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Revista de Neurologia Jun 2016Essential tremor is the most frequent movement disorder in adults. It has been considered a benign disease, but can result in significant physical and psychosocial... (Review)
Review
INTRODUCTION
Essential tremor is the most frequent movement disorder in adults. It has been considered a benign disease, but can result in significant physical and psychosocial disability. Pharmacological treatment is still not very satisfactory. Its causation, pathophysiology and anatomy remain only partially understood.
AIMS
An understanding of its neurochemical basis is essential to be able to develop more efficient therapies. We review what is currently known in this field in order to motivate further research and ideas that allow an enhanced understanding of the disease and which foster the development of new pharmacological therapies.
DEVELOPMENT
We review the studies conducted to date in humans and in animal models of neurotransmitters (gamma-aminobutyric acid, glutamate, noradrenalin, serotonin, adenosine), proteins and other neurochemical phenomena, such as T-type calcium channels, in essential tremor.
CONCLUSIONS
Four neurochemical dysfunctions have been described that basically occur in the cerebellum and the inferior olivary nucleus: alteration of the GABAergic system, increased post-inhibitory rebound via T-type calcium currents, decreased neuronal inhibition mechanisms and an increase in excitatory neurotransmitter activity. These neurochemical dysfunctions would involve an increase in the activity of the deep neurons of the cerebellum with an oscillatory activity that would shift to the thalamic nucleus and the motor cortex, which in turn would lead to the appearance of tremor. Further research is needed to be able to confirm these hypotheses and to continue to advance towards achieving more efficient pharmacological treatments for patients with essential tremor.
Topics: Animals; Calcium Channels, T-Type; Cerebellum; Essential Tremor; Humans; Neurons; Neurotransmitter Agents
PubMed: 27222085
DOI: No ID Found -
ELife Aug 2023The inferior olive provides the climbing fibers to Purkinje cells in the cerebellar cortex, where they elicit all-or-none complex spikes and control major forms of...
The inferior olive provides the climbing fibers to Purkinje cells in the cerebellar cortex, where they elicit all-or-none complex spikes and control major forms of plasticity. Given their important role in both short-term and long-term coordination of cerebellum-dependent behaviors, it is paramount to understand the factors that determine the output of olivary neurons. Here, we use mouse models to investigate how the inhibitory and excitatory inputs to the olivary neurons interact with each other, generating spiking patterns of olivary neurons that align with their intrinsic oscillations. Using dual color optogenetic stimulation and whole-cell recordings, we demonstrate how intervals between the inhibitory input from the cerebellar nuclei and excitatory input from the mesodiencephalic junction affect phase and gain of the olivary output at both the sub- and suprathreshold level. When the excitatory input is activated shortly (~50 ms) after the inhibitory input, the phase of the intrinsic oscillations becomes remarkably unstable and the excitatory input can hardly generate any olivary spike. Instead, when the excitatory input is activated one cycle (~150 ms) after the inhibitory input, the excitatory input can optimally drive olivary spiking, riding on top of the first cycle of the subthreshold oscillations that have been powerfully reset by the preceding inhibitory input. Simulations of a large-scale network model of the inferior olive highlight to what extent the synaptic interactions penetrate in the neuropil, generating quasi-oscillatory spiking patterns in large parts of the olivary subnuclei, the size of which also depends on the relative timing of the inhibitory and excitatory inputs.
Topics: Mice; Animals; Cerebellar Nuclei; Olivary Nucleus; Neurons; Purkinje Cells; Cerebellum; Action Potentials
PubMed: 37526175
DOI: 10.7554/eLife.83239 -
PLoS Computational Biology May 2019Inferior olivary activity causes both short-term and long-term changes in cerebellar output underlying motor performance and motor learning. Many of its neurons engage...
