebellar cortex that send intermediate output to deep cerebellar nuclei, the only output from the cerebellum. Beside this main picture there are several feedback routes, mainly not included in models. In this paper we use new model for neuronal circuit of the cerebellar granule cell layer, as collection of idealized granule cell–golgi cell building blocks with capability of generating multi-dimensional receptive fields modulated by separate input coming to lower dendrite tree of Golgi cell. Resulting cerebellar model controller with two-phase learning will acquire multitude of generalization capabilities when used as robot joint controller. This will usually require more than one Purkinje cell per output. Functionality of granule cell-Golgi cell building block was evaluated with simulations using Simulink single compartment spiking neuronal model. Trained averaging cerebellar model controller attains very good tracking results for wide range of unlearned slower and faster trajectories, with additional improvements by relearning at faster trajectories. Inclusion of new dynamical effects to the controller results with linear growth in complexity for inputs targeting lower dendrite tree of Golgi cell, important for control applications in robotics, but not only.
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Shiba, Kazuhiro, Takashi Torashima, Hirokazu Hirai, Kazuma Ogawa, Nasima Akhter, Kenichi Nakajima, Seigo Kinuya, and Hirofumi Mori. "Potential Usefulness of D2R Reporter Gene Imaging by IBF as Gene Therapy Monitoring for Cerebellar Neurodegenerative Diseases." Journal of Cerebral Blood Flow & Metabolism 29, no. 2 (November 12, 2008): 434–40. http://dx.doi.org/10.1038/jcbfm.2008.137.
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We investigated a gene expression imaging method to examine the level of therapeutic gene expression in the cerebellum. Using a human immunodeficiency virus derived lentivial vector, we expressed the dopamine D2 receptor (D2R) as a reporter protein to mouse cerebellar Purkinje cells. Biodistribution and ex vivo autoradiography studies were performed by giving [125I]5-iodo-7- N-[(1-ethyl-2-pyrrolidinyl)methyl]carboxamide-2,3-dihydrobenzofuran ([125I]IBF) (1.85MBq), as a radioactive D2R ligand, to model mice expressing the D2R with an HA tag (HA-D2R) in the cerebellum. In this study, [125I]IBF was bound to the D2R expressed in the cerebellum of the model mice selectively. Immunostaining was performed to confirm the HA-D2R expression in the cerebellum of the model mice. A significant correlation ( r = 0.900, P< 0.001) between areas that expressed HA-D2R by immunostaining and areas in which [125I]IBF accumulated by the ex vivo autoradiograms was found. These results indicated that radioiodinated IBF is useful as a reporter probe to detect D2R reporter gene expression, which can be used for monitoring therapeutic gene expression in the cerebellum.
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Kotz, Sonja A., Anika Stockert, and Michael Schwartze. "Cerebellum, temporal predictability and the updating of a mental model." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1658 (December 19, 2014): 20130403. http://dx.doi.org/10.1098/rstb.2013.0403.
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We live in a dynamic and changing environment, which necessitates that we adapt to and efficiently respond to changes of stimulus form (‘what’) and stimulus occurrence (‘when’). Consequently, behaviour is optimal when we can anticipate both the ‘what’ and ‘when’ dimensions of a stimulus. For example, to perceive a temporally expected stimulus, a listener needs to establish a fairly precise internal representation of its external temporal structure, a function ascribed to classical sensorimotor areas such as the cerebellum. Here we investigated how patients with cerebellar lesions and healthy matched controls exploit temporal regularity during auditory deviance processing. We expected modulations of the N2b and P3b components of the event-related potential in response to deviant tones, and also a stronger P3b response when deviant tones are embedded in temporally regular compared to irregular tone sequences. We further tested to what degree structural damage to the cerebellar temporal processing system affects the N2b and P3b responses associated with voluntary attention to change detection and the predictive adaptation of a mental model of the environment, respectively. Results revealed that healthy controls and cerebellar patients display an increased N2b response to deviant tones independent of temporal context. However, while healthy controls showed the expected enhanced P3b response to deviant tones in temporally regular sequences, the P3b response in cerebellar patients was significantly smaller in these sequences. The current data provide evidence that structural damage to the cerebellum affects the predictive adaptation to the temporal structure of events and the updating of a mental model of the environment under voluntary attention.
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Kidani, Naoya, Tomohito Hishikawa, Masafumi Hiramatsu, Shingo Nishihiro, Kyohei Kin, Yu Takahashi, Satoshi Murai, et al. "Cerebellar Blood Flow and Gene Expression in Crossed Cerebellar Diaschisis after Transient Middle Cerebral Artery Occlusion in Rats." International Journal of Molecular Sciences 21, no. 11 (June 10, 2020): 4137. http://dx.doi.org/10.3390/ijms21114137.
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Crossed cerebellar diaschisis (CCD) is a state of hypoperfusion and hypometabolism in the contralesional cerebellar hemisphere caused by a supratentorial lesion, but its pathophysiology is not fully understood. We evaluated chronological changes in cerebellar blood flow (CbBF) and gene expressions in the cerebellum using a rat model of transient middle cerebral artery occlusion (MCAO). CbBF was analyzed at two and seven days after MCAO using single photon emission computed tomography (SPECT). DNA microarray analysis and western blotting of the cerebellar cortex were performed and apoptotic cells in the cerebellar cortex were stained. CbBF in the contralesional hemisphere was significantly decreased and this lateral imbalance recovered over one week. Gene set enrichment analysis revealed that a gene set for “oxidative phosphorylation” was significantly upregulated while fourteen other gene sets including “apoptosis”, “hypoxia” and “reactive oxygen species” showed a tendency toward upregulation in the contralesional cerebellum. MCAO upregulated the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the contralesional cerebellar cortex. The number of apoptotic cells increased in the molecular layer of the contralesional cerebellum. Focal cerebral ischemia in our rat MCAO model caused CCD along with enhanced expression of genes related to oxidative stress and apoptosis.
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Zhang, Xu, Roeland Hancock, and Sabato Santaniello. "Transcranial direct current stimulation of cerebellum alters spiking precision in cerebellar cortex: A modeling study of cellular responses." PLOS Computational Biology 17, no. 12 (December 9, 2021): e1009609. http://dx.doi.org/10.1371/journal.pcbi.1009609.
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Transcranial direct current stimulation (tDCS) of the cerebellum has rapidly raised interest but the effects of tDCS on cerebellar neurons remain unclear. Assessing the cellular response to tDCS is challenging because of the uneven, highly stratified cytoarchitecture of the cerebellum, within which cellular morphologies, physiological properties, and function vary largely across several types of neurons. In this study, we combine MRI-based segmentation of the cerebellum and a finite element model of the tDCS-induced electric field (EF) inside the cerebellum to determine the field imposed on the cerebellar neurons throughout the region. We then pair the EF with multicompartment models of the Purkinje cell (PC), deep cerebellar neuron (DCN), and granule cell (GrC) and quantify the acute response of these neurons under various orientations, physiological conditions, and sequences of presynaptic stimuli. We show that cerebellar tDCS significantly modulates the postsynaptic spiking precision of the PC, which is expressed as a change in the spike count and timing in response to presynaptic stimuli. tDCS has modest effects, instead, on the PC tonic firing at rest and on the postsynaptic activity of DCN and GrC. In Purkinje cells, anodal tDCS shortens the repolarization phase following complex spikes (-14.7 ± 6.5% of baseline value, mean ± S.D.; max: -22.7%) and promotes burstiness with longer bursts compared to resting conditions. Cathodal tDCS, instead, promotes irregular spiking by enhancing somatic excitability and significantly prolongs the repolarization after complex spikes compared to baseline (+37.0 ± 28.9%, mean ± S.D.; max: +84.3%). tDCS-induced changes to the repolarization phase and firing pattern exceed 10% of the baseline values in Purkinje cells covering up to 20% of the cerebellar cortex, with the effects being distributed along the EF direction and concentrated in the area under the electrode over the cerebellum. Altogether, the acute effects of tDCS on cerebellum mainly focus on Purkinje cells and modulate the precision of the response to synaptic stimuli, thus having the largest impact when the cerebellar cortex is active. Since the spatiotemporal precision of the PC spiking is critical to learning and coordination, our results suggest cerebellar tDCS as a viable therapeutic option for disorders involving cerebellar hyperactivity such as ataxia.
