Inferior Olivary nucleus degeneration does not lessen tremor in essential tremor

Louis, Elan D.; Diaz, Daniel Trujillo; Kuo, Sheng Han; Gan, Shi Rui; Cortés, Etty; Vonsattel, Jean Paul; Faust, Phyllis L.

doi:10.1186/s40673-018-0080-3

Cited by 22 publications

(6 citation statements)

References 61 publications

(78 reference statements)

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“…In the majority of ET cases, other than a subset of ET cases with Lewy bodies [144,154], the postmortem changes that have been observed to date are exclusively in the cerebellum. Furthermore, the inferior olivary nucleus has appeared normal in postmortem studies, which echoes data from neuroimaging and clinical studies, which suggest that structural changes in this nucleus do not play a role in tremor generation in ET [55,57,125,139,140].…”

Section: Pathologicalsupporting

confidence: 64%

“…In part, this was due to the lack of postmortem studies; indeed, during the 100-year period from 1903 to 2003, there were only 15 published postmortems [130], mainly comprising isolated case reports that lacked rigor as none used quantitative or immunohistochemical approaches nor compared ET to control brains [131][132][133][134][135][136][137]. A popular disease model, initially proposed in the 1970s [138], attempted to link ET to an abnormal inferior olivary nucleus; however, empiric support for that model is limited [57,139,140] and the model has recently fallen out of favor [55,56]. More recent research in the field has focused on the cerebellum, where there has been a reconceptualization of the disease as one of cerebellar degeneration, as will be discussed below [29,35,[37][38][39][40][41][42][43][44][45][46][47].…”

Section: Pathologicalmentioning

confidence: 99%

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Essential tremor: the most common form of cerebellar degeneration?

Louis

Faust

2020

cerebellum ataxias

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Background: The degenerative cerebellar ataxias comprise a large and heterogeneous group of neurological diseases whose hallmark clinical feature is ataxia, and which are accompanied, to variable degrees, by other features that are attributable to cerebellar dysfunction. Essential tremor (ET) is an exceptionally common neurological disease whose primary motor feature is action tremor, although patients often manifest intention tremor, mild gait ataxia and several other features of cerebellar dysfunction. Main Body: In this paper, we review the abundant evidence derived from clinical, neuroimaging and postmortem studies, linking ET to cerebellar dysfunction. Furthermore, we review the combination of clinical, natural history and postmortem features suggesting that ET is neurodegenerative. We then compare the prevalence of ET (400-900 cases per 100,000) to that of the other cerebellar degenerations (ranging from <0.5-9 cases per 100,000, and in composite likely to be on the order of 20 cases per 100,000) and conclude that ET is 20 to 45 times more prevalent than all other forms of cerebellar degeneration combined. Conclusion: Given the data we present, it is logical to conclude that ET is, by far, the most common form of cerebellar degeneration.

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Section: Pathologicalsupporting

confidence: 64%

Section: Pathologicalmentioning

confidence: 99%

Essential tremor: the most common form of cerebellar degeneration?

Louis

Faust

2020

cerebellum ataxias

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“…Our model predicts that such currents can facilitate the after-hyperpolarization rebound of the deep cerebellar neurons, which robustly activates the olivary neurons at a preferred phase of their subthreshold oscillations, thus facilitating the synchronization along the olivocerebellar loop. Also, other ET-related pathologies such as the increased Purkinje cell axonal branching, recurrent collaterals, and terminal axonal sprouting may further amplify such synchronization and therefore exacerbate tremor symptoms, even with substantial losses of inferior olive neurons and Purkinje cells (70,71). Finally, our model shows that the range of tremor-related GABAergic currents to the dentate nucleus increases as the synaptic current from the nucleoolivary neurons to the inferior olivary nucleus (NO→ION) decreases.…”

Section: Slow-decaying Gabaergic Currents In the Dentate Nucleus Contmentioning

confidence: 76%

Role of cerebellar GABAergic dysfunctions in the origins of essential tremor

Zhang

Santaniello

2019

Proc. Natl. Acad. Sci. U.S.A.

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Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive. The inferior olivary nucleus (ION) has been hypothesized as the prime generator of tremor because of the pacemaker properties of ION neurons, but structural and functional changes in ION are unlikely under ET. Abnormalities have instead been reported in the cerebello-thalamo-cortical network, including dysfunctions of the GABAergic projections from the cerebellar cortex to the dentate nucleus. It remains unclear, though, how tremor would relate to a dysfunction of cerebellar connectivity. To address this question, we built a computational model of the cortico-cerebello-thalamo-cortical loop. We simulated the effects of a progressive loss of GABAA α1-receptor subunits and up-regulation of α2/3-receptor subunits in the dentate nucleus, and correspondingly, we studied the evolution of the firing patterns along the loop. The model closely reproduced experimental evidence for each structure in the loop. It showed that an alteration of amplitudes and decay times of the GABAergic currents to the dentate nucleus can facilitate sustained oscillatory activity at tremor frequency throughout the network as well as a robust bursting activity in the thalamus, which is consistent with observations of thalamic tremor cells in ET patients. Tremor-related oscillations initiated in small neural populations and spread to a larger network as the synaptic dysfunction increased, while thalamic high-frequency stimulation suppressed tremor-related activity in thalamus but increased the oscillation frequency in the olivocerebellar loop. These results suggest a mechanism for tremor generation under cerebellar dysfunction, which may explain the origin of ET.

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“…cates dysfunction within the central motor control (cortico-bulbo-cerebello-thalamocortical) network. [1][2][3] Cover. Approximate anatomic locations for the inferior olive nucleus (blue) in the medulla and ventral intermediate nucleus (red) in the thalamus are color-coded onto representative MRI.…”

mentioning

confidence: 99%

“…It is generally agreed that the action tremor characterizing ET indicates dysfunction within the motor control network (Figure 1 and Cover). [1][2][3] There is much debate regarding which component or components give rise to the oscillatory activity that drives tremor. 1,2,19 The initial proposal was the olivary hypothesis, based on harmalineinduced tremor in animal models, which resembles ET.…”

mentioning

confidence: 99%