Inferior olivary activity causes both short-term and long-term changes in cerebellar output underlying motor performance and motor learning. Many of its neurons engage in coherent subthreshold oscillations and are extensively coupled via gap junctions. Studies in reduced preparations suggest that these properties promote rhythmic, synchronized output. However, the interaction of these properties with torrential synaptic inputs in awake behaving animals is not well understood. Here we combine electrophysiological recordings in awake mice with a realistic tissue-scale computational model of the inferior olive to study the relative impact of intrinsic and extrinsic mechanisms governing its activity. Our data and model suggest that if subthreshold oscillations are present in the awake state, the period of these oscillations will be transient and variable. Accordingly, by using different temporal patterns of sensory stimulation, we found that complex spike rhythmicity was readily evoked but limited to short intervals of no more than a few hundred milliseconds and that the periodicity of this rhythmic activity was not fixed but dynamically related to the synaptic input to the inferior olive as well as to motor output. In contrast, in the long-term, the average olivary spiking activity was not affected by the strength and duration of the sensory stimulation, while the level of gap junctional coupling determined the stiffness of the rhythmic activity in the olivary network during its dynamic response to sensory modulation. Thus, interactions between intrinsic properties and extrinsic inputs can explain the variations of spiking activity of olivary neurons, providing a temporal framework for the creation of both the short-term and long-term changes in cerebellar output.
Topics: Action Potentials; Animals; Cerebellum; Electrophysiological Phenomena; Female; Gap Junctions; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Olivary Nucleus; Periodicity
PubMed: 31059498
DOI: 10.1371/journal.pcbi.1006475 -
Hearing Research Sep 2018The human auditory brainstem, especially the cochlear nucleus (CN) and the superior olivary complex (SOC) are characterized by a high density of neurons associated with... (Comparative Study)
Comparative Study
The human auditory brainstem, especially the cochlear nucleus (CN) and the superior olivary complex (SOC) are characterized by a high density of neurons associated with perineuronal nets (PNs). PNs build a specific form of extracellular matrix surrounding the neuronal somata, proximal dendrites and axon initial segments. They restrict synaptic plasticity and control high-frequency synaptic activity, a prominent characteristic of neurons of the auditory brainstem. The distribution of PNs within the auditory brainstem has been investigated in a number of mammalian species. However, much less is known regarding PNs in the human auditory brainstem. The present study aimed at the immunohistochemical identification of PNs in the cochlear nucleus (CN) and superior olivary complex (SOC) in the human brainstem. We focused on the complex nature and molecular variability of PNs in the CN and SOC by using specific antibodies against the main PN components (aggrecan, brevican, neurocan and hyaluronan and proteoglycan link protein 1). Virtually all subnuclei within the ventral CN and SOC were found to be associated with PNs. Direct comparison between gerbil and human yielded similar fine structure of PNs and confirmed the typical tight interdigitation of PNs with synaptic terminals in both species. Noticeably, an elaborate combination of immunohistochemical labelings clearly supports the still debated existence of the medial nucleus of trapezoid body (MNTB) in the human brain. In conclusion, the present study demonstrates that PNs form a prominent extracellular structure on CN and SOC neurons in the human brain, potentially stabilizing synaptic contacts, which is in agreement with many other mammalian species.
Topics: Aged, 80 and over; Aggrecans; Animals; Auditory Pathways; Biomarkers; Brevican; Cadaver; Chondroitin Sulfate Proteoglycans; Cochlear Nucleus; Female; Gerbillinae; Humans; Hyaluronic Acid; Immunohistochemistry; Lectins, C-Type; Male; Middle Aged; Nerve Net; Nerve Tissue Proteins; Neuroanatomical Tract-Tracing Techniques; Neurocan; Presynaptic Terminals; Superior Olivary Complex; Trapezoid Body
PubMed: 30025262
DOI: 10.1016/j.heares.2018.07.005 -
Journal of Neurological Surgery. Part... Jan 2016Hypertrophic olivary degeneration (HOD) is a rare form of transsynaptic degeneration characterized by hypertrophy of the inferior olivary nucleus situated in the olivary... (Review)
Review
Hypertrophic olivary degeneration (HOD) is a rare form of transsynaptic degeneration characterized by hypertrophy of the inferior olivary nucleus situated in the olivary body, part of the medulla oblongata, representing a major source of input to the cerebellum. HOD typically results from focal lesions interrupting connections from the inferior olive within the dentato-rubro-olivary pathway, a region also known as the triangle of Guillain-Mollaret (TGM) (red nucleus, inferior olivary nucleus, and contralateral dentate nucleus). Clinically, HOD presents classically as palatal tremor and can include dentatorubral tremor and/or ocular myoclonus. The pathologic changes associated with HOD feature radiologic changes with the inferior olivary nucleus appearing larger and increasing its T2-weighted signal intensity on magnetic resonance images. HOD is commonly managed with pharmacotherapy but may require surgical intervention in extreme cases. HOD has been found to develop as a consequence of any injury that disrupts the TGM pathways (e.g., pontine cavernoma).These findings highlight the critical importance of a thorough knowledge of TGM anatomy to avoid secondary HOD. We present a patient who developed HOD secondary to resection of a tectal plate cavernous malformation and review the literature with an emphasis on the current knowledge of this disorder.