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Cabaraux, Pierre, Jordi Gandini, Shinji Kakei, Mario Manto, Hiroshi Mitoma, and Hirokazu Tanaka. "Dysmetria and Errors in Predictions: The Role of Internal Forward Model." International Journal of Molecular Sciences 21, no. 18 (September 20, 2020): 6900. http://dx.doi.org/10.3390/ijms21186900.
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The terminology of cerebellar dysmetria embraces a ubiquitous symptom in motor deficits, oculomotor symptoms, and cognitive/emotional symptoms occurring in cerebellar ataxias. Patients with episodic ataxia exhibit recurrent episodes of ataxia, including motor dysmetria. Despite the consensus that cerebellar dysmetria is a cardinal symptom, there is still no agreement on its pathophysiological mechanisms to date since its first clinical description by Babinski. We argue that impairment in the predictive computation for voluntary movements explains a range of characteristics accompanied by dysmetria. Within this framework, the cerebellum acquires and maintains an internal forward model, which predicts current and future states of the body by integrating an estimate of the previous state and a given efference copy of motor commands. Two of our recent studies experimentally support the internal-forward-model hypothesis of the cerebellar circuitry. First, the cerebellar outputs (firing rates of dentate nucleus cells) contain predictive information for the future cerebellar inputs (firing rates of mossy fibers). Second, a component of movement kinematics is predictive for target motions in control subjects. In cerebellar patients, the predictive component lags behind a target motion and is compensated with a feedback component. Furthermore, a clinical analysis has examined kinematic and electromyography (EMG) features using a task of elbow flexion goal-directed movements, which mimics the finger-to-nose test. Consistent with the hypothesis of the internal forward model, the predictive activations in the triceps muscles are impaired, and the impaired predictive activations result in hypermetria (overshoot). Dysmetria stems from deficits in the predictive computation of the internal forward model in the cerebellum. Errors in this fundamental mechanism result in undershoot (hypometria) and overshoot during voluntary motor actions. The predictive computation of the forward model affords error-based motor learning, coordination of multiple degrees of freedom, and adequate timing of muscle activities. Both the timing and synergy theory fit with the internal forward model, microzones being the elemental computational unit, and the anatomical organization of converging inputs to the Purkinje neurons providing them the unique property of a perceptron in the brain. We propose that motor dysmetria observed in attacks of ataxia occurs as a result of impaired predictive computation of the internal forward model in the cerebellum.
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Brandauer, B., D. Timmann, A. Häusler, and J. Hermsdörfer. "Influences of Load Characteristics on Impaired Control of Grip Forces in Patients With Cerebellar Damage." Journal of Neurophysiology 103, no. 2 (February 2010): 698–708. http://dx.doi.org/10.1152/jn.00337.2009.
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Various studies showed a clear impairment of cerebellar patients to modulate grip force in anticipation of the loads resulting from movements with a grasped object. This failure corroborated the theory of internal feedforward models in the cerebellum. Cerebellar damage also impairs the coordination of multiple-joint movements and this has been related to deficient prediction and compensation of movement-induced torques. To study the effects of disturbed torque control on feedforward grip-force control, two self-generated load conditions with different demands on torque control—one with movement-induced and the other with isometrically generated load changes—were directly compared in patients with cerebellar degeneration. Furthermore the cerebellum is thought to be more involved in grip-force adjustment to self-generated loads than to externally generated loads. Consequently, an additional condition with externally generated loads was introduced to further test this hypothesis. Analysis of 23 patients with degenerative cerebellar damage revealed clear impairments in predictive feedforward mechanisms in the control of both self-generated load types. Besides feedforward control, the cerebellar damage also affected more reactive responses when the externally generated load destabilized the grip, although this impairment may vary with the type of load as suggested by control experiments. The present findings provide further support that the cerebellum plays a major role in predictive control mechanisms. However, this impact of the cerebellum does not strongly depend on the nature of the load and the specific internal forward model. Contributions to reactive (grip force) control are not negligible, but seem to be dependent on the physical characteristics of an externally generated load.
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Sreelakshmy, R., Anita Titus, N. Sasirekha, E. Logashanmugam, R. Benazir Begam, G. Ramkumar, and Raja Raju. "An Automated Deep Learning Model for the Cerebellum Segmentation from Fetal Brain Images." BioMed Research International 2022 (June 16, 2022): 1–13. http://dx.doi.org/10.1155/2022/8342767.
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Cerebellum measures taken from routinely obtained ultrasound (US) images have been frequently employed to determine gestational age and identify developing central nervous system’s anatomical abnormalities. Standardized cerebellar assessments from large-scale clinical datasets are required to investigate correlations between the growing cerebellum and postnatal neurodevelopmental results. These studies could uncover structural abnormalities that could be employed as indicators to forecast neurodevelopmental and growth consequences. To achieve this, higher-throughput, precise, and impartial measures must be used to replace the existing human, semiautomatic, and advanced algorithms, which seem to be time-consuming and inaccurate. In this article, we presented an innovative deep learning (DL) technique for automatic fetal cerebellum segmentation from 2-dimensional (2D) US brain images. We present ReU-Net, a semantic segmentation network tailored to the anatomy of the fetal cerebellum. Moreover, we use U-Net as a foundation models with the incorporation of residual blocks and Wiener filter over the last 2 layers to segregate the cerebellum (c) from the noisy US data. 590 images for training and 150 images for testing were taken; also, we employed a 5-fold cross-assessment method. Our ReU-Net scored 91%, 92%, 25.42, 98%, 92%, and 94% for Dice Score Coefficient (DSC), F1-score, Hausdorff Distance (HD), accuracy, recall, and precision, correspondingly. The suggested method outperforms the other U-Net predicated techniques by a quantitatively significant margin ( p 0.001 ). Our presented approach can be used to allow high bandwidth imaging techniques in medical study fetal US images as well as biometric evaluation on a broader scale in fetal US images.
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Pinheiro, Ana, Sylvain Bouix, Nikos Makris, Michael Schwartze, Martha Shenton, and Sonja Kotz. "T163. STRUCTURAL AND CONNECTIVITY CHANGES IN THE CEREBELLUM CONTRIBUTE TO EXPERIENCING AUDITORY VERBAL HALLUCINATIONS." Schizophrenia Bulletin 46, Supplement_1 (April 2020): S293. http://dx.doi.org/10.1093/schbul/sbaa029.723.
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Abstract Background Auditory verbal hallucinations (AVH) have been explained in the context of the forward model, giving the cerebellum a prominent role. However, research utilizing multiple neuroimaging modalities has rendered results on the specificity of cerebellar contribution to AVH unclear. Methods To examine the reliability and regional specificity of cerebellar changes in AVH, a systematic search of electronic databases through October 2019 was conducted to identify neuroimaging studies of the cerebellum in psychotic patients or nonclinical participants reporting AVH, focusing on structural MRI, diffusion tensor imaging, and resting state functional connectivity studies. Twenty-two studies were selected, including 892 participants with AVH (792 psychotic patients; 100 at-risk subjects) and 775 healthy controls. Activation likelihood estimate analysis (ALE) examined the reported coordinates for reduced volume, fractional anisotropy (FA) or connectivity (control participants > participants with AVH) and increased volume, FA or connectivity (participants with AVH > control participants). The consistency of cerebellar changes and their relationship with sociodemographic and clinical measures were meta-analyzed. Results The ALE meta-analysis revealed changes in both anterior and posterior cerebellar lobes, with opposite patterns: whereas decreased volume or connectivity was identified in the right anterior cerebellum (lobule IV/V), increased volume or connectivity was identified in the bilateral posterior cerebellum (Crus I and II). A random-effects model with small sample corrections identified consistent changes in both volume and functional connectivity of the cerebellum in participants with AVH (g = .84; SE = .24, 95% CI [.33, 1.34]), which were enhanced in Crus I (g = 1.52, SE = .28, p = .006, 95% CI [.73, 2.31]) but not moderated by age, sex, medication, or illness duration. Discussion The ALE meta-analysis confirms cerebellar structural and connectivity changes in psychotic and nonclinical participants reporting AVH. These changes may contribute to AVH due to altered sensory feedback and consequently to erratic prediction as described by the forward model. The current findings also indicate that not all cerebellar regions are equally affected by AVH: the most pronounced changes were observed in Crus I. Specifically, altered communication between Crus I and neocortical network nodes, including the prefrontal cortex, may contribute to ineffective cognitive control in AVH, leading to external misattributions of auditory feedback and a reduced sense of control over events in the environment.
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Wilson, Emma D., Tareq Assaf, Martin J. Pearson, Jonathan M. Rossiter, Sean R. Anderson, John Porrill, and Paul Dean. "Cerebellar-inspired algorithm for adaptive control of nonlinear dielectric elastomer-based artificial muscle." Journal of The Royal Society Interface 13, no. 122 (September 2016): 20160547. http://dx.doi.org/10.1098/rsif.2016.0547.
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Electroactive polymer actuators are important for soft robotics, but can be difficult to control because of compliance, creep and nonlinearities. Because biological control mechanisms have evolved to deal with such problems, we investigated whether a control scheme based on the cerebellum would be useful for controlling a nonlinear dielectric elastomer actuator, a class of artificial muscle. The cerebellum was represented by the adaptive filter model, and acted in parallel with a brainstem, an approximate inverse plant model. The recurrent connections between the two allowed for direct use of sensory error to adjust motor commands. Accurate tracking of a displacement command in the actuator's nonlinear range was achieved by either semi-linear basis functions in the cerebellar model or semi-linear functions in the brainstem corresponding to recruitment in biological muscle. In addition, allowing transfer of training between cerebellum and brainstem as has been observed in the vestibulo-ocular reflex prevented the steady increase in cerebellar output otherwise required to deal with creep. The extensibility and relative simplicity of the cerebellar-based adaptive-inverse control scheme suggests that it is a plausible candidate for controlling this type of actuator. Moreover, its performance highlights important features of biological control, particularly nonlinear basis functions, recruitment and transfer of training.
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Fauzi, Anwar, Widjiati Widjiati, and Hermanto T. Joewono. "Fifty percent of food restriction during gestation reduced the dendritic density of cerebrum and cerebellum of Rattus norvegicus newborn." Majalah Obstetri & Ginekologi 26, no. 3 (February 9, 2019): 112. http://dx.doi.org/10.20473/mog.v26i32018.112-117.
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Objectives: To analyze the influence of 50 percent food restriction during pregnancy to the dendritic density of cerebellum and cerebellum of newborn Rattus norvegicus.Materials and Methods: Laboratory experimental study with single blind randomized post-test only control group design using animal model; pregnant Rattus norvegicus as treatment models. Subjects were divided into two groups: control group and treatment group which was exposed to 50% food restriction (FR 50%). At day 21, both group sacrificed and the cerebrum and cerebelum of the offsprings were prepared and stained with silver impregnation. We used parametric independent t-test in analyzing dendritic density.Results: In the cerebrum there was a significant difference in dendritic density between control (4.98+2.17) and treatment (2.69+0.76) groups with p=0.001 (p<0.05). In the cerebellum there was ALSO a significant difference in dendritic density between control (7.37+2.23) and treatment groups (3.01+0.64) with p=0.000 (p<0.05).Conclusions: The dendritic density of cerebrum and cerebellum of newborn Rattus norvegicusexposed to 50 percent of food restriction during pregnancy were lower than control.
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Oliveira-Ferreira, Ana I., Sebastian Major, Ingo Przesdzing, Eun-Jeung Kang, and Jens P. Dreier. "Spreading depolarizations in the rat endothelin-1 model of focal cerebellar ischemia." Journal of Cerebral Blood Flow & Metabolism 40, no. 6 (July 7, 2019): 1274–89. http://dx.doi.org/10.1177/0271678x19861604.
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Focal brain ischemia is best studied in neocortex and striatum. Both show highly vulnerable neurons and high susceptibility to spreading depolarization (SD). Therefore, it has been hypothesized that these two variables generally correlate. However, this hypothesis is contradicted by findings in cerebellar cortex, which contains highly vulnerable neurons to ischemia, the Purkinje cells, but is said to be less susceptible to SD. Here, we found in the rat cerebellar cortex that elevated K+ induced a long-lasting depolarizing event superimposed with SDs. Cerebellar SDs resembled those in neocortex, but negative direct current (DC) shifts and regional blood flow responses were usually smaller. The K+ threshold for SD was higher in cerebellum than in previous studies in neocortex. We then topically applied endothelin-1 (ET-1) to the cerebellum, which is assumed to cause SD via vasoconstriction-induced focal ischemia. Although the blood flow decrease was similar to that in previous studies in neocortex, the ET-1 threshold for SD was higher. Quantitative cell counting found that the proportion of necrotic Purkinje cells was significantly higher in ET-1-treated rats than sham controls even if ET-1 had not caused SDs. Our results suggest that ischemic death of Purkinje cells does not require the occurrence of SD.
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Calatrava-Ferreras, Lucía, Rafael Gonzalo-Gobernado, Antonio S. Herranz, Diana Reimers, Teresa Montero Vega, Adriano Jiménez-Escrig, Luis Alberto Richart López, and Eulalia Bazán. "Effects of Intravenous Administration of Human Umbilical Cord Blood Stem Cells in 3-Acetylpyridine-Lesioned Rats." Stem Cells International 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/135187.
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Cerebellar ataxias include a heterogeneous group of infrequent diseases characterized by lack of motor coordination caused by disturbances in the cerebellum and its associated circuits. Current therapies are based on the use of drugs that correct some of the molecular processes involved in their pathogenesis. Although these treatments yielded promising results, there is not yet an effective therapy for these diseases. Cell replacement strategies using human umbilical cord blood mononuclear cells (HuUCBMCs) have emerged as a promising approach for restoration of function in neurodegenerative diseases. The aim of this work was to investigate the potential therapeutic activity of HuUCBMCs in the 3-acetylpyridine (3-AP) rat model of cerebellar ataxia. Intravenous administered HuUCBMCs reached the cerebellum and brain stem of 3-AP ataxic rats. Grafted cells reduced 3-AP-induced neuronal loss promoted the activation of microglia in the brain stem, and prevented the overexpression of GFAP elicited by 3-AP in the cerebellum. In addition, HuUCBMCs upregulated the expression of proteins that are critical for cell survival, such as phospho-Akt and Bcl-2, in the cerebellum and brain stem of 3-AP ataxic rats. As all these effects were accompanied by a temporal but significant improvement in motor coordination, HuUCBMCs grafts can be considered as an effective cell replacement therapy for cerebellar disorders.
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Roger, F. BuutterWoth. "Pathophysiology of Cerebellar Dysfunction in the Wernicke-Korsakoff Syndrome." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 20, S3 (May 1993): S123—S126. http://dx.doi.org/10.1017/s0317167100048630.
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ABSTRACT:Cerebellar ataxia is a common presenting sign in the Wernicke-Korsakoff syndrome (WKS). Recovery from ataxia following thiamine treatment is rarely complete, suggesting the existence of both a reversible (“biochemical”) lesion as well as irreversible, neuropathological damage. Cerebellar pathology in WKS includes severeloss of Purkinje cells in superior cerebellar vermis as well as neuronal loss from the granular layer. In addition, damage to inferior olivary nucleus could result in loss of climbing fibre input to cerebellum in this condition. Experiments using an animal model of WKS, the pyrithiamine-treated rat, reveal selective reversible decreases of α-ketoglutarate dehydrogenase (αKGDH) in cerebellum. Decreased enzyme activities are associated with decreased cerebellar content of GABA and aspartate. Thiamine reversal of neurological symptoms results in normalization of cerebellar enzyme activities and GABA content suggesting that reduced activities of αKGDH constitute “the biochemical lesion” in these animals. Possible mechanisms implicated in neuronal cell death in cerebellum include impaired cellular energy metabolism, focal lactic acidosis and excitotoxic damage resulting from excess glutamate release mediated by Nmethyl-D-aspartate (NMDA) receptors. Similar mechanisms could be involved in the reversible and irreversible neurological symptoms of WKS in humans.
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Dahmane, N., and A. Ruiz-i-Altaba. "Sonic hedgehog regulates the growth and patterning of the cerebellum." Development 126, no. 14 (July 15, 1999): 3089–100. http://dx.doi.org/10.1242/dev.126.14.3089.
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The molecular bases of brain development and CNS malignancies remain poorly understood. Here we show that Sonic hedgehog (Shh) signaling controls the development of the cerebellum at multiple levels. SHH is produced by Purkinje neurons, it is required for the proliferation of granule neuron precursors and it induces the differentiation of Bergmann glia. Blocking SHH function in vivo results in deficient granule neuron and Bergmann glia differentiation as well as in abnormal Purkinje neuron development. Thus, our findings provide a molecular model for the growth and patterning of the cerebellum by SHH through the coordination of the development of cortical cerebellar cell types. In addition, they provide a cellular context for medulloblastomas, childhood cancers of the cerebellum.