Topics: Female; Gait Disorders, Neurologic; Hemangioma, Cavernous, Central Nervous System; Humans; Hypertrophy; Magnetic Resonance Imaging; Middle Aged; Neurodegenerative Diseases; Neurosurgical Procedures; Olivary Nucleus; Postoperative Complications
PubMed: 26588253
DOI: 10.1055/s-0035-1566114 -
Journal of Otology Apr 2022Objective tinnitus is defined as a type of tinnitus perceived by both the patient and external observer. This paper presents two cases of objective tinnitus related to... (Review)
Review
Objective tinnitus is defined as a type of tinnitus perceived by both the patient and external observer. This paper presents two cases of objective tinnitus related to palatal tremor, along with a literature review. Palatal tremor is a condition characterized by soft palate involuntary contractions. Two types of palatal tremor have been described: symptomatic palatal tremor and essential palatal tremor, with different clinical manifestations. Diagnostic workup is based on medical history and physical examination, including direct oropharynx exploration and cavum visualization through nasopharyngoscopy. Brain MRI is mandatory in all cases. If a secondary origin is suspected, additional lab tests should be performed based on clinical suspicion. First-line treatment is botulinum toxin injection into the and muscles, with velopharyngeal insufficiency being its main adverse effect. Other medications have not been shown to be effective.
PubMed: 35949555
DOI: 10.1016/j.joto.2021.11.003 -
Frontiers in Neural Circuits 2022The lateral superior olive (LSO) is a key structure in the central auditory system of mammals that exerts efferent control on cochlear sensitivity and is involved in the...
The lateral superior olive (LSO) is a key structure in the central auditory system of mammals that exerts efferent control on cochlear sensitivity and is involved in the processing of binaural level differences for sound localization. Understanding how the LSO contributes to these processes requires knowledge about the resident cells and their connections with other auditory structures. We used standard histological stains and retrograde tracer injections into the inferior colliculus (IC) and cochlea in order to characterize two basic groups of neurons: (1) Principal and periolivary (PO) neurons have projections to the IC as part of the ascending auditory pathway; and (2) lateral olivocochlear (LOC) intrinsic and shell efferents have descending projections to the cochlea. Principal and intrinsic neurons are intermixed within the LSO, exhibit fusiform somata, and have disk-shaped dendritic arborizations. The principal neurons have bilateral, symmetric, and tonotopic projections to the IC. The intrinsic efferents have strictly ipsilateral projections, known to be tonotopic from previous publications. PO and shell neurons represent much smaller populations (<10% of principal and intrinsic neurons, respectively), have multipolar somata, reside outside the LSO, and have non-topographic, bilateral projections. PO and shell neurons appear to have widespread projections to their targets that imply a more diffuse modulatory function. The somata and dendrites of principal and intrinsic neurons form a laminar matrix within the LSO and share quantifiably similar alignment to the tonotopic axis. Their restricted projections emphasize the importance of frequency in binaural processing and efferent control for auditory perception. This study addressed and expanded on previous findings of cell types, circuit laterality, and projection tonotopy in the LSO of the mouse.