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Bo, Jin, Hannah J. Block, Jane E. Clark, and Amy J. Bastian. "A Cerebellar Deficit in Sensorimotor Prediction Explains Movement Timing Variability." Journal of Neurophysiology 100, no. 5 (November 2008): 2825–32. http://dx.doi.org/10.1152/jn.90221.2008.
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A popular theory is that the cerebellum functions as a timer for clocking motor events (e.g., initiation, termination). Consistent with this idea, cerebellar patients have been reported to show greater deficits during hand movements that repeatedly start and stop (i.e., discontinuous movements) compared with continuous hand movements. Yet, this finding could potentially be explained by an alternate theory in which the cerebellum acts as an internal model of limb mechanics. We tested whether a timing or internal model hypothesis best explains results from a circle-drawing task, where individuals trace a circle with the hand at a desired tempo. We first attempted to replicate prior results showing greater impairment for discontinuous versus continuous circling movements, and then asked whether we could improve patient performance by reducing demands in each domain. First, we slowed the movement down to reduce the need to predict and compensate for limb dynamics. Second, we supplied external timing information to reduce the need for an internal event timer. Results showed that we did not replicate the previous findings—cerebellar patients were impaired in both discontinuous and continuous movements. Slowing the movement improved cerebellar performance to near control values. The addition of an external visual timing signal paradoxically worsened timing deficits rather than mitigating them. One interpretation of these combined results is that the cerebellum is indeed functioning as an internal model and is needed to make appropriate predictions for movement initiation and termination.
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Holloway, Kalee N., Marisa R. Pinson, James C. Douglas, Tonya M. Rafferty, Cynthia J. M. Kane, Rajesh R. Miranda, and Paul D. Drew. "Cerebellar Transcriptomic Analysis in a Chronic plus Binge Mouse Model of Alcohol Use Disorder Demonstrates Ethanol-Induced Neuroinflammation and Altered Glial Gene Expression." Cells 12, no. 5 (February 25, 2023): 745. http://dx.doi.org/10.3390/cells12050745.
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Alcohol use disorder (AUD) is one of the most common preventable mental health disorders and can result in pathology within the CNS, including the cerebellum. Cerebellar alcohol exposure during adulthood has been associated with disruptions in proper cerebellar function. However, the mechanisms regulating ethanol-induced cerebellar neuropathology are not well understood. High-throughput next generation sequencing was performed to compare control versus ethanol-treated adult C57BL/6J mice in a chronic plus binge model of AUD. Mice were euthanized, cerebella were microdissected, and RNA was isolated and submitted for RNA-sequencing. Down-stream transcriptomic analyses revealed significant changes in gene expression and global biological pathways in control versus ethanol-treated mice that included pathogen-influenced signaling pathways and cellular immune response pathways. Microglial-associated genes showed a decrease in homeostasis-associated transcripts and an increase in transcripts associated with chronic neurodegenerative diseases, while astrocyte-associated genes showed an increase in transcripts associated with acute injury. Oligodendrocyte lineage cell genes showed a decrease in transcripts associated with both immature progenitors as well as myelinating oligodendrocytes. These data provide new insight into the mechanisms by which ethanol induces cerebellar neuropathology and alterations to the immune response in AUD.
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Otoda, Yuji, Hiroshi Kimura, and Kunikatsu Takase. "Construction of Gait Adaptation Model in Human Splitbelt Treadmill Walking." Applied Bionics and Biomechanics 6, no. 3-4 (2009): 269–84. http://dx.doi.org/10.1155/2009/305061.
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There are a huge number of studies that measure kinematics, dynamics, the oxygen uptake and so on in human walking on the treadmill. Especially in walking on the splitbelt treadmill where the speed of the right and left belt is different, remarkable differences in kinematics are seen between normal and cerebellar disease subjects. In order to construct the gait adaptation model of such human splitbelt treadmill walking, we proposed a simple control model and made a newly developed 2D biped robot walk on the splitbelt treadmill. We combined the conventional limit-cycle based control consisting of joint PD-control, cyclic motion trajectory planning and a stepping reflex with a newly proposed adjustment of P-gain at the hip joint of the stance leg. We showed that the data of robot (normal subject model and cerebellum disease subject model) experiments had high similarities with the data of normal subjects and cerebellum disease subjects experiments carried out by Reisman et al. (2005) and Morton and Bastian (2006) in ratios and patterns. We also showed that P-gain at the hip joint of the stance leg was the control parameter of adaptation for symmetric gaits in splitbelt walking and P-gain adjustment corresponded to muscle stiffness adjustment by the cerebellum. Consequently, we successfully proposed the gait adaptation model in human splitbelt treadmill walking and confirmed the validity of our hypotheses and the proposed model using the biped robot.
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Swart, Jacobus A. A., Jan F. van der Werf, Tonnie Wiegman, Anne M. J. Paans, Willem Vaalburg, and Jakob Korf. "In vivo Binding of Spiperone and N-Methylspiperone to Dopaminergic and Serotonergic Sites in the Rat Brain: Multiple Modeling and Implications for PET Scanning." Journal of Cerebral Blood Flow & Metabolism 10, no. 3 (May 1990): 297–306. http://dx.doi.org/10.1038/jcbfm.1990.58.
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Equilibrium models are derived and applied to in vivo binding of spiperone in the rat brain. The models express the concentration of the ligand in the striatum and frontal cortex as a function of the accumulation in the cerebellum. The models differ with respect to the description of specific binding. Nonlinear regression analysis shows that the in vivo specific binding of 3H-labeled spiperone in the frontal cortex (mainly serotonergic) can be described by a noninteracting sites model, whereas the specific binding in the striatum (mainly dopaminergic) can best be described by models that lead to sigmoid saturation curves. These results were tested and partly confirmed by determining the region-of-interest/cerebellar radioactivity ratio of 11C-labeled N-methylspiperone, with and without pretreatment with haloperidol. The estimated Bmax was 32 fmol/mg wet tissue in the frontal cortex and ∼90 fmol/mg wet tissue in the striatum. The free plus nonspecific binding of spiperone was similar in the frontal cortex but lower in the striatum than in the cerebellum. The occurrence of sigmoidicity can be best explained by the existence of high-affinity/low-capacity sites in the cerebellum rather than mutual interactions of striatal sites. The consequence of the present analysis for positron emission tomography is that the striatal/cerebellar activity ratio is not an accurate parameter of specific binding features at tracer doses of spiperone or N-methylspiperone.
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Topka, Helge, and Johannes Dichgans. "The cerebellum and the physics of movement." Behavioral and Brain Sciences 20, no. 2 (June 1997): 266. http://dx.doi.org/10.1017/s0140525x97461435.
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This commentary reviews the basic physical principles underlying human single- and multi-joint arm movements. The potential role of the cerebellum in dealing with the physics of movement is discussed in the light of recent physiological findings and the theoretical model of cerebellar detection and generation of input and output sequences put forward by Braitenberg and colleagues.
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Quaia, Christian, Philippe Lefèvre, and Lance M. Optican. "Model of the Control of Saccades by Superior Colliculus and Cerebellum." Journal of Neurophysiology 82, no. 2 (August 1, 1999): 999–1018. http://dx.doi.org/10.1152/jn.1999.82.2.999.
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Experimental evidence indicates that the superior colliculus (SC) is important but neither necessary nor sufficient to produce accurate saccadic eye movements. Furthermore both clinical and experimental evidence points to the cerebellum as an indispensable component of the saccadic system. Accordingly, we have devised a new model of the saccadic system in which the characteristics of saccades are determined by the cooperation of two pathways, one through the SC and the other through the cerebellum. Both pathways are influenced by feedback information: the feedback determines the decay of activity for collicular neurons and the timing of the activation for cerebellar neurons. We have modeled three types of cells (burst, buildup, and fixation neurons) found in the intermediate layers of the superior colliculus. We propose that, from the point of view of motor execution, the burst neurons and the buildup neurons are not functionally distinct with both providing a directional drive to the brain stem circuitry. The fixation neurons determine the onset of the saccade by disfacilitating the omnipause neurons in the brain stem. Excluding noise-related variations, the ratio of the horizontal to the vertical components of the collicular drive is fixed throughout the saccade (i.e., its direction is fixed); the duration of the drive is such that it always would produce hypermetric movements. The cerebellum plays three roles: first, it provides an additional directional drive, which improves the acceleration of the eyes; second, it keeps track of the progress of the saccade toward the target; and third, it ends the saccade by choking off the collicular drive. The drive provided by the cerebellum can be adjusted in direction to exert a directional control over the saccadic trajectory. We propose here a control mechanism that incorporates a spatial displacement integrator in the cerebellum; under such conditions, we show that a partial directional control arises automatically. Our scheme preserves the advantages of several previous models of the saccadic system (e.g., the lack of a spatial-to-temporal transformation between the SC and the brain stem; the use of efference copy feedback to control the saccade), without incurring many of their drawbacks, and it accounts for a large amount of experimental data.
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Buonomano, Dean V., and Michael D. Mauk. "Neural Network Model of the Cerebellum: Temporal Discrimination and the Timing of Motor Responses." Neural Computation 6, no. 1 (January 1994): 38–55. http://dx.doi.org/10.1162/neco.1994.6.1.38.
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Substantial evidence has established that the cerebellum plays an important role in the generation of movements. An important aspect of motor output is its timing in relation to external stimuli or to other components of a movement. Previous studies suggest that the cerebellum plays a role in the timing of movements. Here we describe a neural network model based on the synaptic organization of the cerebellum that can generate timed responses in the range of tens of milliseconds to seconds. In contrast to previous models, temporal coding emerges from the dynamics of the cerebellar circuitry and depends neither on conduction delays, arrays of elements with different time constants, nor populations of elements oscillating at different frequencies. Instead, time is extracted from the instantaneous granule cell population vector. The subset of active granule cells is time-varying due to the granule—Golgi—granule cell negative feedback. We demonstrate that the population vector of simulated granule cell activity exhibits dynamic, nonperiodic trajectories in response to a periodic input. With time encoded in this manner, the output of the network at a particular interval following the onset of a stimulus can be altered selectively by changing the strength of granule → Purkinje cell connections for those granule cells that are active during the target time window. The memory of the reinforcement at that interval is subsequently expressed as a change in Purkinje cell activity that is appropriately timed with respect to stimulus onset. Thus, the present model demonstrates that a network based on cerebellar circuitry can learn appropriately timed responses by encoding time as the population vector of granule cell activity.
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Wu, Yuan Yuan, and Shao Bai Zhang. "Research on Cerebellar Contributions to Speech Acquisition and Production Based on DIVA Model." Applied Mechanics and Materials 462-463 (November 2013): 175–81. http://dx.doi.org/10.4028/www.scientific.net/amm.462-463.175.
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DIVA (Directions Into Velocities of Articulators) is a mathematical model of the processes behind speech acquisition and production, supposed to achieve a functional representation of areas in the brain that are involved in speech production and speech perception. Owing to its especial structure and roles, introducing cerebellum control modules into the model plays a significant role in improving the mechanism of speech acquisition and production based on DIVA model. To solve this problem, the paper studies its learning process, and explores cerebellar contributions to the model, that is feedforward learning, sensory predictions, feedback command production and the timing of delays, and then adds the corresponding cerebellum modules into the feedback control subsystem on the basis of the current model. Simulation results show that the improved DIVA model can produce more clear and explicit speech sounds, and is more close to human-like pronunciation system.
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Monaco, Jessica, Lorenzo Rocchi, Francesca Ginatempo, Egidio D'Angelo, and John C. Rothwell. "Cerebellar Theta-Burst Stimulation Impairs Memory Consolidation in Eyeblink Classical Conditioning." Neural Plasticity 2018 (October 9, 2018): 1–8. http://dx.doi.org/10.1155/2018/6856475.
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Associative learning of sensorimotor contingences, as it occurs in eyeblink classical conditioning (EBCC), is known to involve the cerebellum, but its mechanism remains controversial. EBCC involves a sequence of learning processes which are thought to occur in the cerebellar cortex and deep cerebellar nuclei. Recently, the extinction phase of EBCC has been shown to be modulated after one week by cerebellar continuous theta-burst stimulation (cTBS). Here, we asked whether cerebellar cTBS could affect retention and reacquisition of conditioned responses (CRs) tested immediately after conditioning. We also investigated a possible lateralized cerebellar control of EBCC by applying cTBS on both the right and left cerebellar hemispheres. Both right and left cerebellar cTBSs induced a statistically significant impairment in retention and new acquisition of conditioned responses (CRs), the disruption effect being marginally more effective when the left cerebellar hemisphere was stimulated. These data support a model in which cTBS impairs retention and reacquisition of CR in the cerebellum, possibly by interfering with the transfer of memory to the deep cerebellar nuclei.
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Parsey, Ramin V., Victoria Arango, Doreen M. Olvet, Maria A. Oquendo, Ronald L. Van Heertum, and J. John Mann. "Regional Heterogeneity of 5-HT1A Receptors in Human Cerebellum as Assessed by Positron Emission Tomography." Journal of Cerebral Blood Flow & Metabolism 25, no. 7 (February 16, 2005): 785–93. http://dx.doi.org/10.1038/sj.jcbfm.9600072.
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Two measures used in brain imaging are binding potential (BP) and the specific to nonspecific equilibrium partition coefficient ( V3“). V3” determined using the 5-HT1A ligand [11C]WAY-100635 is sensitive to changes in the free and nonspecific binding of the ligand in the reference region ( V2). Healthy female volunteers have higher 5-HT1A BP but not V3“ compared with men, because V2 is higher in women. While there could be several explanations for this observation, we hypothesized that women have more 5-HT1A receptors in the cerebellum. We explore the cerebellum to define a subregion that more accurately represents the free and nonspecific binding, potentially allowing the use of V3”. A quantitative autoradiogram in human brain using [3H]WAY-100635 identified a cerebellar subregion devoid of 5-HT1A receptors. In vivo 5-HT1A receptors were evaluated using [11C]WAY-100635 in 12 healthy women and 13 healthy men. Each subject had a metabolite-corrected arterial input function. The autoradiogram demonstrates the lowest concentration of 5-HT1A receptors in the cerebellar white matter (CW) and highest concentration in the cerebellar vermis (CV). The CW volume of distribution ( VT) is lower than CV. Cerebellar white matter is adequately modeled by a one-tissue compartmental model, while a two-tissue model is necessary to model CV or the total cerebellum (CT). Women have a higher CW VT compared with men, suggesting a difference in V2. Use of CW improves identifiability and time stability of BP in cortical regions. Cerebellar white matter might be a better reference region for use in future 5-HT1A studies using [11C]WAY-100635. With CW as a reference region, V3“ cannot be used to detect differences in 5-HT1A receptors between men and women, suggesting the need for arterial input functions to determine BP.
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Armstrong, Carol L., and Richard Hawkes. "Pattern formation in the cerebellar cortex." Biochemistry and Cell Biology 78, no. 5 (October 1, 2000): 551–62. http://dx.doi.org/10.1139/o00-071.
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The cerebellar cortex is subdivided rostrocaudally and mediolaterally into a reproducible array of zones and stripes. This makes the cerebellum a valuable model for studying pattern formation in the vertebrate central nervous system. The structure of the adult mouse cerebellar cortex and the series of embryological events that generate the topography are reviewed.Key words: zebrin, Hsp25, Purkinje cells.
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Antonietti, Alberto, Jessica Monaco, Egidio D'Angelo, Alessandra Pedrocchi, and Claudia Casellato. "Dynamic Redistribution of Plasticity in a Cerebellar Spiking Neural Network Reproducing an Associative Learning Task Perturbed by TMS." International Journal of Neural Systems 28, no. 09 (September 26, 2018): 1850020. http://dx.doi.org/10.1142/s012906571850020x.