Topics: Animals; Mice; Superior Olivary Complex; Olivary Nucleus; Auditory Pathways; Inferior Colliculi; Neurons; Mammals
PubMed: 36338332
DOI: 10.3389/fncir.2022.1038500 -
Cellular and Molecular Life Sciences :... Feb 2015Development and evolution of auditory hindbrain nuclei are two major unsolved issues in hearing research. Recent characterization of transgenic mice identified the... (Review)
Review
Development and evolution of auditory hindbrain nuclei are two major unsolved issues in hearing research. Recent characterization of transgenic mice identified the rhombomeric origins of mammalian auditory nuclei and unraveled genes involved in their formation. Here, we provide an overview on these data by assembling them into rhombomere-specific gene regulatory networks (GRNs), as they underlie developmental and evolutionary processes. To explore evolutionary mechanisms, we compare the GRNs operating in the mammalian auditory hindbrain with data available from the inner ear and other vertebrate groups. Finally, we propose that the availability of genomic sequences from all major vertebrate taxa and novel genetic techniques for non-model organisms provide an unprecedented opportunity to investigate development and evolution of the auditory hindbrain by comparative molecular approaches. The dissection of the molecular mechanisms leading to auditory structures will also provide an important framework for auditory processing disorders, a clinical problem difficult to tackle so far. These data will, therefore, foster basic and clinical hearing research alike.
Topics: Animals; Auditory Perception; Biological Evolution; Cochlear Nucleus; Gene Regulatory Networks; Hearing; Humans; Inferior Colliculi; Mice; Models, Biological; Species Specificity; Superior Olivary Complex; Tretinoin
PubMed: 25332098
DOI: 10.1007/s00018-014-1759-0 -
Neuroscience Research Sep 2021The principal olivary nucleus is the largest part of the inferior olivary complex and is involved in the spatial and temporal organization of movement and motor...
The principal olivary nucleus is the largest part of the inferior olivary complex and is involved in the spatial and temporal organization of movement and motor learning. Nearly all neurons in this nucleus is multipolar along with having a highly complex dendritic tree and significant asymmetry in shape. In this study, we updated the current classification scheme, examined morphological differences between the proposed groups, and investigated age-related morphological changes. Histological preparations were digitized by a light microscope and a sample of 259 images of neurons was analyzed by 17 computationally generated parameters of morphology. These were reduced to the four variables of principal component analysis and the sample was classified by k-means method of clustering into three clusters. The differences between clusters were documented and for medium-sized neurons the relationship between four morphological parameters and age were investigated. Finally, for two of the age groups the changes in the morphology were explored. This study includes a detailed and robust classification of the PON neurons and the findings improve upon past qualitative work.
Topics: Humans; Neurons; Olivary Nucleus
PubMed: 33347909
DOI: 10.1016/j.neures.2020.10.005 -
Tremor and Other Hyperkinetic Movements... 2017Although essential tremor (ET) is the most common tremor disorder, its pathogenesis is not fully understood. The traditional model of ET, proposed in the early 1970s,... (Review)
Review
BACKGROUND
Although essential tremor (ET) is the most common tremor disorder, its pathogenesis is not fully understood. The traditional model of ET, proposed in the early 1970s, posited that the inferior olivary nucleus (ION) was the prime generator of tremor in ET and that ET is a disorder of electrophysiological derangement, much like epilepsy. This article comprehensively reviews the origin and basis of this model, its merits and problems, and discusses whether it is time to lay this model to rest.
METHODS
A PubMed search was performed in March 2017 to identify articles for this review.
RESULTS
The olivary model gains support from the recognition of neurons with pacemaker property in the ION and the harmaline-induced tremor models (as the ION is the prime target of harmaline). However, the olivary model is problematic, as neurons with pacemaker property are not specific to the ION and the harmaline model does not completely represent the human disease ET. In addition, a large number of neuroimaging studies in ET have not detected structural or functional changes in the ION; rather, abnormalities have been reported in structures related to the cerebello-thalamo-cortical network. Moreover, a post-mortem study of microscopic changes in the ION did not detect any differences between ET cases and controls.
DISCUSSION
The olivary model largely remains a physiological construct. Numerous observations have cast considerable doubt as to the validity of this model in ET. Given the limitations of the model, we conclude that it is time now to lay this model to rest.
Topics: Animals; Essential Tremor; Humans; Models, Neurological; Olivary Nucleus
PubMed: 28966877
DOI: 10.7916/D8FF40RX