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During natural learning, synaptic plasticity is thought to evolve dynamically and redistribute within and among subcircuits. This process should emerge in plastic neural networks evolving under behavioral feedback and should involve changes distributed across multiple synaptic sites. In eyeblink classical conditioning (EBCC), the cerebellum learns to predict the precise timing between two stimuli, hence EBCC represents an elementary yet meaningful paradigm to investigate the cerebellar network functioning. We have simulated EBCC mechanisms by reconstructing a realistic cerebellar microcircuit model and embedding multiple plasticity rules imitating those revealed experimentally. The model was tuned to fit experimental EBCC human data, estimating the underlying learning time-constants. Learning started rapidly with plastic changes in the cerebellar cortex followed by slower changes in the deep cerebellar nuclei. This process was characterized by differential development of long-term potentiation and depression at individual synapses, with a progressive accumulation of plasticity distributed over the whole network. The experimental data included two EBCC sessions interleaved by a trans-cranial magnetic stimulation (TMS). The experimental and the model response data were not significantly different in each learning phase, and the model goodness-of-fit was [Formula: see text] for all the experimental conditions. The models fitted on TMS data revealed a slowed down re-acquisition (sessions-2) compared to the control condition ([Formula: see text]). The plasticity parameters characterizing each model significantly differ among conditions, and thus mechanistically explain these response changes. Importantly, the model was able to capture the alteration in EBCC consolidation caused by TMS and showed that TMS affected plasticity at cortical synapses thereby altering the fast learning phase. This, secondarily, also affected plasticity in deep cerebellar nuclei altering learning dynamics in the entire sensory-motor loop. This observation reveals dynamic redistribution of changes over the entire network and suggests how TMS affects local circuit computation and memory processing in the cerebellum.
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Giangiardi, Vivian Farahte, Sandra Maria Sbeghen F. de Freitas, Flávia P. de Paiva Silva, Renata Morales Banjai, and Sandra Regina Alouche. "Functional Capacity and Motor Performance of Upper Limbs in Individuals with Cerebellar Disorders: A Pilot Study." Behavioural Neurology 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/8980103.
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In simple daily activities carried out by the upper limbs, the cerebellum is responsible for the adaptations required for the accurate movement based on previous experiences and external references. This paper aims to characterize the performance of the upper limbs after a cerebellar disease. We evaluated the digital and handgrip strength, dexterity, and function of the upper limbs. The motor performance of the upper limbs was assessed through the use of a digitizing tablet by performing aiming movements with the upper limb most affected by cerebellar disease and the paired limb of the healthy group. The results showed differences between groups: the cerebellar group had higher latency to movement onset, was slower, and presented less smooth trajectories and higher initial direction errors. Moreover, the movement direction influenced the peak velocity and the smoothness for both groups (contralateral directions were slower and less smooth). We concluded that cerebellar disorder leads to movement planning impairment compromising the formulation of an internal model. Alterations on movement execution seem to be a consequence from disruptions in the anticipatory model, leading to more adaptations. These findings are compatible with the roles of the cerebellum on the control of voluntary movement.
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Parvez, Md Sorwer Alam, and Gen Ohtsuki. "Acute Cerebellar Inflammation and Related Ataxia: Mechanisms and Pathophysiology." Brain Sciences 12, no. 3 (March 10, 2022): 367. http://dx.doi.org/10.3390/brainsci12030367.
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The cerebellum governs motor coordination and motor learning. Infection with external microorganisms, such as viruses, bacteria, and fungi, induces the release and production of inflammatory mediators, which drive acute cerebellar inflammation. The clinical observation of acute cerebellitis is associated with the emergence of cerebellar ataxia. In our animal model of the acute inflammation of the cerebellar cortex, animals did not show any ataxia but hyperexcitability in the cerebellar cortex and depression-like behaviors. In contrast, animal models with neurodegeneration of the cerebellar Purkinje cells and hypoexcitability of the neurons show cerebellar ataxia. The suppression of the Ca2+-activated K+ channels in vivo is associated with a type of ataxia. Therefore, there is a gap in our interpretation between the very early phase of cerebellar inflammation and the emergence of cerebellar ataxia. In this review, we discuss the hypothesized scenario concerning the emergence of cerebellar ataxia. First, compared with genetically induced cerebellar ataxias, we introduce infection and inflammation in the cerebellum via aberrant immunity and glial responses. Especially, we focus on infections with cytomegalovirus, influenza virus, dengue virus, and SARS-CoV-2, potential relevance to mitochondrial DNA, and autoimmunity in infection. Second, we review neurophysiological modulation (intrinsic excitability, excitatory, and inhibitory synaptic transmission) by inflammatory mediators and aberrant immunity. Next, we discuss the cerebellar circuit dysfunction (presumably, via maintaining the homeostatic property). Lastly, we propose the mechanism of the cerebellar ataxia and possible treatments for the ataxia in the cerebellar inflammation.
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Tolu, Silvia, Marie Claire Capolei, Lorenzo Vannucci, Cecilia Laschi, Egidio Falotico, and Mauricio Vanegas Hernández. "A Cerebellum-Inspired Learning Approach for Adaptive and Anticipatory Control." International Journal of Neural Systems 30, no. 01 (November 27, 2019): 1950028. http://dx.doi.org/10.1142/s012906571950028x.
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The cerebellum, which is responsible for motor control and learning, has been suggested to act as a Smith predictor for compensation of time-delays by means of internal forward models. However, insights about how forward model predictions are integrated in the Smith predictor have not yet been unveiled. To fill this gap, a novel bio-inspired modular control architecture that merges a recurrent cerebellar-like loop for adaptive control and a Smith predictor controller is proposed. The goal is to provide accurate anticipatory corrections to the generation of the motor commands in spite of sensory delays and to validate the robustness of the proposed control method to input and physical dynamic changes. The outcome of the proposed architecture with other two control schemes that do not include the Smith control strategy or the cerebellar-like corrections are compared. The results obtained on four sets of experiments confirm that the cerebellum-like circuit provides more effective corrections when only the Smith strategy is adopted and that minor tuning in the parameters, fast adaptation and reproducible configuration are enabled.
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Blot, François G. C., Wilhelmina H. J. J. Krijnen, Sandra Den Hoedt, Catarina Osório, Joshua J. White, Monique T. Mulder, and Martijn Schonewille. "Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice." Proceedings of the National Academy of Sciences 118, no. 36 (September 3, 2021): e2016969118. http://dx.doi.org/10.1073/pnas.2016969118.
Full textAbstract:
Patterned degeneration of Purkinje cells (PCs) can be observed in a wide range of neuropathologies, but mechanisms behind nonrandom cerebellar neurodegeneration remain unclear. Sphingolipid metabolism dyshomeostasis typically leads to PC neurodegeneration; hence, we questioned whether local sphingolipid balance underlies regional sensitivity to pathological insults. Here, we investigated the regional compartmentalization of sphingolipids and their related enzymes in the cerebellar cortex in healthy and pathological conditions. Analysis in wild-type animals revealed higher sphingosine kinase 1 (Sphk1) levels in the flocculonodular cerebellum, while sphingosine-1-phosphate (S1P) levels were higher in the anterior cerebellum. Next, we investigated a model for spinocerebellar ataxia type 1 (SCA1) driven by the transgenic expression of the expanded Ataxin 1 protein with 82 glutamine (82Q), exhibiting severe PC degeneration in the anterior cerebellum while the flocculonodular region is preserved. In Atxn1[82Q]/+ mice, we found that levels of Sphk1 and Sphk2 were region-specific decreased and S1P levels increased, particularly in the anterior cerebellum. To determine if there is a causal link between sphingolipid levels and neurodegeneration, we deleted the Sphk1 gene in Atxn1[82Q]/+ mice. Analysis of Atxn1[82Q]/+; Sphk1−/− mice confirmed a neuroprotective effect, rescuing a subset of PCs in the anterior cerebellum, in domains reminiscent of the modules defined by AldolaseC expression. Finally, we showed that Sphk1 deletion acts on the ATXN1[82Q] protein expression and prevents PC degeneration. Taken together, our results demonstrate that there are regional differences in sphingolipid metabolism and that this metabolism is directly involved in PC degeneration in Atxn1[82Q]/+ mice.
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Dani, Krishna A., Celestine Santosh, David Brennan, Donald M. Hadley, and Keith W. Muir. "Crossed Cerebellar Diaschisis: Insights into Oxygen Challenge MRI." Journal of Cerebral Blood Flow & Metabolism 32, no. 12 (October 10, 2012): 2114–17. http://dx.doi.org/10.1038/jcbfm.2012.142.
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Hyperoxia during T2∗-weighted magnetic resonance imaging (oxygen challenge imaging (OCI)) causes T2∗-weighted signal change that is dependent on cerebral blood volume (CBV) and oxygen extraction fraction (OEF). Crossed cerebellar diaschisis (CCD), where CBV is reduced but OEF is maintained, may be used to understand the relative contributions of OEF and CBV to OCI results. In subjects with large hemispheric strokes, OCI showed reduced signal change in the contralesional cerebellum ( P = 0.027, n = 12). This was associated with reduced CBV in contralesional cerebellum ( P = 0.039, n = 9). CCD may be a useful model to determine the relative contribution of CBV to signal change measured by OCI.
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Hiyoshi, Kanae, Kaito Saito, Narumi Fukuda, Takahisa Matsuzaki, Hiroshi Y. Yoshikawa, and Sachiko Tsuda. "Two-Photon Laser Ablation and In Vivo Wide-Field Imaging of Inferior Olive Neurons Revealed the Recovery of Olivocerebellar Circuits in Zebrafish." International Journal of Environmental Research and Public Health 18, no. 16 (August 6, 2021): 8357. http://dx.doi.org/10.3390/ijerph18168357.
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The cerebellum, a brain region with a high degree of plasticity, is pivotal in motor control, learning, and cognition. The cerebellar reserve is the capacity of the cerebellum to respond and adapt to various disorders via resilience and reversibility. Although structural and functional recovery has been reported in mammals and has attracted attention regarding treatments for cerebellar dysfunction, such as spinocerebellar degeneration, the regulatory mechanisms of the cerebellar reserve are largely unidentified, particularly at the circuit level. Herein, we established an optical approach using zebrafish, an ideal vertebrate model in optical techniques, neuroscience, and developmental biology. By combining two-photon laser ablation of the inferior olive (IO) and long-term non-invasive imaging of “the whole brain” at a single-cell resolution, we succeeded in visualization of the morphological changes occurring in the IO neuron population and showed at a single-cell level that structural remodeling of the olivocerebellar circuit occurred in a relatively short period. This system, in combination with various functional analyses, represents a novel and powerful approach for uncovering the mechanisms of the cerebellar reserve, and highlights the potential of the zebrafish model to elucidate the organizing principles of neuronal circuits and their homeostasis in health and disease.
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Lametti, Daniel R., Leonie Oostwoud Wijdenes, James Bonaiuto, Sven Bestmann, and John C. Rothwell. "Cerebellar tDCS dissociates the timing of perceptual decisions from perceptual change in speech." Journal of Neurophysiology 116, no. 5 (November 1, 2016): 2023–32. http://dx.doi.org/10.1152/jn.00433.2016.
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Neuroimaging studies suggest that the cerebellum might play a role in both speech perception and speech perceptual learning. However, it remains unclear what this role is: does the cerebellum help shape the perceptual decision, or does it contribute to the timing of perceptual decisions? To test this, we used transcranial direct current stimulation (tDCS) in combination with a speech perception task. Participants experienced a series of speech perceptual tests designed to measure and then manipulate (via training) their perception of a phonetic contrast. One group received cerebellar tDCS during speech perceptual learning, and a different group received sham tDCS during the same task. Both groups showed similar learning-related changes in speech perception that transferred to a different phonetic contrast. For both trained and untrained speech perceptual decisions, cerebellar tDCS significantly increased the time it took participants to indicate their decisions with a keyboard press. By analyzing perceptual responses made by both hands, we present evidence that cerebellar tDCS disrupted the timing of perceptual decisions, while leaving the eventual decision unaltered. In support of this conclusion, we use the drift diffusion model to decompose the data into processes that determine the outcome of perceptual decision-making and those that do not. The modeling suggests that cerebellar tDCS disrupted processes unrelated to decision-making. Taken together, the empirical data and modeling demonstrate that right cerebellar tDCS dissociates the timing of perceptual decisions from perceptual change. The results provide initial evidence in healthy humans that the cerebellum critically contributes to speech timing in the perceptual domain.
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Rajendran, Ranjithkumar, Vinothkumar Rajendran, Mario Giraldo-Velasquez, Fevronia-Foivi Megalofonou, Fynn Gurski, Christine Stadelmann, Srikanth Karnati, and Martin Berghoff. "Oligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG35-55-Induced EAE." International Journal of Molecular Sciences 22, no. 17 (August 31, 2021): 9495. http://dx.doi.org/10.3390/ijms22179495.
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Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1ind−/−) was achieved by tamoxifen application, EAE was induced using the MOG35-55 peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1ind−/− mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1ind−/−mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1ind−/− mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1ind−/− mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.
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Mepyans, Molly, Livia Andrzejczuk, Jahree Sosa, Sierra Smith, Shawn Herron, Samantha DeRosa, Susan A. Slaugenhaupt, Albert Misko, Yulia Grishchuk, and Kirill Kiselyov. "Early evidence of delayed oligodendrocyte maturation in the mouse model of mucolipidosis type IV." Disease Models & Mechanisms 13, no. 7 (June 25, 2020): dmm044230. http://dx.doi.org/10.1242/dmm.044230.
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ABSTRACTMucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that encodes the endolysosomal transient receptor potential channel mucolipin-1, or TRPML1. MLIV results in developmental delay, motor and cognitive impairments, and vision loss. Brain abnormalities include thinning and malformation of the corpus callosum, white-matter abnormalities, accumulation of undegraded intracellular ‘storage’ material and cerebellar atrophy in older patients. Identification of the early events in the MLIV course is key to understanding the disease and deploying therapies. The Mcoln1−/− mouse model reproduces all major aspects of the human disease. We have previously reported hypomyelination in the MLIV mouse brain. Here, we investigated the onset of hypomyelination and compared oligodendrocyte maturation between the cortex/forebrain and cerebellum. We found significant delays in expression of mature oligodendrocyte markers Mag, Mbp and Mobp in the Mcoln1−/− cortex, manifesting as early as 10 days after birth and persisting later in life. Such delays were less pronounced in the cerebellum. Despite our previous finding of diminished accumulation of the ferritin-bound iron in the Mcoln1−/− brain, we report no significant changes in expression of the cytosolic iron reporters, suggesting that iron-handling deficits in MLIV occur in the lysosomes and do not involve broad iron deficiency. These data demonstrate very early deficits of oligodendrocyte maturation and critical regional differences in myelination between the forebrain and cerebellum in the mouse model of MLIV. Furthermore, they establish quantitative readouts of the MLIV impact on early brain development, useful to gauge efficacy in pre-clinical trials.
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Walia, Pushpinder, Abhishek Ghosh, Shubhmohan Singh, and Anirban Dutta. "Portable Neuroimaging-Guided Noninvasive Brain Stimulation of the Cortico-Cerebello-Thalamo-Cortical Loop—Hypothesis and Theory in Cannabis Use Disorder." Brain Sciences 12, no. 4 (March 26, 2022): 445. http://dx.doi.org/10.3390/brainsci12040445.
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Background: Maladaptive neuroplasticity-related learned response in substance use disorder (SUD) can be ameliorated using noninvasive brain stimulation (NIBS); however, inter-individual variability needs to be addressed for clinical translation. Objective: Our first objective was to develop a hypothesis for NIBS for learned response in SUD based on a competing neurobehavioral decision systems model. The next objective was to develop the theory by conducting a computational simulation of NIBS of the cortico-cerebello-thalamo-cortical (CCTC) loop in cannabis use disorder (CUD)-related dysfunctional “cue-reactivity”—a construct closely related to “craving”—that is a core symptom. Our third objective was to test the feasibility of a neuroimaging-guided rational NIBS approach in healthy humans. Methods: “Cue-reactivity” can be measured using behavioral paradigms and portable neuroimaging, including functional near-infrared spectroscopy (fNIRS) and electroencephalogram (EEG) metrics of sensorimotor gating. Therefore, we conducted a computational simulation of NIBS, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) of the cerebellar cortex and deep cerebellar nuclei (DCN) of the CCTC loop for its postulated effects on fNIRS and EEG metrics. We also developed a rational neuroimaging-guided NIBS approach for the cerebellar lobule (VII) and prefrontal cortex based on a healthy human study. Results: Simulation of cerebellar tDCS induced gamma oscillations in the cerebral cortex, while transcranial temporal interference stimulation induced a gamma-to-beta frequency shift. A preliminary healthy human study (N = 10) found that 2 mA cerebellar tDCS evoked similar oxyhemoglobin (HbO) response in the range of 5 × 10−6 M across the cerebellum and PFC brain regions (α = 0.01); however, infra-slow (0.01–0.10 Hz) prefrontal cortex HbO-driven phase–amplitude-coupled (PAC; 4 Hz, ±2 mA (max)) cerebellar tACS evoked HbO levels in the range of 10−7 M that were statistically different (α = 0.01) across these brain regions. Conclusion: Our healthy human study showed the feasibility of fNIRS of cerebellum and PFC and closed-loop fNIRS-driven ctACS at 4 Hz, which may facilitate cerebellar cognitive function via the frontoparietal network. Future work needs to combine fNIRS with EEG for multi-modal imaging for closed-loop NIBS during operant conditioning.
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Gąssowska-Dobrowolska, Magdalena, Agnieszka Kolasa, David Q. Beversdorf, and Agata Adamczyk. "Alterations in Cerebellar Microtubule Cytoskeletal Network in a ValproicAcid-Induced Rat Model of Autism Spectrum Disorders." Biomedicines 10, no. 12 (November 24, 2022): 3031. http://dx.doi.org/10.3390/biomedicines10123031.
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Autism spectrum disorders (ASD) are neurodevelopmental diseases characterised by deficits in social communication, restricted interests, and repetitive behaviours. The growing body of evidence points to a role for cerebellar changes in ASD pathology. Some of the findings suggest that not only motor problems but also social deficits, repetitive behaviours, and mental inflexibility associated with ASD are connected with damage to the cerebellum. However, the understanding of this brain structure’s functions in ASD pathology needs future investigations. Therefore, in this study, we generated a rodent model of ASD through a single prenatal administration of valproic acid (VPA) into pregnant rats, followed by cerebellar morphological studies of the offspring, focusing on the alterations of key cytoskeletal elements. The expression (Western blot) of α/β-tubulin and the major neuronal MT-associated proteins (MAP) such as MAP-Tau and MAP1B, MAP2, MAP6 (STOP) along with actin-crosslinking αII-spectrin and neurofilament light polypeptide (NF-L) was investigated. We found that maternal exposure to VPA induces a significant decrease in the protein levels of α/β-tubulin, MAP-Tau, MAP1B, MAP2, and αII-spectrin. Moreover, excessive MAP-Tau phosphorylation at (Ser396) along with key Tau-kinases activation was indicated. Immunohistochemical staining showed chromatolysis in the cerebellum of autistic-like rats and loss of Purkinje cells shedding light on one of the possible molecular mechanisms underpinning neuroplasticity alterations in the ASD brain.
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Abe, Yuichi, Masanori Honsho, Ryota Itoh, Ryoko Kawaguchi, Masashi Fujitani, Kazushirou Fujiwara, Masaaki Hirokane, et al. "Peroxisome biogenesis deficiency attenuates the BDNF-TrkB pathway-mediated development of the cerebellum." Life Science Alliance 1, no. 6 (December 2018): e201800062. http://dx.doi.org/10.26508/lsa.201800062.
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Peroxisome biogenesis disorders (PBDs) manifest as neurological deficits in the central nervous system, including neuronal migration defects and abnormal cerebellum development. However, the mechanisms underlying pathogenesis remain enigmatic. Here, to investigate how peroxisome deficiency causes neurological defects of PBDs, we established a new PBD model mouse defective in peroxisome assembly factor Pex14p, termed Pex14ΔC/ΔC mouse. Pex14ΔC/ΔC mouse manifests a severe symptom such as disorganization of cortical laminar structure and dies shortly after birth, although peroxisomal biogenesis and metabolism are partially defective. The Pex14ΔC/ΔC mouse also shows malformation of the cerebellum including the impaired dendritic development of Purkinje cells. Moreover, extracellular signal-regulated kinase and AKT signaling are attenuated in this mutant mouse by an elevated level of brain-derived neurotrophic factor (BDNF) together with the enhanced expression of TrkB-T1, a dominant-negative isoform of the BDNF receptor. Our results suggest that dysregulation of the BDNF-TrkB pathway, an essential signaling for cerebellar morphogenesis, gives rise to the pathogenesis of the cerebellum in PBDs.
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Jiang, Yiming, Chenguang Yang, Min Wang, Ning Wang, and Xiaofeng Liu. "Bioinspired control design using cerebellar model articulation controller network for omnidirectional mobile robots." Advances in Mechanical Engineering 10, no. 8 (August 2018): 168781401879434. http://dx.doi.org/10.1177/1687814018794349.
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As a learning mechanism that emulates the structure of the cerebellum, cerebellar model articulation controllers have been widely adopted in the control of robotic systems because of the fast learning ability and simple computational structure. In this article, a cerebellar model articulation controller–based neural network controller is developed for an omnidirectional mobile robot. With the powerful learning ability of cerebellar model articulation controller, a cerebellar model articulation controller neural network is constructed to learn the complex dynamics of the omnidirectional mobile robot such that the robot is controlled without a priori knowledge of the robot dynamics. In addition, to overcome the limitation of the neural network controller, a global control technique with a group of smooth switching functions is designed such that the global ultimately uniformly boundedness of cerebellar model articulation controller is achieved instead of conventional semi-global ultimately uniformly boundedness. Moreover, smooth decreasing boundary functions are synthesized into the controller to guarantee the transient control performance. Based on an omnidirectional mobile robot, numerical experiments have been conducted to demonstrate the effectiveness of the proposed cerebellar model articulation controller controller.
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Williams, Brent L., Kavitha Yaddanapudi, Mady Hornig, and W. Ian Lipkin. "Spatiotemporal Analysis of Purkinje Cell Degeneration Relative to Parasagittal Expression Domains in a Model of Neonatal Viral Infection." Journal of Virology 81, no. 6 (December 20, 2006): 2675–87. http://dx.doi.org/10.1128/jvi.02245-06.
Full textAbstract:
ABSTRACT Infection of newborn Lewis rats with Borna disease virus (neonatal Borna disease [NBD]) results in cerebellar damage without the cellular inflammation associated with infections in later life. Purkinje cell (PC) damage has been reported for several models of early-life viral infection, including NBD; however, the time course and distribution of PC pathology have not been investigated rigorously. This study examined the spatiotemporal relationship between PC death and zonal organization in NBD cerebella. Real-time PCR at postnatal day 28 (PND28) revealed decreased cerebellar levels of mRNAs encoding the glycolytic enzymes aldolase C (AldoC, also known as zebrin II) and phosphofructokinase C and the excitatory amino acid transporter 4 (EAAT4). Zebrin II and EAAT4 immunofluorescence analysis in PND21, PND28, PND42, and PND84 NBD rat cerebella revealed a complex pattern of PC degeneration. Early cell loss (PND28) was characterized by preferential apoptotic loss of zebrin II/EAAT4-negative PC subsets in the anterior vermis. Consistent with early preferential loss of zebrin II/EAAT4-negative PCs in the vermis, the densities of microglia and the Bergmann glial expression of metallothionein I/II and the hyaluronan receptor CD44 were higher in zebrin II/EAAT4-negative zones. In contrast, early loss in lateral cerebellar lobules did not reflect a similar discrimination between PC phenotypes. Patterns of vermal PC loss became more heterogeneous at PND42, with the loss of both zebrin II/EAAT4-negative and zebrin II/EAAT4-positive neurons. At PND84, zebrin II/EAAT4 patterning was abolished in the anterior cerebellum, with preferential PC survival in lobule X. Our investigation reveals regional discrimination between patterns of PC subset loss, defined by zebrin II/EAAT4 expression domains, following neonatal viral infection. These findings suggest a differential vulnerability of PC subsets during the early stages of virus-induced neurodegeneration.
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Trillenberg, P., and K. Wessel. "Detection of input sequences in the cerebellum: Clinical and neuroimaging aspects." Behavioral and Brain Sciences 20, no. 2 (June 1997): 267. http://dx.doi.org/10.1017/s0140525x97471431.
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We add evidence from functional imaging supporting the concept of activation of coronally oriented zones corresponding to parallel fibers. Braitenberg et al.'s suggestion that there is an operating mode of the cerebellum relies on the idea introduced by Eccles and refined by the concept of tidal waves which Heck found in vitro. Recent evidence from functional imaging has shown zones of activation in accordance with this model and hence provides support for Braitenberg et al.'s hypothesis from the intact and healthy human cerebellum. In a second section, we discuss vulnerability of the structures described by Braitenberg et al. with respect to slow and fast movements in the context of clinical symptoms in cerebellar disease.